WO2011050160A1 - Pharmaceuticals, compositions and methods of making and using the same - Google Patents

Pharmaceuticals, compositions and methods of making and using the same Download PDF

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Publication number
WO2011050160A1
WO2011050160A1 PCT/US2010/053542 US2010053542W WO2011050160A1 WO 2011050160 A1 WO2011050160 A1 WO 2011050160A1 US 2010053542 W US2010053542 W US 2010053542W WO 2011050160 A1 WO2011050160 A1 WO 2011050160A1
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amine
pyrimidin
triazolo
pyridin
methylbenzyl
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PCT/US2010/053542
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French (fr)
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Kevin M. Guckian
Gnanasambandam Kumaravel
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Biogen Idec Ma Inc.
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Publication of WO2011050160A1 publication Critical patent/WO2011050160A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to pharmaceutical compositions and methods, and methods of making and using the same.
  • Movement disorders constitute a serious health problem, especially among the elderly. These movement disorders can often be the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
  • Parkinson's disease There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per
  • Parkinson's disease 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years.
  • Degeneration of dopaminergic neurons in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra can be destroyed before the clinical symptoms of Parkinson's disease become apparent.
  • L-dihydroxyphenylacetic acid L-DOPA
  • L-DOPA L-dihydroxyphenylacetic acid
  • DeprenylTM monoamine oxidase
  • dopamine receptor agonists e.g., bromocriptine and apomorphine
  • anticholinergics e.g., benztrophine, orphenadrine
  • Transmitter replacement therapy may not provide consistent clinical benefit, especially after prolonged treatment when "on-off" symptoms develop.
  • such treatments have also been associated with involuntary movements of athetosis and chorea, nausea and vomiting.
  • current therapies do not treat the underlying
  • Blocking of purine receptors, particularly adenosine receptors, and more particularly adenosine A2A receptors may be beneficial in treatment or prevention of movement disorders such as Parkinson's disease, or disorders such as depression, cognitive, or memory impairment, acute and chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject.
  • movement disorders such as Parkinson's disease, or disorders such as depression, cognitive, or memory impairment, acute and chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject.
  • a compound can have formula (I):
  • R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, halogen, -CN, -NR 5 R 6 , -N(R a )C(0)R 4 , -N(R a )C(0)NR 5 R 6 , -N(R a )C0 2 R 4 , and -N(R a )S0 2 R 4 .
  • R 2 is aryl or heteroaryl wherein aryl is optionally substituted by 1-5 substituents selected from R 4 ; and heteroaryl is optionally substituted by 1-5 substituents selected from R 4 .
  • L 1 is a bond, -(CR a R b ) n -, -C(O)-, -C(0)N(R a , -(CR a R b ) n -C(0)N(R a )-,
  • Ar 3 is arylene or heteroarylene.
  • Each R 4 is H, oxo, CN, halogen, -CF 3 , -CHF 2 , -CHO, -OH, -N0 2 -SH, -OCF 3 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C0 2 R a , -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH 2 ) n -alkyl, -(CH 2 ) n -alkoxy, -(CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -cycloalkyl, -
  • L 2 is a bond, -(CR a R b ) n -, -C(O)-, -C(0)N(R a )-, -(CR a R b ) n -C(0)N(R a )-,
  • Each R 5 and each R 6 are independently H, alkyl or aryl wherein alkyl and aryl are each independently substituted by 1-3 substituents selected from R 7 ; or R 5 and R 6 together with the atom to which they are attached form a heterocyclic group which is optionally substituted by 1-3 substituents selected from R 7 .
  • i is an integer selected from 0, 1, 2, 3, 4 and 5.
  • R 7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl.
  • Each R a is H, halogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • Each R b is H, halogen, C 1 -C5 alkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • R a and R b together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • Each m, independently, is 0, 1, or 2.
  • n is 0, 1, 2, 3, or 4.
  • the compound can be prepared in the form of a pharmaceutically acceptable salt.
  • L 1 can be -CH 2 - and Ar 3 can be heteroarylene.
  • Ar 3 can be pyridylene.
  • R 1 can be -NR 5 R 6 .
  • R 2 can be heteroaryl optionally substituted by 1-5 substituents selected from R 4 .
  • R 2 can be aryl optionally substituted by 1-5 substituents selected from R 4 .
  • R 2 can be selected from the group consisting of furyl, phenyl, thiophenyl, oxazolyl, imidazolyl, triazolyl, indolyl, pyrollyl, pyridinyl, pyrimidinyl, pyrazolyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothiophenyl, thiazolyl, thiabendazolyl, and thiazolyl, each of which is optionally substituted by 1-5 substituents selected from R 4 .
  • R 2 can be selected from the group consisting offuran-2-yl; 5-methyl-furan-2-yl; phenyl; 3-methoxyphenyl; 3- cyanophenyl; oxazol-2-yl; and 4-methylthiazol-2-yl.
  • L 2 can be -CH 2 -O-.
  • each R independently, is fluoro, chloro, bromo, iodo, methyl, cyano, hydroxy, methoxy, trifluoromethyl, formyl, trifluoromethoxy, nitro, amino, thiol, or acetyl, andj is an integer selected from 0, 1, 2, 3, or 4.
  • a compound in another aspect, can have formula (la):
  • the compound can be prepared in the form of a pharmaceutically acceptable salt.
  • a compound can have formula (II):
  • the compound can be prepared in the form of a pharmaceutically acceptable salt.
  • a pharmaceutical composition in another aspect, includes a pharmaceutically acceptable carrier and a compound of formula (I) as defined above.
  • a method of treating a disorder includes administering an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of treatment of a disorder treatable by purine receptor blocking.
  • the disorder can be related to hyper functioning of purine receptors.
  • the subject can be in need of adenosine receptor blocking.
  • the adenosine receptors can be A2A receptors.
  • the disorder can be a movement disorder.
  • the movement disorder can be Parkinson's disease; or the movement disorder can be drug-induced Parkinsonism, post- encephalitic Parkinsonism, Parkinsonism induced by poisoning or post-traumatic Parkinson's disease.
  • the movement disorder can be progressive supernuclear palsy, Huntington's disease, multiple system atrophy, corticobasal degeneration, Wilson's disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia- Parkinsonism, spasticity or other disorders of the basal ganglia which result in dyskinesias.
  • the method can include administering to the subject an additional drug useful in the treatment of movement disorders.
  • the additional drug useful in the treatment of movement disorders can be a drug useful in the treatment of Parkinson's disease, such as, for example, L-DOPA or a dopamine agonist.
  • the disorder can be depression, a cognitive or memory impairment disorder, acute or chronic pain, ADHD or narcolepsy.
  • the cognitive or memory impairment disorder can be Alzheimer's disease.
  • Blockade of A2 adenosine receptors has been implicated in the treatment of movement disorders such as Parkinson's disease and in the treatment of cerebral ischemia. See, for example, WO 02/055083; Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344; and Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65, each of which is incorporated by reference in its entirety.
  • Adenosine A 2 A receptor antagonists have potential use in the treatment of movement disorders such as Parkinson's Disease (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320, which is incorporated by reference in its entirety).
  • Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects.
  • the central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, because of the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., /. Med. Chem 1992, 35, 407-422, and Bhagwhat, S. S.; Williams, M. E. Opin. Ther. Patents 1995, 5,547-558, each which is incorporated by reference in its entirety).
  • Adenosine receptors represent a subclass (Pi) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors.
  • the main pharmacologically distinct adenosine receptor subtypes are known as Ai, A 2 A, A 2 B (of high and low affinity) and A3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156, which is incorporated by reference in its entirety).
  • the adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128, which is incorporated by reference in its entirety).
  • Pi receptor-mediated agents can be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Jacobson, K. A., Suzuki, F., Drug Dev. Res. , 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707- 722; and Williams, M. and Bumnstock, G. Purinergic Approaches Exp. Ther. (1997), 3- 26. Editor. Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-liss, New York, N.Y., which is incorporated by reference in its entirety).
  • Parkinson's disease Jacobson, K. A., Suzuki, F., Drug Dev. Res. , 1997, 39, 289-300
  • Baraldi P. G. et al., Curr. Med. Chem. 1995, 2, 707- 722
  • xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD).
  • ADHD attention-deficit hyperactivity disorder
  • Antagonism of adenosine receptors is thought to account for the majority of the behavioral effects of caffeine in humans and thus blockade of adenosine A2A receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective adenosine A2A receptor antagonist may provide an effective treatment for ADHD but with decreased side-effects.
  • Adenosine receptors can play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268, which is incorporated by reference in its entirety).
  • Adenosine's sleep regulation can be mediated by the adenosine A2A receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA,
  • a selective adenosine A2A receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.
  • adenosine A2A receptor antagonists may be useful in treatment of major depression and other affective disorders in patients.
  • A2A receptors may be functionally linked dopamine D2 receptors in the CNS. See, for example, Ferre, S. et al., Proc. Natl. Acad. Sci. USA 1991, 88, 7238-7241; Puxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., (Proc. Int. Symp.), 5th (1995), 499-507. Editors: Belardinelr, Luiz;
  • adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated. See, e.g., Ongini, E.; Adami, M.; Ferri, C; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 3048, which is incorporated by reference in its entirety.
  • blockade of adenosine A2A receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J- F., /. Neurosci. 2001, 21, RC143, which is incorporated by reference in its entirety).
  • adenosine A2A receptor antagonist may confer neuroprotection in neurodegenerative diseases such as Parkinson's disease.
  • Xanthine derivatives have been disclosed as adenosine A2A receptor antagonists for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson's disease (see, for example, EP-A-565377, which is incorporated by reference in its entirety).
  • One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett. , 1993, 323, 141-144, which is incorporated by reference in its entirety).
  • Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine Ai and A 2 A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in
  • Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week.
  • the patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515- 517, which is incorporated by reference in its entirety).
  • KF 17837 (E-8-(3,4dimethoxystyryl)-l,3-dipropyl-7-methylxanthine) is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine.
  • KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A 2 A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A 2 A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268, which is incorporated by reference in its entirety).
  • SAR structure activity relationship
  • Non- anthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., /. Med Chem. 1996, 39, 1164-71, which is incorporated by reference in its entirety).
  • SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2- furyl)-pyrazolo-[4,3-e]-l,2,4triazolo[l,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70, which is incorporated by reference in its entirety) and has been followed up by a later series of compounds (Baraldi, P. G. et al., /. Med. Chem. 1998,41(12), 2126-2133, which is incorporated by reference in its entirety).
  • R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, halogen, -CN, -NR 5 R 6 , -N(R a )C(0)R 4 , -N(R a )C(0)NR 5 R 6 , -N(R a )C0 2 R 4 , and -N(R a )S0 2 R 4 .
  • R 2 is aryl or heteroaryl; aryl optionally substituted by 1-5 substituents selected from R 4 ; or heteroaryl optionally substituted by 1-5 substituents selected from R 4 .
  • L 1 is a bond, -(CR a R b ) n -, -C(O)-, -C(0)N(R a , -(CR a R b ) n -C(0)N(R a )-,
  • Ar 3 is arylene or heteroarylene.
  • Each R 4 is H, oxo, CN, halogen, -CF 3 , -CHF 2 , -CHO, -OH, -N0 2 , -SH, -OCF 3 , alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C0 2 R a , -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH 2 ) n -alkyl, -(CH 2 ) n -alkoxy, -(CH 2 ) n -alkenyl, -(CH 2 ) n -alkynyl, -(CH 2 ) n -cycloalkyl,
  • L 2 is a bond, -(CR a R b ) n -, -C(O)-, -C(0)N(R a )-, -(CR a R b ) n -C(0)N(R a )-,
  • Each R 5 and each R 6 are independently H, alkyl or aryl wherein alkyl and aryl are each independently substituted by 1-3 substituents selected from R 7 ; or R 5 and R 6 together with the atom to which they are attached form a heterocyclic group which is optionally substituted by 1-3 substituents selected from R 7 .
  • i is an integer selected from 0, 1, 2, 3, 4 and 5.
  • R 7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl.
  • Each R a is H, halogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • Each R b is H, halogen, Ci-C 6 alkyl, C 3 -C 8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • R a and R b together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF 3 , -CN, -N0 2 , oxo, alkyl, alkoxy or cycloalkyl.
  • Each m, independently, is 0, 1, or 2.
  • n is 0, 1, 2, 3, or 4.
  • compositions of formula (I) as described above are also suitable as purine receptor antagonists, for example, as adenosine A2A antagonists.
  • compounds of formula (II) can be useful as purine receptor antagonists, for example, as adenosine A2A antagonists.
  • the compound can be prepared in the form of a pharmaceutically acceptable salt.
  • alkyl refers to a straight-chain or branched-chain alkyl radical containing 1 to 10, 1 to 6, or 1 to 4, carbon atoms.
  • radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, decyl and the like.
  • alkenyl alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
  • radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like.
  • alkynyl refers to a straight-chain or branched-chain alkynyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
  • radicals include, but are not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
  • cycloalkyl refers to a cyclic alkyl radical containing 3 to 10, 3 to 8, or 3 to 6, carbon atoms.
  • examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and bicylic groups including bicyclo[3.4.0]nonyl, bicyclo[2.2.2]octyl, norbornyl, spiro[4.5]decyl, and the like.
  • cycloalkenyl alone or in combination, refers to a cyclic carbocycle containing 4 to 10, 4 to 8, or 5 or 6, carbon atoms and one or more double bonds.
  • cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and bicyclic groups such as norbornenyl, and the like.
  • aryl refers to a carbocyclic aromatic group, and includes fused bicyclic or tricyclic systems where one or more rings are not aromatic, e.g., indanyl.
  • carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl.
  • heteroaryl refers to a heterocyclic aromatic group, and includes fused bicyclic or tricyclic systems where one or more rings are not aromatic, e.g., indolinyl.
  • heterocyclic aromatic groups include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,
  • cycloalkylether refers to a cyclic alkyl ether radical containing 3 to 10, 3 to 8, or 3 to 6, atoms, at least one of which is an oxygen atom.
  • cycloalkylether radicals include, but are not limited to,
  • heterocycle or “heterocyclyl,” alone or in combination, refer to a saturated or unsaturated monocyclic, bicyclic or tricyclic non-aromatic group containing 5- 14 or 5- 10 ring atoms and including 1 to 5 ring heteroatoms selected from O, N, and S.
  • the heteroatom can be an oxidized heteroatom, for example, when the heteroatom is N, it can be an N-oxide, or when the heteroatom is S, it can be a sulfoxide or sulfone.
  • Bicyclic and tricyclic heterocycle groups can include an aromatic ring, e.g., 2,3- dihydrobenzofuran, or 2,3-dihydronaphtho[2,3-b]furan.
  • heterocycle groups include monocyclic groups such as, for example, morpholino, tetrahydrofuranyl, pyrrolidinyl, 2,3-dihydropyrrolyl, piperidinyl, 1,4-dihydropyridinyl, tetrahydrothienyl, thiomorpholino, tetrahydropyranyl,
  • bicyclic heterocycle groups including, for example, fused bicyclic groups (e.g., octahydrobenzofuran, octahydro- 1H- indole, hexahydro-2H-furo[2,3-&]pyrrole,
  • Tricyclic groups can include rings that are fused, bridged, or spiro.
  • alkoxy refers to an alkyl ether radical, or cycloalkyl ether radical, where the terms “alkyl” and “cycloalkyl” are as defined above.
  • suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclopropoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • halogen means fluorine, chlorine, bromine and iodine.
  • heterorocylyl refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic non-aromatic group including 1 to 5 heteroatoms selected from -0-, -S-, -S(O)-, - S(0)2-, -N-, and -N(O)-.
  • saturated monocyclic heterocyclic groups include morpholino, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydrothienyl, thiomorpholino, tetrahydropyranyl, butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, and the like.
  • unsaturated monocyclic heterocyclic groups examples include 2,3-dihydropyran, 2,3-dihydropyrrolidyl, 1,2-dihydropyridine, maleimidiyl, and the like.
  • a bicyclic heterocyclyl radical includes fused bicyclic groups, bridged bicyclic groups, and spiro bicyclic groups.
  • aryloxy refers to an aryl ether radical, where "aryl” is as defined above. Examples include, but are not limited to, phenoxy and naphthyloxy.
  • heteroaryloxy refers to a heteroaryl ether radical, where "heteroaryl” is as defined above. Examples include, but are not limited to, pyridyloxy, pyrrolyloxy, furyloxy, and thienyloxy.
  • alkylthio refers to an alkyl thioether radical, or cycloalkyl thioether radical, where the terms “alkyl” and “cycloalkyl” are as defined above.
  • suitable alkyl thioether radicals include, but are not limited to, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec- butylthio, tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
  • arylthio refers to an aryl thioether radical, where "aryl” is as defined above. Examples include, but are not limited to, phenylthio and naphthylthio.
  • heteroarylthio refers to a heteroaryl thioether radical, where "heteroaryl” is as defined above. Examples include, but are not limited to, pyridylthio, pyrrolylthio, furylthio, and thienylthio.
  • arylene refers to a carbocyclic aryl diradical, such as phenylene or naphthylene.
  • heteroarylene refers to a heterocyclic aromatic diradical.
  • Examples include but are not limited to pyridinylene, furylene, pyrimidinylene, and thienylene.
  • the compounds of formula (I) can be used for treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial.
  • the compounds can be administered to a subject in need of such treatment.
  • an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof can be administered to a subject.
  • the disorder may be caused by the hyperfunctioning of the purine receptors.
  • disorders of particular interest include those in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. These include movement disorders such as Parkinson's disease, drug- induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MIP, manganese, carbon monoxide) and post-traumatic movement disorders such as Parkinson's disease, drug- induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MIP, manganese, carbon monoxide) and post-traumatic
  • Parkinson's disease Punch-drunk syndrome
  • Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture.
  • the present invention may also be effective in treating Parkinson's with on-off phenomena;
  • Parkinson's with freezing end of dose deterioration
  • Parkinson's with prominent dyskinesias are the Parkinson's with prominent dyskinesias.
  • the compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L- DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • additional drugs useful in the treatment of movement disorders such as L- DOPA or a dopamine agonist
  • disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal
  • demyelinating disease multiple sclerosis, disseminated sclerosis), Friedrich's ataxia, motoneuron disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related psychoses; cognitive disorders including dementia, Alzheimer's Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntington's Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD
  • cerebral ischemia including transient ischemic attack, stroke (thrombotic stroke, ischemic stroke, embolic stroke, hemorrhagic stroke, lacunar stroke) subarachnoid hemorrhage, cerebral vasospasm, neuroprotection for stroke, perinatal asphyxia, drowning, cardiac arrest, subdural hematoma; myocardial ischemia;
  • muscle ischemia sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.
  • Compounds of formula (4) may be prepared from compounds of formula (3) by standard methods such as reaction with an appropriate alkyl halide, or substituted alkyl halide (e.g., an arylalkyl halide) in the presence of a suitable base such as sodium hydride.
  • Compounds of formula (4) where R 3 is -CONH-Ar 3 (R 4 )i-L 2 -R 7 can be prepared from compounds of formula (4) where R 3 is -COC1 by standard methods such as direct reaction with an appropriate amine or hydrazine.
  • Compounds of formula (3) may be prepared from the known chloro compound of formula (2) by standard methods such as aryl or heteroaryl coupling reactions.
  • Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl- or heteroaryl-boronic acid derivative, an aryl- or heteroaryl-trialkylstannane derivative or an aryl- or heteroaryl-zinc halide derivative in the presence of a suitable catalyst such as a palladium complex.
  • Compounds of formula (3) may also be prepared from compounds of formula (7) by standard methods such as treatment with isoamyl nitrite or sodium nitrite.
  • Compounds of formula (7) are either known in the literature or can be prepared from compounds of formula (6) by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd.
  • Compounds of formula (6) are either known in the literature or can be prepared from the known compound of formula (5) by standard methods such as aryl or heteroaryl coupling reactions as described above.
  • Compounds of formula (I) where R 1 is -NR 5 R 6 may be prepared from compounds of formula (4) by standard methods such as reductive amination with an appropriate aldehyde or ketone, or by treatment with an appropriate alkyl halide in the presence of a suitable base.
  • Compounds of formula (I) where R 1 is -NR a COR 4 , -NR a C0 2 R 4 or -NR a S0 2 R 4 , where R a is H, may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate acid chloride (R 5 COCl), chloroformate (CICO 2 R 4 ) or sulfonyl chloride (R 4 S0 2 C1) in the presence of a suitable base.
  • Compounds of formula (I) where R 1 is -NR 4 COR 4 , -NR a C0 2 R 4 or -NR a S0 2 R 4 , where R a is alkyl may be prepared as described above having first performed an additional alkylation step as described above.
  • Compounds of formula (I) where Ri is -N3 ⁇ 4 may also be synthesized by standard methods such as those illustrated in Reaction Scheme 2.
  • Compounds of formula (4) may be prepared from compounds of formula (10) by standard methods such as aryl or heteroaryl coupling reactions as described above.
  • Compounds of formula (10) where R 3 is arylalkyl are can be prepared by methods analogous to those described in the literature.
  • compounds of formula (10) where R 3 is arylalkyl may be prepared from compounds of formula (9) where R 3 is arylalkyl by standard methods such as treatment with isoamyl nitrite or sodium nitrite.
  • Compounds of formula (9) where R 3 is arylalkyl can be prepared by methods described in the literature such as the treatment of the compound of formula (8) with an appropriate amine in a suitable solvent at elevated temperature.
  • Compounds of formula (10) can be prepared from compounds of formula (9 A) by standard methods such as treatment with isoamyl nitrite or sodium nitrite.
  • Compounds of formula (9A) where R 3 is arylalkyl can be prepared by methods such as the treatment of the compound of formula (8A) with an appropriate amine in a suitable solvent at elevated temperature.
  • Compounds of formula (4) where R 3 is arylalkyl can be prepared from compounds of formula (15) where R 3 is arylalkyl by standard methods such as treatment with isoamyl nitrite.
  • Compounds of formula (15) where R 3 is arylalkyl may be prepared from compounds of formula (14) where R 3 is arylalkyl by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd.
  • Compounds of formula (14) where R 3 is arylalkyl may be prepared from compounds of formula (13), where X is a suitable leaving group such as a tosylate or triflate group, by standard methods such as treatment with a suitable amine in the presence of a suitable base such as triethylamine.
  • Compounds of formula (13) where X is a suitable leaving group are either known in the literature or may be prepared from compounds of formula (12) by standard methods such as treatment with tosyl chloride or triflic anhydride in the presence of a suitable base such as triethylamine or 2,6-dimethylpyridine.
  • Compounds of formula (12) are either known in the literature or may be prepared from the known compound of formula (11) by standard methods such as aryl or heteroaryl coupling reactions as described above.
  • R 1 can be prepared from compounds of formula (I) where R 1 is halogen by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (NHR 5 R 6 ) in the presence of a suitable base if required.
  • Compounds of formula (1) where R 1 is halogen may be prepared from compounds of formula (16) where R 1 is halogen as described above.
  • Compounds of formula (16) where R 1 is halogen are either known in the literature or may be prepared by methods analogous to those described in the literature.
  • a suitable protecting group would be a benzyl group or substituted benzyl group such as a 3,4- dimethoxybenzyl group.
  • Compounds of this nature may prepared as described above and the protecting group R 3 may be removed by standard methods such as treatment with, for example, TFA to give a compound where R 3 is -H.
  • Compounds of formula (I) where R 3 is -H may then be used to prepare other compounds of formula (I), where R 3 is as previously defined, by the methods described above.
  • compound of formula (I) can be prepared according to Reaction
  • Substituted pyrimidine (12) can be prepared from precursor (11) and an aryl- or heteroaryl boronic acid as shown; or an aryl- or heteroaryl trialkyl tin compound can be used in place of the aryl or heteroaryl boronic acid.
  • Compound (12) is treated to convert the hydroxide group into a good leaving group.
  • Reaction of (13) with an appropriate amine, NH 2 R 3 affords compound (14), which is converted to a compound of formula (4) by treatment with a suitable reducing agent, followed by sodium nitrite.
  • Compounds of formula (I) can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
  • glycerophosphate hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • the compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions can include a compound of formula (I), or pharmaceutically acceptable derivatives thereof, together with any pharmaceutically acceptable carrier.
  • carrier includes acceptable adjuvants and vehicles.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
  • compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler.
  • a nebulizer a dry powder inhaler or a metered dose inhaler.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co-administered.
  • a pharmaceutical composition can include an effective amount of a compound of formula (I).
  • An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day of the active ingredient compound are useful. The following examples are for the purpose of illustration only and are not intended to be limiting.
  • R 3 5-(tetrahydrofuran-3-yl-
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl rr 1 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
  • R 2 R 3 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl

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Abstract

Compounds that are capable of acting as purine receptor antagonists, pharmaceutical compositions including the compounds, and methods of making the compounds, are disclosed. The compounds and compositions can be used in treating or preventing disorders related to purine receptor hyperfunctioning.

Description

PHARMACEUTICALS, COMPOSITIONS AND METHODS OF MAKING AND USING THE SAME
CLAIM OF PRIORITY
This application claims priority to provisional U.S. Patent Application No.
61/254,066, filed October 22, 2009, which is incorporated by reference in its entirety.
TECHNICAL FIELD
The present invention relates to pharmaceutical compositions and methods, and methods of making and using the same.
BACKGROUND
Movement disorders constitute a serious health problem, especially among the elderly. These movement disorders can often be the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.
There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per
1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurons in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra can be destroyed before the clinical symptoms of Parkinson's disease become apparent.
Some strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g., Deprenyl™), dopamine receptor agonists (e.g., bromocriptine and apomorphine) and anticholinergics (e.g., benztrophine, orphenadrine). Transmitter replacement therapy may not provide consistent clinical benefit, especially after prolonged treatment when "on-off" symptoms develop. Furthermore, such treatments have also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally, current therapies do not treat the underlying
neurodegenerative disorder resulting in a continuing cognitive decline in patients.
SUMMARY
Blocking of purine receptors, particularly adenosine receptors, and more particularly adenosine A2A receptors may be beneficial in treatment or prevention of movement disorders such as Parkinson's disease, or disorders such as depression, cognitive, or memory impairment, acute and chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject.
In one aspect, a compound can have formula (I):
Figure imgf000003_0001
R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, halogen, -CN, -NR5R6, -N(Ra)C(0)R4, -N(Ra)C(0)NR5R6, -N(Ra)C02R4, and -N(Ra)S02R4.
R2 is aryl or heteroaryl wherein aryl is optionally substituted by 1-5 substituents selected from R4; and heteroaryl is optionally substituted by 1-5 substituents selected from R4.
L1 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra , -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, or -(CRaRb)n-0-.
Ar3 is arylene or heteroarylene.
Each R4, independently, is H, oxo, CN, halogen, -CF3, -CHF2, -CHO, -OH, -N02 -SH, -OCF3, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C02Ra, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH2)n-alkyl, -(CH2)n-alkoxy, -(CH2)n-alkenyl, -(CH2)n-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -N(Ra)Rb, -N(Ra)-alkyl, -N(Ra)-alkoxy, -N(Ra)-alkenyl, -N(Ra)-alkynyl, -N(Ra)-cycloalkyl, -N(Ra)-aryl, -N(Ra)-heteroaryl, -N(Ra)-heterocyclyl, -SOm-alkyl, -SOm-alkoxy,
-SOm-alkenyl, -SOm-alkynyl, -SOm-cycloalkyl, -SOm-aryl, -SOm-heteroaryl,
-SOm-heterocyclyl, -N(Ra)C(0)-alkyl, -N(Ra)C(0)-alkoxy, -N(Ra)C(0)-alkenyl, -N(Ra)C(0)-alkynyl, -N(Ra)C(0)-cycloalkyl, -N(Ra)C(0)-aryl, -N(Ra)C(0)-heteroaryl, -N(Ra)C(0)-heterocyclyl, -C(0)N(Ra)-alkyl, -C(0)N(Ra)-alkoxy, -C(0)N(Ra)-alkenyl, -C(0)N(Ra)-alkynyl, -C(0)N(Ra)-cycloalkyl, -C(0)N(Ra)-aryl, -C(0)N(Ra)-heteroaryl, or -C(0)N(Ra)-neterocyclyl.
L2 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra)-, -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, -(CRaRb)n-N(Ra)C(0)-, -N(Ra)C(0)-(CRaRb)n-, -0-, or -(CRaRb)n- 0-.
Each R5 and each R6 are independently H, alkyl or aryl wherein alkyl and aryl are each independently substituted by 1-3 substituents selected from R7; or R5 and R6 together with the atom to which they are attached form a heterocyclic group which is optionally substituted by 1-3 substituents selected from R7.
i is an integer selected from 0, 1, 2, 3, 4 and 5.
R7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl.
Each Ra, independently, is H, halogen, Ci-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Each Rb, independently, is H, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Or, Ra and Rb together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Each m, independently, is 0, 1, or 2.
Each n, independently, is 0, 1, 2, 3, or 4.
The compound can be prepared in the form of a pharmaceutically acceptable salt.
L1 can be -CH2- and Ar3 can be heteroarylene. Ar3 can be pyridylene. R1 can be -NR5R6. R2 can be heteroaryl optionally substituted by 1-5 substituents selected from R4. R2 can be aryl optionally substituted by 1-5 substituents selected from R4. R2 can be selected from the group consisting of furyl, phenyl, thiophenyl, oxazolyl, imidazolyl, triazolyl, indolyl, pyrollyl, pyridinyl, pyrimidinyl, pyrazolyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothiophenyl, thiazolyl, thiabendazolyl, and thiazolyl, each of which is optionally substituted by 1-5 substituents selected from R4. R2 can be selected from the group consisting offuran-2-yl; 5-methyl-furan-2-yl; phenyl; 3-methoxyphenyl; 3- cyanophenyl; oxazol-2-yl; and 4-methylthiazol-2-yl. L2 can be -CH2-O-.
Figure imgf000005_0001
each R , independently, is fluoro, chloro, bromo, iodo, methyl, cyano, hydroxy, methoxy, trifluoromethyl, formyl, trifluoromethoxy, nitro, amino, thiol, or acetyl, andj is an integer selected from 0, 1, 2, 3, or 4.
In another aspect, a compound can have formula (la):
Figure imgf000005_0002
in which X is =CH- or =N-, each Y is independently -CR4=, -C(R4)2-, -N=, -NR4-, -0-, - S-, or a bond, provided that no more than two of Y are -N=, -NR4-, -0-, -S-, and provided that no more than one of Y is a bond, and R2, R4, i, L2 and R7 are as defined above. The compound can be prepared in the form of a pharmaceutically acceptable salt. In another aspect, a compound can have formula (II):
Figure imgf000006_0001
(II)
in which X is =CH- or =N-, and R2, R4, i, L2 and R7 are as defined above. The compound can be prepared in the form of a pharmaceutically acceptable salt.
In another aspect, a pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound of formula (I) as defined above.
In another aspect, a method of treating a disorder includes administering an effective dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need of treatment of a disorder treatable by purine receptor blocking.
The disorder can be related to hyper functioning of purine receptors. The subject can be in need of adenosine receptor blocking. The adenosine receptors can be A2A receptors. The disorder can be a movement disorder. The movement disorder can be Parkinson's disease; or the movement disorder can be drug-induced Parkinsonism, post- encephalitic Parkinsonism, Parkinsonism induced by poisoning or post-traumatic Parkinson's disease. The movement disorder can be progressive supernuclear palsy, Huntington's disease, multiple system atrophy, corticobasal degeneration, Wilson's disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia- Parkinsonism, spasticity or other disorders of the basal ganglia which result in dyskinesias.
The method can include administering to the subject an additional drug useful in the treatment of movement disorders. The additional drug useful in the treatment of movement disorders can be a drug useful in the treatment of Parkinson's disease, such as, for example, L-DOPA or a dopamine agonist. The disorder can be depression, a cognitive or memory impairment disorder, acute or chronic pain, ADHD or narcolepsy. The cognitive or memory impairment disorder can be Alzheimer's disease.
Other aspects, features, and objects will be apparent from the description and drawings. DETAILED DESCRIPTION
Blockade of A2 adenosine receptors has been implicated in the treatment of movement disorders such as Parkinson's disease and in the treatment of cerebral ischemia. See, for example, WO 02/055083; Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344; and Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65, each of which is incorporated by reference in its entirety. Adenosine A2A receptor antagonists have potential use in the treatment of movement disorders such as Parkinson's Disease (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320, which is incorporated by reference in its entirety).
Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, because of the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., /. Med. Chem 1992, 35, 407-422, and Bhagwhat, S. S.; Williams, M. E. Opin. Ther. Patents 1995, 5,547-558, each which is incorporated by reference in its entirety).
Adenosine receptors represent a subclass (Pi) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as Ai, A2A, A2B (of high and low affinity) and A3 (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156, which is incorporated by reference in its entirety). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128, which is incorporated by reference in its entirety).
Pi receptor-mediated agents can be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Jacobson, K. A., Suzuki, F., Drug Dev. Res. , 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707- 722; and Williams, M. and Bumnstock, G. Purinergic Approaches Exp. Ther. (1997), 3- 26. Editor. Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-liss, New York, N.Y., which is incorporated by reference in its entirety).
It has been speculated that xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD). A number of studies have demonstrated a beneficial effect of caffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al., Psychiatry, 1981, 26, 395-401, which is incorporated by reference in its entirety). Antagonism of adenosine receptors is thought to account for the majority of the behavioral effects of caffeine in humans and thus blockade of adenosine A2A receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective adenosine A2A receptor antagonist may provide an effective treatment for ADHD but with decreased side-effects.
Adenosine receptors can play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268, which is incorporated by reference in its entirety). Adenosine's sleep regulation can be mediated by the adenosine A2A receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA,
1996, 93: 5980-5984, which is incorporated by reference in its entirety). Thus, a selective adenosine A2A receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.
Patients with major depression demonstrate a blunted response to adenosine agonist-induced stimulation in platelets, suggesting that a dysregulation of adenosine A2A receptor function may occur during depression (Berk, M. et al., 2001, Eur.
Neuropsycopharmacol. 11, 183-186, which is incorporated by reference in its entirety). Experimental evidence in animal models has shown that blockade of adenosine A2A receptor function confers antidepressant activity (El Yacoubi, M et al., Br. J. Pharmacol. 2001, 134, 68-77, which is incorporated by reference in its entirety). Thus, adenosine A2A receptor antagonists may be useful in treatment of major depression and other affective disorders in patients.
The pharmacology of adenosine A2A receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372, which is incorporated by reference in its entirety). One possible mechanism in the treatment of movement disorders by adenosine A2A antagonists is that A2A receptors may be functionally linked dopamine D2 receptors in the CNS. See, for example, Ferre, S. et al., Proc. Natl. Acad. Sci. USA 1991, 88, 7238-7241; Puxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., (Proc. Int. Symp.), 5th (1995), 499-507. Editors: Belardinelr, Luiz;
Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; and Ferre, S. et al., Trends Neurosci.
1997, 20, 482-487, each of which is incorporated by reference in its entirety. Interest in the role of adenosine A2A receptors in the CNS, due in part to in vivo studies linking A2A receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 1624; and Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141, each of which is incorporated by reference in its entirety), has prompted investigations into agents that selectively bind to adenosine A2A receptors.
One advantage of adenosine A2A antagonist therapy is that the underlying neurodegenerative disorder may also be treated. See, e.g., Ongini, E.; Adami, M.; Ferri, C; Bertorelli, R., Ann. N. Y. Acad. Sci. 1997, 825(Neuroprotective Agents), 3048, which is incorporated by reference in its entirety. In particular, blockade of adenosine A2A receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J- F., /. Neurosci. 2001, 21, RC143, which is incorporated by reference in its entirety). In addition, consumption of dietary caffeine (a known adenosine A2A receptor antagonist), is associated with a reduced risk of Parkinson's disease (Ascherio, A. et al, Ann. Neurol., 2001, 50, 56-63; and Ross G.W., et al., JAMA, 2000, 283, 2674-9, each of which is incorporated by reference in its entirety). Thus, adenosine A2A receptor antagonists may confer neuroprotection in neurodegenerative diseases such as Parkinson's disease.
Xanthine derivatives have been disclosed as adenosine A2A receptor antagonists for treating various diseases caused by hyperfunctioning of adenosine A2 receptors, such as Parkinson's disease (see, for example, EP-A-565377, which is incorporated by reference in its entirety). One prominent xanthine-derived adenosine A2A selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett. , 1993, 323, 141-144, which is incorporated by reference in its entirety).
Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine Ai and A2A receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in
Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophylline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W. J. Pharm. Pharmacol. 1994, 46, 515- 517, which is incorporated by reference in its entirety). KF 17837 (E-8-(3,4dimethoxystyryl)-l,3-dipropyl-7-methylxanthine) is a selective adenosine A2A receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A2A receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268, which is incorporated by reference in its entirety). The structure activity relationship (SAR) of KF 17837 has been published
(Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352, which is incorporated by reference in its entirety). Recent data has also been provided on the adenosine A2A receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997,23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998,43(4), 507-513, each of which is incorporated by reference in its entirety).
Non- anthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., /. Med Chem. 1996, 39, 1164-71, which is incorporated by reference in its entirety). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2- furyl)-pyrazolo-[4,3-e]-l,2,4triazolo[l,5-c] pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70, which is incorporated by reference in its entirety) and has been followed up by a later series of compounds (Baraldi, P. G. et al., /. Med. Chem. 1998,41(12), 2126-2133, which is incorporated by reference in its entirety).
A number of adenosine A2A antagonists are described in International Patent Application Publication WO 02/055083 Al, which is incorporated by reference in its entirety.
Compounds of formula (I) are useful as purine receptor antagonists, for example, as adenosine A2A antagonists. In particular the compounds can have formula (I) as detailed below:
Figure imgf000011_0001
R is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, halogen, -CN, -NR5R6, -N(Ra)C(0)R4, -N(Ra)C(0)NR5R6, -N(Ra)C02R4, and -N(Ra)S02R4.
R2 is aryl or heteroaryl; aryl optionally substituted by 1-5 substituents selected from R4; or heteroaryl optionally substituted by 1-5 substituents selected from R4.
L1 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra , -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, or -(CRaRb)n-0-.
Ar3 is arylene or heteroarylene.
Each R4, independently, is H, oxo, CN, halogen, -CF3, -CHF2, -CHO, -OH, -N02, -SH, -OCF3, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C02Ra, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH2)n-alkyl, -(CH2)n-alkoxy, -(CH2)n-alkenyl, -(CH2)n-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -N(Ra)Rb, -N(Ra)-alkyl, -N(Ra)-alkoxy, -N(Ra)-alkenyl, -N(Ra)-alkynyl, -N(Ra)-cycloalkyl, -N(Ra)-aryl, -N(Ra)-heteroaryl, -N(Ra)-heterocyclyl, -SOm-alkyl, -SOm-alkoxy,
-SOm-alkenyl, -SOm-alkynyl, -SOm-cycloalkyl, -SOm-aryl, -SOm-heteroaryl,
-SOm-heterocyclyl, -N(Ra)C(0)-alkyl, -N(Ra)C(0)-alkoxy, -N(Ra)C(0)-alkenyl, -N(Ra)C(0)-alkynyl, -N(Ra)C(0)-cycloalkyl, -N(Ra)C(0)-aryl, -N(Ra)C(0)-heteroaryl, -N(Ra)C(0)-heterocyclyl, -C(0)N(Ra)-alkyl, -C(0)N(Ra)-alkoxy, -C(0)N(Ra)-alkenyl, -C(0)N(Ra)-alkynyl, -C(0)N(Ra)-cycloalkyl, -C(0)N(Ra)-aryl, -C(0)N(Ra)-heteroaryl, or -C(0)N(Ra)-heterocyclyl.
L2 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra)-, -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, -(CRaRb)n-N(Ra)C(0)-, -N(Ra)C(0)-(CRaRb)n-, -0-, or -(CRaRb)n- 0-.
Each R5 and each R6 are independently H, alkyl or aryl wherein alkyl and aryl are each independently substituted by 1-3 substituents selected from R7; or R5 and R6 together with the atom to which they are attached form a heterocyclic group which is optionally substituted by 1-3 substituents selected from R7. i is an integer selected from 0, 1, 2, 3, 4 and 5.
R7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl.
Each Ra, independently, is H, halogen, Ci-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Each Rb, independently, is H, halogen, Ci-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Or, Ra and Rb together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl.
Each m, independently, is 0, 1, or 2.
Each n, independently, is 0, 1, 2, 3, or 4.
Pharmaceutically acceptable salts of the compounds of formula (I) as described above are also suitable as purine receptor antagonists, for example, as adenosine A2A antagonists.
In some embodiments, compounds of formula (II) can be useful as purine receptor antagonists, for example, as adenosine A2A antagonists.
Figure imgf000012_0001
(Π)
in which X is =CH- or =N-, and R2, R4, i, L2 and R7 are as defined above. The compound can be prepared in the form of a pharmaceutically acceptable salt.
As used herein, the term "alkyl," alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing 1 to 10, 1 to 6, or 1 to 4, carbon atoms.
Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, decyl and the like.
The term "alkenyl," alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
Examples of such radicals include, but are not limited to, ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl, decenyl and the like.
The term "alkynyl," alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing 2 to 10, 2 to 6, or 2 to 4, carbon atoms.
Examples of such radicals include, but are not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
The term "cycloalkyl," alone or in combination, refers to a cyclic alkyl radical containing 3 to 10, 3 to 8, or 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; and bicylic groups including bicyclo[3.4.0]nonyl, bicyclo[2.2.2]octyl, norbornyl, spiro[4.5]decyl, and the like.
The term "cycloalkenyl," alone or in combination, refers to a cyclic carbocycle containing 4 to 10, 4 to 8, or 5 or 6, carbon atoms and one or more double bonds.
Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and bicyclic groups such as norbornenyl, and the like.
The term "aryl" refers to a carbocyclic aromatic group, and includes fused bicyclic or tricyclic systems where one or more rings are not aromatic, e.g., indanyl. Examples of such carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, and anthracenyl.
The term "heteroaryl" refers to a heterocyclic aromatic group, and includes fused bicyclic or tricyclic systems where one or more rings are not aromatic, e.g., indolinyl. Examples of such heterocyclic aromatic groups include, but are not limited to, furyl, thienyl, pyridyl, pyrrolyl, oxazolyly, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3- dihydrobenzofuranyl, benzo[b]thiophenyl, lH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.
The term "cycloalkylether," alone or in combination, refers to a cyclic alkyl ether radical containing 3 to 10, 3 to 8, or 3 to 6, atoms, at least one of which is an oxygen atom. Examples of cycloalkylether radicals include, but are not limited to,
tetrahydrofuranyl, tetrahydropyranyl, 1 ,3-dioxolanyl, 1,4-dioxanyl, and the like.
The terms "heterocycle" or "heterocyclyl," alone or in combination, refer to a saturated or unsaturated monocyclic, bicyclic or tricyclic non-aromatic group containing 5- 14 or 5- 10 ring atoms and including 1 to 5 ring heteroatoms selected from O, N, and S. The heteroatom can be an oxidized heteroatom, for example, when the heteroatom is N, it can be an N-oxide, or when the heteroatom is S, it can be a sulfoxide or sulfone. Bicyclic and tricyclic heterocycle groups can include an aromatic ring, e.g., 2,3- dihydrobenzofuran, or 2,3-dihydronaphtho[2,3-b]furan.
Some examples of heterocycle groups include monocyclic groups such as, for example, morpholino, tetrahydrofuranyl, pyrrolidinyl, 2,3-dihydropyrrolyl, piperidinyl, 1,4-dihydropyridinyl, tetrahydrothienyl, thiomorpholino, tetrahydropyranyl,
butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, maleimidyl, 2,3- dihydropyran, 2,3-dihydropyrrolidyl, 1,2-dihydropyridine, maleimidiyl, and the like; bicyclic heterocycle groups including, for example, fused bicyclic groups (e.g., octahydrobenzofuran, octahydro- 1H- indole, hexahydro-2H-furo[2,3-&]pyrrole,
3a,4,5,6,7,7a-hexahydro- lH-indole), bridged bicyclic groups (e.g., 2-oxa- bicyclo[2.2.1]heptane, 2-aza-bicyclo[2.2.1]heptane, and the like ), and spiro bicyclic groups. Tricyclic groups can include rings that are fused, bridged, or spiro.
The term "alkoxy," alone or in combination, refers to an alkyl ether radical, or cycloalkyl ether radical, where the terms "alkyl" and "cycloalkyl" are as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclopropoxy, cyclopentyloxy, cyclohexyloxy, and the like.
The term "halogen" means fluorine, chlorine, bromine and iodine.
The term "heterocylyl" refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic non-aromatic group including 1 to 5 heteroatoms selected from -0-, -S-, -S(O)-, - S(0)2-, -N-, and -N(O)-. Examples of saturated monocyclic heterocyclic groups include morpholino, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydrothienyl, thiomorpholino, tetrahydropyranyl, butyrolactonyl, caprolactonyl, caprolactamyl, succinimidyl, and the like. Examples of unsaturated monocyclic heterocyclic groups include 2,3-dihydropyran, 2,3-dihydropyrrolidyl, 1,2-dihydropyridine, maleimidiyl, and the like. A bicyclic heterocyclyl radical includes fused bicyclic groups, bridged bicyclic groups, and spiro bicyclic groups.
The term "aryloxy," alone or in combination, refers to an aryl ether radical, where "aryl" is as defined above. Examples include, but are not limited to, phenoxy and naphthyloxy. The term "heteroaryloxy" refers to a heteroaryl ether radical, where "heteroaryl" is as defined above. Examples include, but are not limited to, pyridyloxy, pyrrolyloxy, furyloxy, and thienyloxy.
The term "alkylthio," alone or in combination, refers to an alkyl thioether radical, or cycloalkyl thioether radical, where the terms "alkyl" and "cycloalkyl" are as defined above. Examples of suitable alkyl thioether radicals include, but are not limited to, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec- butylthio, tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
The term "arylthio," alone or in combination, refers to an aryl thioether radical, where "aryl" is as defined above. Examples include, but are not limited to, phenylthio and naphthylthio. The term "heteroarylthio" refers to a heteroaryl thioether radical, where "heteroaryl" is as defined above. Examples include, but are not limited to, pyridylthio, pyrrolylthio, furylthio, and thienylthio.
The term "arylene" refers to a carbocyclic aryl diradical, such as phenylene or naphthylene. The term "heteroarylene" refers to a heterocyclic aromatic diradical.
Examples include but are not limited to pyridinylene, furylene, pyrimidinylene, and thienylene.
The compounds of formula (I) can be used for treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. The compounds can be administered to a subject in need of such treatment. For example, an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof can be administered to a subject. The disorder may be caused by the hyperfunctioning of the purine receptors.
Disorders of particular interest include those in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors, may be beneficial. These include movement disorders such as Parkinson's disease, drug- induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MIP, manganese, carbon monoxide) and post-traumatic
Parkinson's disease (punch-drunk syndrome).
Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson's with on-off phenomena;
Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.
The compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L- DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A2A receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal
degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Friedrich's ataxia, motoneuron disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related psychoses; cognitive disorders including dementia, Alzheimer's Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntington's Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD), attention deficit disorder, minimal brain dysfunction, brain-injured child syndrome, hyperkinetic reaction childhood, and hyperactive child syndrome; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral edema,
hydrocephalus, spinal cord injury; cerebral ischemia including transient ischemic attack, stroke (thrombotic stroke, ischemic stroke, embolic stroke, hemorrhagic stroke, lacunar stroke) subarachnoid hemorrhage, cerebral vasospasm, neuroprotection for stroke, perinatal asphyxia, drowning, cardiac arrest, subdural hematoma; myocardial ischemia;
muscle ischemia; sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.
Compounds of formula (I) may be prepared according to conventional synthetic methods. For example compounds of formula (I) where R1 is N¾ may be synthesized by methods such as those illustrated in Reaction Scheme 1.
Reaction Scheme 1
Figure imgf000017_0001
Compounds of formula (4) may be prepared from compounds of formula (3) by standard methods such as reaction with an appropriate alkyl halide, or substituted alkyl halide (e.g., an arylalkyl halide) in the presence of a suitable base such as sodium hydride. Compounds of formula (4) where R3 is -CONH-Ar3(R4)i-L2-R7 can be prepared from compounds of formula (4) where R3 is -COC1 by standard methods such as direct reaction with an appropriate amine or hydrazine.
Compounds of formula (3) may be prepared from the known chloro compound of formula (2) by standard methods such as aryl or heteroaryl coupling reactions. Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl- or heteroaryl-boronic acid derivative, an aryl- or heteroaryl-trialkylstannane derivative or an aryl- or heteroaryl-zinc halide derivative in the presence of a suitable catalyst such as a palladium complex.
Compounds of formula (3) may also be prepared from compounds of formula (7) by standard methods such as treatment with isoamyl nitrite or sodium nitrite. Compounds of formula (7) are either known in the literature or can be prepared from compounds of formula (6) by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd. Compounds of formula (6) are either known in the literature or can be prepared from the known compound of formula (5) by standard methods such as aryl or heteroaryl coupling reactions as described above.
Compounds of formula (I) where R1 is -NR5R6 may be prepared from compounds of formula (4) by standard methods such as reductive amination with an appropriate aldehyde or ketone, or by treatment with an appropriate alkyl halide in the presence of a suitable base.
Compounds of formula (I) where R1 is -NRaCONR5R6, where Ra is H, may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate isocyanate R5NCO or R6NCO) or carbamoyl chloride R5R6NC(0)C1).
Compounds of formula (I) where R1 is NRaCONR5R6, where Ra is alkyl, may be prepared as described above having first performed an additional alkylation step as described above.
Compounds of formula (I) where R1 is -NRaCOR4, -NRaC02R4 or -NRaS02R4, where Ra is H, may be prepared from compounds of formula (4) by standard methods such as treatment with an appropriate acid chloride (R5COCl), chloroformate (CICO2R4) or sulfonyl chloride (R4S02C1) in the presence of a suitable base. Compounds of formula (I) where R1 is -NR4COR4, -NRaC02R4 or -NRaS02R4, where Ra is alkyl may be prepared as described above having first performed an additional alkylation step as described above. Compounds of formula (I) where Ri is -N¾ may also be synthesized by standard methods such as those illustrated in Reaction Scheme 2.
Reaction Sche
Figure imgf000019_0001
Compounds of formula (4) may be prepared from compounds of formula (10) by standard methods such as aryl or heteroaryl coupling reactions as described above.
Compounds of formula (10) where R3 is arylalkyl are can be prepared by methods analogous to those described in the literature. For example compounds of formula (10) where R3 is arylalkyl may be prepared from compounds of formula (9) where R3 is arylalkyl by standard methods such as treatment with isoamyl nitrite or sodium nitrite. Compounds of formula (9) where R3 is arylalkyl can be prepared by methods described in the literature such as the treatment of the compound of formula (8) with an appropriate amine in a suitable solvent at elevated temperature.
Compounds of formula (10) can also be prepared by a modified version of Reaction Scheme 2, in which the 5-amino group of compound (8) is protected, as shown in Reaction Scheme 2A.
Reaction Scheme 2A:
Figure imgf000019_0002
(8A) R = H, formyl (9A) (10)
Compounds of formula (10) can be prepared from compounds of formula (9 A) by standard methods such as treatment with isoamyl nitrite or sodium nitrite. Compounds of formula (9A) where R3 is arylalkyl can be prepared by methods such as the treatment of the compound of formula (8A) with an appropriate amine in a suitable solvent at elevated temperature.
Compounds of formula (I) where R1 is -N¾ may also be synthesized by standard methods such as those illustrated in Reaction Scheme 3.
Reaction Scheme 3
Figure imgf000020_0001
Figure imgf000020_0002
Compounds of formula (4) where R3 is arylalkyl can be prepared from compounds of formula (15) where R3 is arylalkyl by standard methods such as treatment with isoamyl nitrite. Compounds of formula (15) where R3 is arylalkyl may be prepared from compounds of formula (14) where R3 is arylalkyl by standard methods such as reduction with hydrogen in the presence of a suitable catalyst such as Pd. Compounds of formula (14) where R3 is arylalkyl may be prepared from compounds of formula (13), where X is a suitable leaving group such as a tosylate or triflate group, by standard methods such as treatment with a suitable amine in the presence of a suitable base such as triethylamine. Compounds of formula (13) where X is a suitable leaving group are either known in the literature or may be prepared from compounds of formula (12) by standard methods such as treatment with tosyl chloride or triflic anhydride in the presence of a suitable base such as triethylamine or 2,6-dimethylpyridine. Compounds of formula (12) are either known in the literature or may be prepared from the known compound of formula (11) by standard methods such as aryl or heteroaryl coupling reactions as described above.
Other compounds of formula (I) may be prepared by standard methods such as those illustrated in Reaction Scheme 4. Reaction Scheme 4
Figure imgf000021_0001
Compounds of formula (I) can be prepared from compounds of formula (16) by standard methods such as aryl or heteroaryl coupling reactions as described above.
Compounds of formula (I) where R1 is alkoxy, aryloxy, alkylthio, arylthio, -CN or
can be prepared from compounds of formula (I) where R1 is halogen by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (NHR5R6) in the presence of a suitable base if required. Compounds of formula (1) where R1 is halogen may be prepared from compounds of formula (16) where R1 is halogen as described above. Compounds of formula (16) where R1 is halogen are either known in the literature or may be prepared by methods analogous to those described in the literature.
Compounds of formula (I) where R1 is -NRaCONR5R6 , -NRaCOR4, -NRaC02R4 or -NRaSC>2R4, where Ra is alkyl or aryl, may be prepared from compounds of formula (I) where R1 is -NR5R6, where R5 is -H and R6 is alkyl or aryl, by the methods described above.
In certain cases it may be advantageous to prepare a compound of where R3 is selected to perform the function of a protecting group, for example a suitable protecting group would be a benzyl group or substituted benzyl group such as a 3,4- dimethoxybenzyl group. Compounds of this nature may prepared as described above and the protecting group R3 may be removed by standard methods such as treatment with, for example, TFA to give a compound where R3 is -H. Compounds of formula (I) where R3 is -H may then be used to prepare other compounds of formula (I), where R3 is as previously defined, by the methods described above.
In particular, compound of formula (I) can be prepared according to Reaction
Scheme 5. Reaction Scheme 5
Figure imgf000022_0001
(13) + (NH2R3) NEt3'
Figure imgf000022_0002
(14) (4)
Substituted pyrimidine (12) can be prepared from precursor (11) and an aryl- or heteroaryl boronic acid as shown; or an aryl- or heteroaryl trialkyl tin compound can be used in place of the aryl or heteroaryl boronic acid. Compound (12) is treated to convert the hydroxide group into a good leaving group. Reaction of (13) with an appropriate amine, NH2R3, affords compound (14), which is converted to a compound of formula (4) by treatment with a suitable reducing agent, followed by sodium nitrite.
Compounds of formula (I) can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids and bases. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl- propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen- containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained.
The compound may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
Pharmaceutical compositions can include a compound of formula (I), or pharmaceutically acceptable derivatives thereof, together with any pharmaceutically acceptable carrier. The term "carrier" as used herein includes acceptable adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long- chain alcohol diluent or dispersant.
The pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic agent, if any, with which the ingredient is co-administered.
A pharmaceutical composition can include an effective amount of a compound of formula (I). An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the judgment of the treating physician. For reference, see Freireich et al., Cancer Chemother. Rep. 1966, 50, 219 and Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. Dosage levels of between about 0.001 and about 100 mg/kg body weight per day, preferably between about 0.1 and about 10 mg/kg body weight per day of the active ingredient compound are useful. The following examples are for the purpose of illustration only and are not intended to be limiting.
Examples
The compounds presented in Table 1 are prepared using methods analogous to those described above. In T ds are described by the general formula:
Figure imgf000026_0001
TABLE 1
Figure imgf000026_0002
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-chlorofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chlorofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
(5-bromofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
[l,2,3]triazolo[4,5-d]pyrimidin- (5-bromofuran-2-yl)-3H-
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000027_0001
[l,2,3]triazolo[4,5-d]pyrimidin- (3-bromofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methylfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NC 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-cyanofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- °Q [l,2,3]triazolo[4,5-d]pyrimidin- (5-cyanofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- cO [l,2,3]triazolo[4,5-d]pyrimidin- (4-cyanofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-cyanofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-cyanofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -hydroxyfur an -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-hydroxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 -hydroxyfur an -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-hydroxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxyfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-hydroxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxyfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxyfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methoxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxyfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methoxyfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethylfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- cO 3H-[l,2,3]triazolo[4,5- (5-trifluoromethylfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethylfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- cQ 3H-[l,2,3]triazolo[4,5- (4-trifluoromethylfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-trifluoromethylfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-trifluoromethylfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OHC 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5 - f ormylfur an -2 -y 1) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4 - f ormylfur an -2 -yl) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
0N^-CHO (3-formylfuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylfuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3CO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethoxyfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-trifluoromethoxyfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxyfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-trifluoromethoxyfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
<^^OCF3 (3-trifluoromethoxyfuran-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-trifluoromethoxyfuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
02N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitrofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitrofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitrofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-nitrofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-nitrofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-nitrofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxypyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-hydroxypyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxypyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxypyrrol-2-yl)-3H-
Figure imgf000033_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxypyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
HN^ [l,2,3]triazolo[4,5-d]pyrimidin- (4-methoxypyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxypyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methoxypyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluoromethylpyrrol-2 -yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-trifluoromethylpyrrol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethylpyrrol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-trifluoromethylpyrrol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -trifluoromethylpyrrol-2 -yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-trifluoromethylpyrrol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OHC 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
HN^-CHO (3-formylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000034_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thiolpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-thiolpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-thiolpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-thiolpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
HN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- ^Ac (3-acetylpyrrol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-acetylpyrrol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (thiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (thiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluorothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4 - fluoro thiophen -2 - yl) - 3 H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-fluorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-fluorothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chlorothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chlorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-chlorothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-chlorothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chlorothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-bromothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methylthiophen- 2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylthiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylthiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylthiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylthiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methylthiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
(5-cyanothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
[l,2,3]triazolo[4,5-d]pyrimidin- (5-cyanothiophen-2-yl)-3H-
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-cyanothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-cyanothiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-cyanothiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -hydroxy thiophen- 2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-hydroxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 -hydroxy thiophen- 2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-hydroxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxythiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-hydroxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxythiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxythiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methoxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxythiophen-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methoxythiophen-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-acetylpyrazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-acetylpyrazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylpyrazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylpyrazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (isoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000043_0001
[l,2,3]triazolo[4,5-d]pyrimidin- (isoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-fluoroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-fluoroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluoroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000043_0002
[l,2,3]triazolo[4,5-d]pyrimidin- (4-fluoroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
/Cl (3-chloroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chloroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chloroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000043_0003
[l,2,3]triazolo[4,5-d]pyrimidin- (4-chloroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromoisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-bromoisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromoisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000043_0004
[l,2,3]triazolo[4,5-d]pyrimidin- (4-bromoisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodoisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodoisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000044_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethylisoxazol-5- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000045_0001
yl)-3H-[l ,2,3]triazolo[4,5- (4-trifluoromethylisoxazol-5-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-formylisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000045_0002
[l,2,3]triazolo[4,5-d]pyrimidin- (4-formylisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-trifluoromethoxyisoxazol-5- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (3-trifluoromethoxyisoxazol-5-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxyisoxazol-5- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000045_0003
yl)-3H-[l ,2,3]triazolo[4,5- (4-trifluoromethoxyisoxazol-5-yl)- d] pyrimidin -5 - amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
N0 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-nitroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-nitroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitroisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000045_0004
[l,2,3]triazolo[4,5-d]pyrimidin- (4-nitroisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-aminoisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-aminoisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-aminoisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000045_0005
[l,2,3]triazolo[4,5-d]pyrimidin- (4-aminoisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-thiolisoxazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-thiolisoxazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-miolimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
ΗΝγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiolimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thiolimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
ΗΝγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (4-thiolimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
ΗΝγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
ΗΝγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
f=\ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (thiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (thiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluorothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- δγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluorothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluorothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-fluorothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- βγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-chlorothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chlorothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- βγΝa [l,2,3]triazolo[4,5-d]pyrimidin- (4-chlorothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br^ ^ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- βγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000050_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
F3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
)=\ (5 -trifluoromethylthiazol-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- δγΝ 3H-[l,2,3]triazolo[4,5- (5-ttifluoromethylthiazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
,CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- r=\ (4-trifluoromethylthiazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- δγΝ 3H-[l,2,3]triazolo[4,5- (4-ttifluoromethylthiazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OHC 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylthiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- δγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylthiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylthiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- β rγ=\Ν [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylthiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3CO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethoxythiazol-2- methyloxy)pyridin-2-ylmethyl]-7- βγΝ yl)-3H-[l ,2,3]triazolo[4,5- (5-ttifluoromethoxythiazol-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
PCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxythiazol-2- methyloxy)pyridin-2-ylmethyl]-7- β rγ=\Ν yl)-3H-[l ,2,3]triazolo[4,5- (4-ttifluoromethoxythiazol-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
02N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitrothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- β HγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitrothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitrothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- βγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (4-nitrothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
H2N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- β HγΝ [l,2,3]triazolo[4,5-d]pyrimidin- (5-aminothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-aminothiazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- 3γΝ [l,2,3]triazolo[4,5-d]pyrimidin- (4-aminothiazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000052_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromoimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
(2-iodoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
[l,2,3]triazolo[4,5-d]pyrimidin- (2-iodoimidazol-5-yl)-3H-
Figure imgf000053_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodoimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-methylimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-methylimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-cyanoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-cyanoimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-cyanoimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-hydroxyimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-hydroxyimidazol-5-yl)-3H-
Figure imgf000053_0002
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
Η Ν ΧΑΌΗ (4-hydroxyimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-hydroxyimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
"V. 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-methoxyimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
HN [l,2,3]triazolo[4,5-d]pyrimidin- (2-methoxyimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000054_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
HN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- -NH2 (4-aminoimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-aminoimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
HS 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
(2-thiolimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
[l,2,3]triazolo[4,5-d]pyrimidin- (2-thiolimidazol-5-yl)-3H-
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
HN .SH (4-thiolimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-thiolimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylimidazol-5-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000055_0001
[l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylimidazol-5-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (pyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-fluoropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-fluoropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluoropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluoropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluoropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-fluoropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-fluoropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-fluoropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -chlorop yridin -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-chloropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CI 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -chlorop yridin -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chloropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 -chlorop yridin -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-chloropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -chlorop yridin -2 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chloropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-bromopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
r* 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N^ Br [l,2,3]triazolo[4,5-d]pyrimidin- (3-bromopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl rr1 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
ίΓΥ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-cyanopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-cyanopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-cyanopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-cyanopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
rrCN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-cyanopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-cyanopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-cyanopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-hydroxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-hydroxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-hydroxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
0H 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-hydroxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-hydroxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N^ OH [l,2,3]triazolo[4,5-d]pyrimidin- (3-hydroxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methoxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methoxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxypyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methoxypyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethylpyridin-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-trifluoromethylpyridin-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluoromethylpyridin-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-trifluoromethylpyridin-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethylpyridin-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-trifluoromethylpyridin-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -trifluoromethylpyridin-2-yl) - methyloxy)pyridin-2-ylmethyl]-7-
N^ CF3 3H-[l,2,3]triazolo[4,5- (3-trifluoromethylpyridin-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-formylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
[TYCHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-formylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N^ CHO [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethoxypyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (6-trifluoromethoxypyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
5 -amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethoxypyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (5-trifluoromethoxypyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxypyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (4-trifluoromethoxypyridin-2-yl)-
Figure imgf000059_0001
d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-trifluoromethoxypyridin-2- methyloxy)pyridin-2-ylmethyl]-7-
N^ OCF3 yl)-3H-[l ,2,3]triazolo[4,5- (3-trifluoromethoxypyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-nitropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-nitropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-nitropyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Ν^ Ν02 [l,2,3]triazolo[4,5-d]pyrimidin- (3-nitropyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6 - aminopyridin -2 -y 1) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5 - aminopyridin -2 -y 1) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- rrN¾ (4-aminopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4 - aminopyridin -2 -y 1) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-aminopyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N^ NH2 [l,2,3]triazolo[4,5-d]pyrimidin- (3-aminopyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-thiolpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-thiolpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiolpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiolpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thiolpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-thiolpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-thiolpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-thiolpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 - acetylpyridin -2 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-acetylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 - acetylpyridin -2 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylpyridin-2-yl)-3H-
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 - acetylpyridin -2 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-acetylpyridin-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N^ Ac [l,2,3]triazolo[4,5-d]pyrimidin- (3-acetylpyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (pyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (pyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2 -fluoropyrimidin -4 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-fluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -fluoropyrimidin -4 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-fluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -fluoropyrimidin -4 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-chloropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2 - chloropyrimidin -4 - yl) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- rNYcl (6-chloropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6 - chloropyrimidin -4 - yl) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chloropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5 - chloropyrimidin -4 - yl) - 3 H -
Figure imgf000062_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
Ύ i (2 -bromopyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-bromopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
γΒΓ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -bromopyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-bromopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -bromopyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-iodopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-iodopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
Ύ i (2 -methylpyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-methylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -methylpyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methylpyrimidin-4 - yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-cyanopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-cyanopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-[5-(tetrahydrofuran-3-yl- iNyCN 3-(4-amino-3-methylbenzyl)-7- (6-cyanopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-cyanopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-cyanopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-cyanopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
ΗΟγ Ν 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-hydroxypyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-hydroxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxypyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-hydroxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -hydroxypyrimidin-4 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-hydroxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-methoxypyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-methoxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxypyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methoxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-memoxypyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxypyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-trifluoropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-trifluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-trifluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluoropyrimidin-4 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-trifluoropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-formylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2 - f ormylpyrimidin-4 - yl) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6 - f ormylpyrimidin-4 - yl) - 3 H - 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5 - f ormylpyrimidin-4 - yl) - 3 H -
Figure imgf000064_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3CO N 3- (4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
T Ί (2-trifluoromethoxypyrimidin- methyloxy)pyridin-2-ylmethyl]-7-
4- yl)-3H-[l,2,3]triazolo[4,5- (2-triiluoromethoxypyrimidin-4-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
OCF3 3- (4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethoxypyrimidin- methyloxy)pyridin-2-ylmethyl]-7-
4- yl)-3H-[l,2,3]triazolo[4,5- (6-triiluoromethoxypyrimidin-4-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3- (4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluoromethoxypyrimidin- methyloxy)pyridin-2-ylmethyl]-7-
4- yl)-3H-[l,2,3]triazolo[4,5- (5-triiluoromethoxypyrimidin-4-yl)-
Figure imgf000064_0002
d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- if (2 -nitropyrimidin -4 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-nitropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -nitropyrimidin -4 -y 1) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-nitropyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitropyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitropyrimidin-4-yl)-3H-
Figure imgf000065_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
H2N N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
T (2-aminopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-aminopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-aminopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminopyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- '- -NH2 [l,2,3]triazolo[4,5-d]pyrimidin- (5-aminopyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-thiolpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-thiolpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- iVSH (6-thiolpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-thiolpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiolpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiolpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (2-acetylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-acetylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-acetylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-acetylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylpyrimidin-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylpyrimidin-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (benzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (benzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-fluorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-fluorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-fluorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-fluorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-fluorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-fluorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-fluorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-chlorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chlorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CI 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chlorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-chlorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chlorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chlorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-chlorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chlorobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-chlorobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-bromobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-bromobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-bromobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-bromobenzofuran-2-yl)-3H-
Br 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodobenzofuran-2-yl)-3H-
Figure imgf000067_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-iodobenzofuran-2-yl)-3H-
1 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -methylbenzofuran-2 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methylbenzofuran-2 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -methylbenzofuran-2 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-methylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-cyanobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-cyanobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-cyanobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-cyanobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-cyanobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-cyanobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-cyanobenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-cyanobenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-cyanobenzofuran-2-yl)-3H-
CN 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -hydroxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-hydroxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-hydroxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-hydroxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -hydroxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-hydroxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-hydroxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -hydroxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-hydroxybenzofuran-2-yl)-3H-
OH d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -methoxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-methoxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
o^ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-methoxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methoxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-methoxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-methoxybenzofuran-2-yl)-3H-
1 d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -methoxybenzofuran-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-methoxybenzofuran-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -trifluoromethylbenzofuran- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-trifluoromethylbenzofuran-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethylbenzofuran- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-trifluoromethylbenzofuran-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluoromethylbenzofuran- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-trifluoromethylbenzofuran-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethylbenzofuran- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-trifluoromethylbenzofuran-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -trifluoromethylbenzofuran- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-trifluoromethylbenzofuran-2-yl)-
CF3 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
OHC 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-formylbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000071_0001
Figure imgf000072_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiolbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiolbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-thiolbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-thiolbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-thiolbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-thiolbenzofuran-2-yl)-3H-
SH 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-acetylbenzofuran-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-acetylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 - acetylbenzof uran-2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 - acetylbenzof uran-2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 - acetylbenzof uran-2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-acetylbenzofuran-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 - acetylbenzof uran-2 -yl) - 3 H - methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-acetylbenzofuran-2-yl)-3H-
Ac 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (indol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
H [l,2,3]triazolo[4,5-d]pyrimidin- (indol-2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-fluoroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-fluoroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H
amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluoroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-fluoroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluoroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluoroindol-2-yl)-3H-
H 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-fluoroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
HXXF [l,2,3]triazolo[4,5-d]pyrimidin- (6-fluoroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-fluoroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-fluoroindol-2-yl)-3H-
F 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-chloroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-chloroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H
amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chloroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-chloroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chloroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chloroindol-2-yl)-3H-
H 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
" 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chloroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000074_0001
[l,2,3]triazolo[4,5-d]pyrimidin- (6-chloroindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chloroindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-chloroindol-2-yl)-3H-
CI 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-bromoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H
amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromoindol-2-yl)-3H-
H 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
' ^ ^^Br [l,2,3]triazolo[4,5-d]pyrimidin- (6-bromoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-bromoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-bromoindol-2-yl)-3H-
Br 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-iodoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H
amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5-
H amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodoindol-2-yl)-3H-
H 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
HXX, 1 [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodoindol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodoindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-iodoindol-2-yl)-3H-
1 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylindol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methylindol-2-yl)-3H-
H 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000076_0001
Figure imgf000077_0001
amine
Figure imgf000078_0001
5 -amine
Figure imgf000079_0001
amine
Figure imgf000080_0001
Figure imgf000081_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-chlorobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-chlorobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CI 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chlorobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-chlorobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-chlorobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chlorobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-chlorobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chlorobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-chlorobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -bromobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-bromobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-bromobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -bromobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-bromobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-bromobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -bromobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-bromobenzothiophen-2-yl)-3H-
Br d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-iodobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-iodobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-iodobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-iodobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-iodobenzothiophen-2-yl)-3H-
1 d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-methylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-methylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-methylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-methylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-methylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-methylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -cyanobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-cyanobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-cyanobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -cyanobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-cyanobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-cyanobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-cyanobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -cyanobenzothiophen-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-cyanobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (3-hydroxybenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [1,2,3] triazolo [4,5 -d]pyrimidin-5 - amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-hydroxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (4-hydroxybenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [1,2,3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-hydroxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (5-hydroxybenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (6-hydroxybenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [ 1 ,2, 3] triazolo [4,5 -d]pyrimidin-5 - amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-hydroxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (7-hydroxybenzothiophen-2-yl)-3H-
OH d]pyrimidin-5-amine [1,2,3] triazolo [4,5 -d]pyrimidin-5 - amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (3-methoxybenzothiophen-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (4-methoxybenzothiophen-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (5-methoxybenzothiophen-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (6-methoxybenzothiophen-2-yl)-
1 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-methoxybenzothiophen-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (7-methoxybenzothiophen-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
F3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzothiophen- (3-trifluoromethylbenzothiophen-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzothiophen- (4-trifluoromethylbenzothiophen-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzothiophen- (5-trifluoromethylbenzothiophen-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzothiophen- (6-trifluoromethylbenzothiophen-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzothiophen- (7-trifluoromethylbenzothiophen-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
Figure imgf000086_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethyoxybenzothiophe (7-
OCF3 n-2-yl)-3H-[l ,2,3]triazolo[4,5- trifluoromethyoxybenzothiophen-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
02N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-nitrobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-nitrobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitrobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4 - nitrobenzo thiophen-2 - yl) - 3H - d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitrobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5 - nitrobenzo thiophen-2 - yl) - 3H - d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitrobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6 - nitrobenzo thiophen-2 - yl) - 3H - d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-nitrobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7 - nitrobenzo thiophen-2 - yl) - 3H -
N02 d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
H2N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-aminobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-aminobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 - aminobenzo thiophen-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-aminobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-aminobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 - aminobenzo thiophen-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-aminobenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminobenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-aminobenzothiophen-2-yl)-3H-
NH2 d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-thiolbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-thiolbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thiolbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-thiolbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiolbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-thiolbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-thiolbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-thiolbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-thiolbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-thiolbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-acetylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-acetylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-acetylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-acetylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-X . (6-acetylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-acetylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-acetylbenzothiophen-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-acetylbenzothiophen-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (isoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (isoxazol-3-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-(4-amino-3-methylbenzyl)-7-(5-
(5-fluoroisoxazol-3-yl)-3H- fluoroisoxazol-3-yl)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5-
5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-(4-amino-3-methylbenzyl)-7-(4- (4-fluoroisoxazol-3-yl)-3H- fluoroisoxazol-3-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
/Cl (5 -chloroisoxazol- 3 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chloroisoxazol-3-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chloroisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H-
Figure imgf000089_0001
[l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5-
Figure imgf000089_0002
5 -amine amine
Figure imgf000090_0001
d]pyrimidin-5-amine amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxyisoxazol-3- methyloxy)pyridin-2-ylmethyl]-3H-
Figure imgf000091_0001
yl)-3H-[l ,2,3]triazolo[4,5- [l,2,3]triazolo[4,5-d]pyrimidin-5- d]pyrimidin-5-amine amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitroisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitroisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H-
Figure imgf000091_0002
[l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
NH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-aminoisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H-
Figure imgf000091_0003
[l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thioisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thioisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H-
Figure imgf000091_0004
[l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylisoxazol-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- N (thiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (thiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
H (5-fluorothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- yN [l,2,3]triazolo[4,5-d]pyrimidin- (2-fluorothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluorothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
F-- N [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluorothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
P 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-chlorothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- ci-- N (4-chlorothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chlorothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- N [l,2,3]triazolo[4,5-d]pyrimidin- (2-bromothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-iodothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylthiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-methylthiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- N (4-methylthiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
H3C-- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylthiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-cyanothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-cyanothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000093_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
F3CO-- N (4-trifluoromethoxythiazol-4- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (5-trifluoromethoxythiazol-4-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitrothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- γ [l,2,3]triazolo[4,5-d]pyrimidin- (2-nitrothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
02N-- N (4-nitrothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitrothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-aminothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
H2N-- N (4-aminothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-aminothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-thiothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
HS- (4-thiothiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiothiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylthiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (2-acetylthiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- V (4-acetylthiazol-4-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Ac- N [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylthiazol-4-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (pyrazine-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (pyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000095_0001
Figure imgf000096_0001
amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxypyrazine-2-yl)-3H- methyloxy)pyridin-2-ylmethyi]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-hydroxypyrazine-2-yl)-3H-
Figure imgf000097_0001
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxypyrazine-2-yl)-3H- methyloxy)pyridin-2-ylmethyi]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methoxypyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxypyrazine-2-yl)-3H- methyloxy)pyridin-2-ylmethyi]-7-
Λ [l,2,3]triazolo[4,5-d]pyrimidin- (5-methoxypyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxypyrazine-2-yl)-3H- methyloxy)pyridin-2-ylmethyi]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (3-methoxypyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluromethylpyrazine-2-yl)- methyloxy)pyridin-2-ylmethyi]-7- 3H-[l,2,3]triazolo[4,5- (6 - trifluro me th yip yrazine -2 -y 1) - 3 H - d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluromethylpyrazine-2-yl) - methyloxy)pyridin-2-ylmethyi]-7- 3H-[l,2,3]triazolo[4,5- (5 - trifluro me th yip yrazine -2 -y 1) - 3 H - d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3 -trifluromethylpyrazine-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (3-trifluromethylpyrazine-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6 -f ormy lp yrazine -2 - yl) - 3 H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-formylpyrazine-2-yl)-3H-
Figure imgf000097_0002
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -f ormy lp yrazine -2 - yl) - 3 H- methyloxy)pyridin-2-ylmethyl]-7- if [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylpyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
N~ S (3 -f ormy lp yrazine -2 - yl) - 3 H- methyloxy)pyridin-2-ylmethyl]-7- ;HO [l,2,3]triazolo[4,5-d]pyrimidin- (3-formylpyrazine-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000098_0001
Figure imgf000099_0001
amine
Figure imgf000100_0001
Figure imgf000101_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluromethylpyridazine- 3 - methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (6-trifluromethylpyridazine-3-yl)- d]pyrimidin-5-amine 3H- [ 1 ,2,3]triazolo [4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluromethylpyridazine- 3 - methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (5 - trifluromethylpyridazine-3 -yl) -
Figure imgf000102_0001
d]pyrimidin-5-amine 3H- [ 1 ,2,3]triazolo [4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluromethylpyridazine- 3 - methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (4-trifluromethylpyridazine-3-yl)- d]pyrimidin-5-amine 3H- [ 1 ,2,3]triazolo [4,5-d]pyrimidin- 5 -amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
? (6-formylpyridazine-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-formylpyridazine-3-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylpyridazine-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylpyridazine-3-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylpyridazine-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylpyridazine-3-yl)-3H-
Figure imgf000102_0002
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluromethoxypyridazine-3- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (6-trifluromethoxypyridazine-3 -yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -trifluromethoxypyridazine-3 - methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (5-trifluromethoxypyridazine-3-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluromethoxypyridazine-3- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l ,2,3]triazolo[4,5- (4-trifluromethoxypyridazine-3 -yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
5 -amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitropyridazine-3-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6 - nitropyridazine -3 - yl) - 3 H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
K rF (6-fluorobenzimidazol-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-fluorobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chlorobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-chlorobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- :acl (6-chlorobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-chlorobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -bromobenzimidazol-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-bromobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromobenzimidazol-2 -yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-bromobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodobenzimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-iodobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodobenzimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -methylbenzimidazol-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-methylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylbenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-methylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-cyanobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-cyanobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-cyanobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-cyanobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-hydroxybenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-hydroxybenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxybenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-hydroxybenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
ocH3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -methoxybenzimidazol-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-methoxybenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxybenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-methoxybenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzimidazol-2- (7-ttifluoromethylbenzimidazol-2- yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethylbenzimidazol-2- (6-ttifluoromethylbenzimidazol-2- yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-formylbenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-formylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylbenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- inte 10 3H-[l,2,3]triazolo[4,5- (6-formylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
0CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxybenzimidazol- (7-ttifluoromethoxybenzimidazol-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxybenzimidazol- (6-trifluoromethoxybenzimidazol-2-
2-yl)-3H-[l,2,3]triazolo[4,5- yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine d]pyrimidin-5 -amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -nitrobenzimidazol-2 -yl)- 3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-nitrobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
|_| 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitrobenzimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-nitrobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-aminobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- i-fccr (6-aminobenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-aminobenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-thiobenzimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-thiobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- κϊχΓ (6-thiobenzimidazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-thiobenzimidazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-acetylbenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (7-acetylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
H 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-acetylbenzimidazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (6-acetylbenzimidazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (benzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (benzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-fluorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-fluorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-fluorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-fluorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-fluorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-fluorobenzoxazol-2-yl)-3H-
F 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chlorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-chlorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chlorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-chlorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-chlorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-chlorobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-chlorobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-chlorobenzoxazol-2-yl)-3H-
CI 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-bromobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-bromobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-bromobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-bromobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-bromobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-bromobenzoxazol-2-yl)-3H-
Br 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-iodobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-Xr' (6-iodobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-iodobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-iodobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-iodobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-iodobenzoxazol-2-yl)-3H-
1 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-methylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-methylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-methylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-methylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-methylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000114_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methoxybenzoxazol-2-yl) - methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000115_0001
3H-[l,2,3]triazolo[4,5- (5-methoxybenzoxazol-2-yl)-3H- d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxybenzoxazol-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-methoxybenzoxazol-2-yl)-3H- ocH3 d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-trifluoromethylbenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-trifluoromethylbenzoxazol-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
K T (6-trifluoromethylbenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-trifluoromethylbenzoxazol-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethylbenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-trifluoromethylbenzoxazol-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
HOQ (4-trifluoromethylbenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-trifluoromethylbenzoxazol-2-yl)-
CF3 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-formylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-formylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-formylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-formylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
N-^^CHO [l,2,3]triazolo[4,5-d]pyrimidin- (5-formylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-formylbenzoxazol-2-yl)-3H-
CHO 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-trifluoromethoxybenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-trifluoromethoxybenzoxazol-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethoxybenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-trifluoromethoxybenzoxazol-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethoxybenzoxazol- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000116_0001
2-yl)-3H-[l,2,3]triazolo[4,5- (5-trifluoromethoxybenzoxazol-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-trifluoromethoxybenzoxazol- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-trifluoromethoxybenzoxazol-2-
OCF3 d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-nitrobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-nitrobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitrobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-nitrobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- XX¾ (5-nitrobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-nitrobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitrobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-nitrobenzoxazol-2-yl)-3H-
N02 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7 - aminobenzoxazol-2-yl) - 3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-aminobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000117_0001
[l,2,3]triazolo[4,5-d]pyrimidin- (5 - aminobenzoxazol-2-yl) - 3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-aminobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-aminobenzoxazol-2-yl)-3H-
NH2 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-thiobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-thiobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
H SH (6-thiobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-thiobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thiobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-thiobenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-thiobenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-thiobenzoxazol-2-yl)-3H-
SH 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-acetylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (7-acetylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-acetylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (6-acetylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (5-acetylbenzoxazol-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylbenzoxazol-2-yl)-3H- methyloxy)pyridin-2-ylmethyl]-7- [l,2,3]triazolo[4,5-d]pyrimidin- (4-acetylbenzoxazol-2-yl)-3H-
Ac 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000118_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8 -chloroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (8-chloroimidazo [ 1 ,2-a]pyridin-2-
CI d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (3-bromoimidazo[l,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (5-bromoimidazo[l,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromoimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (6-bromoimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (7-bromoimidazo[l,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (8-bromoimidazo[l,2-a]pyridin-2-
Br [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodoimidazo[l,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-iodoimidazo[l,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodoimidazo[l,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-iodoimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-iodoimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodoimidazo[l,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-iodoimidazo[l,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-iodoimidazo[l,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (8-iodoimidazo[l,2-a]pyridin-2-yl)-
1 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methylimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (3-methylimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methylimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (5-methylimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methylimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (6-methylimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-methylimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (7-methylimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-methylimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (8-methylimidazo[ 1 ,2-a]pyridin-2-
CN [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
O 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-hydroxyimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (3-hydroxyimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-hydroxyimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (5-hydroxyimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
Γ-Ν y 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-hydroxyimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (6-hydroxyimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-hydroxyimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (7-hydroxyimidazo[ 1 ,2-a]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-hydroxyimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (8-hydroxyimidazo[l,2-a]pyridin-2-
OH [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
H3CO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-methoxyimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (3-methoxyimidazo[l,2-a]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
OCH3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-methoxyimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (5-methoxyimidazo [ 1 ,2-a]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxyimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (6-methoxyimidazo[l,2-a]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-methoxyimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (7-methoxyimidazo [ 1 ,2-a]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-methoxyimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (8-methoxyimidazo[l,2-a]pyridin-
OCH3 [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3C 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-trifluoromethylimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (3-trifluoromethylimidazo [ 1 ,2- [l,2,3]triazolo[4,5-d]pyrimidin- a]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-trifluoromethylimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyridin-2-yl)-3H- (5-trifluoromethylimidazo [ 1 ,2- [l,2,3]triazolo[4,5-d]pyrimidin- a]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethylimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000121_0001
a]pyridin-2-yl)-3H- (6-trifluoromethylimidazo [ 1 ,2- [l,2,3]triazolo[4,5-d]pyrimidin- a]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
Figure imgf000122_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo [1,2- (6-trifluoromethoxyimidazo [ 1 ,2- a]pyridin-2-yl)-3H- a]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo [1,2- (7-trifluoromethoxyimidazo [ 1 ,2- a]pyridin-2-yl)-3H- a]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo [1,2- (8-trifluoromethoxyimidazo [ 1 ,2-
OCF3 a]pyridin-2-yl)-3H- a]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
02N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-nitroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-nitroimidazo[l ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-nitroimidazo[l ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- ι^ χΝθ2 (6-nitroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-nitroimidazo[l ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-nitroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-nitroimidazo[l ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-nitroimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (8-nitroimidazo[l ,2-a]pyridin-2-yl)-
N02 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
H2N 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-aminoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-aminoimidazo[l,2-a]pyridin-2-
1 d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-aminoimidazo[l,2-a]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7-
Figure imgf000124_0001
2-yl)-3H-[l,2,3]triazolo[4,5- (6-aminoimidazo [ 1 ,2-a]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-aminoimidazo[l,2-a]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-aminoimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (8-aminoimidazo[l,2-a]pyridin-2-
NH2 d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
HS 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-thioimidazo[ 1 ,2-a]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (3-thioimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-thioimidazo[ 1 ,2-a]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (5-thioimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-thioimidazo[ 1 ,2-a]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (6-thioimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-thioimidazo[ 1 ,2-a]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7-
N^^^SH yl)-3H-[l,2,3]triazolo[4,5- (7-thioimidazo [ 1 ,2-a]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-thioimidazo[ 1 ,2-a]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (8-thioimidazo [ 1 ,2-a]pyridin-2-yl)-
SH d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-acetylimidazo [ 1 ,2-a]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-acetylimidazo[l,2-a]pyridin-2-
1 d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
Figure imgf000125_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
CI 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -chloroimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (5-chloroimidazo[l,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chloroimidazo [ 1 ,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (6-chloroimidazo[l,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8 -chloroimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (8-chloroimidazo[l,2-a]pyrazin-2-
CI [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (3-bromoimidazo[l,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (5-bromoimidazo[l,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- l^N^YBr (6-bromoimidazo[l,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (6-bromoimidazo[ 1 ,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (8-bromoimidazo [1,2- methyloxy)pyridin-2-ylmethyl]-7- a]pyrazin-2-yl)-3H- (8-bromoimidazo[l,2-a]pyrazin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (3-iodoimidazo[l,2-a]pyrazin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (3-iodoimidazo[l,2-a]pyrazin-2-yl)-
Figure imgf000126_0001
d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
1 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodoimidazo[l,2-a]pyrazin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-iodoimidazo[l,2-a]pyrazin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodoimidazo [ 1 ,2-a]pyrazin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-iodoimidazo[l,2-a]pyrazin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
pyrm n- -amne R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-fluoroimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5 -fluoroimidazo [4 ,5 -fe]pyridin-2 -
Figure imgf000132_0001
d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -chloroimidazo [4,5 -fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-chloroimidazo[4,5-fe]pyridin-2- Ν;ό d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5-amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chloroimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-chloroimidazo[4,5-fe]pyridin-2-
H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -chloroimidazo [4,5 -fejpyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-chloroimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5-amine
Br 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-bromoimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (7-bromoimidazo[4,5-fe]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-bromoimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (6-bromoimidazo[4,5-fe]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-bromoimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7-
Pj N Br fe]pyridin-2-yl)-3H- (5-bromoimidazo[4,5-fe]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-iodoimidazo [4,5 -fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-iodoimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
Figure imgf000132_0002
5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-iodoimidazo [4,5 -fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-iodoimidazo[4,5-fe]pyridin-2-yl)-
H d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-iodoimidazo [4,5 -fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-iodoimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
Figure imgf000133_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxyimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (6-methoxyimidazo[4,5-fe]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -methoxyimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (5-methoxyimidazo[4,5-fe]pyridin-
1 [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
CF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-trifluoromemylimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7-
HN fe]pyridin-2-yl)-3H- (7-trifluoromethylimidazo [4,5- [l,2,3]triazolo[4,5-d]pyrimidin- fe]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromemylimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (6-trifluoromethylimidazo [4,5- [l,2,3]triazolo[4,5-d]pyrimidin- fe]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-imidazo[4,5-fe]pyridin-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (5-imidazo[4,5-fe]pyridin-2-yl)-3H-
Figure imgf000134_0001
d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (7-formylimidazo[4,5-fe]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- H 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (6-formylimidazo[4,5-fe]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- fe]pyridin-2-yl)-3H- (5-formylimidazo[4,5-fe]pyridin-2-
Figure imgf000134_0002
[l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo[4,5- (7-trifluoromethoxyimidazo[4,5- fe]pyridin-2-yl)-3H- fe]pyridin-2-yl)-3H- H N [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo[4,5- (6-trifluoromethoxyimidazo[4,5- fe]pyridin-2-yl)-3H- fe]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo[4,5- (5-trifluoromethoxyimidazo[4,5-
Figure imgf000135_0001
fe]pyridin-2-yl)-3H- fe]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-nitroimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-nitroimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitroimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-nitroimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-nitroimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-nitroimidazo[4,5-fe]pyridin-2-yl)-
Figure imgf000135_0002
d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminoimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-aminoimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
Ν γΝΗ2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminoimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-aminoimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-aminoimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-aminoimidazo[4,5-fe]pyridin-2-
Figure imgf000135_0003
d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
SH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -thioimidazo [4,5 -fe]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7-
HN yl)-3H-[l,2,3]triazolo[4,5- (7-thioimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-thioimidazo[4,5-fe]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (6-thioimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5 -thioimidazo [4,5 -fe]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (5-thioimidazo[4,5-fe]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-acetylimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-acetylimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-acetylimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-acetylimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (5-acetylimidazo[4,5-fe]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (5-acetylimidazo[4,5-fe]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (imidazo [4 ,5 -c]pyridin-2-yl) - methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (imidazo[4,5-c]pyridin-2-yl)-3H-
H
d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
F 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-fluoroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-fluoroimidazo[4,5-c]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-fluoroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-fluoroimidazo[4,5-c]pyridin-2-
H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-fluoroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-fluoroimidazo[4,5-c]pyridin-2-
H T F N d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
CI 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-chloroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-chloroimidazo[4,5-c]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-chloroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-chloroimidazo[4,5-c]pyridin-2-
H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
Figure imgf000137_0001
R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
CN 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-cyanoirrudazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-cyanoimidazo[4,5-c]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-cyanoirrudazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-cyanoimidazo[4,5-c]pyridin-2-
H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-cyanoirrudazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-cyanoimidazo[4,5-c]pyridin-2-
Figure imgf000138_0001
d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
OH 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -hydroxyimidazo [4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (7-hydroxyimidazo[4,5-c]pyridin-2- [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5-
H 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl-
| Y\OH (6 -hydroxyimidazo [4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (6-hydroxyimidazo[4,5-c]pyridin-2-
H [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4 -hydroxyimidazo [4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (4-hydroxyimidazo[4,5-c]pyridin-2-
Figure imgf000138_0002
[l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
O^ 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -methoxyimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (7-methoxyimidazo[4,5-c]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5-
H 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-methoxyimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (6-methoxyimidazo[4,5-c]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5-
H
5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-methoxyimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (4-methoxyimidazo[4,5-c]pyridin- [l,2,3]triazolo[4,5-d]pyrimidin- 2-yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-trifluoromethylimidazo[4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (7-trifluoromethylimidazo [4,5- [l,2,3]triazolo[4,5-d]pyrimidin- c]pyridin-2-yl)-3H-
Figure imgf000138_0003
5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-trifluoromethylimidazo [4,5- methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (6-trifluoromethylimidazo [4,5-
H [l,2,3]triazolo[4,5-d]pyrimidin- c]pyridin-2-yl)-3H- 5 -amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-imidazo[4,5-c]pyridin-2-yl)- methyloxy)pyridin-2-ylmethyl]-7- 3H-[l,2,3]triazolo[4,5- (4-imidazo[4,5-c]pyridin-2-yl)-3H-
Figure imgf000139_0001
d]pyrimidin-5-amine [l,2,3]triazolo[4,5-d]pyrimidin-5- amine
CHO 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (7 - formylimidazo [4 , 5 -c]p yridin-2 - [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5-
H 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (6 - formylimidazo [4 , 5 -c]p yridin-2 -
H [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-formylimidazo [4,5 - methyloxy)pyridin-2-ylmethyl]-7- c]pyridin-2-yl)-3H- (4 - formylimidazo [4 , 5 -c]p yridin-2 -
CHO [l,2,3]triazolo[4,5-d]pyrimidin- yl)-3H-[l,2,3]triazolo[4,5- 5 -amine d]pyrimidin-5 -amine
OCF3 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo[4,5- (7-trifluoromethoxyimidazo[4,5- c]pyridin-2-yl)-3H- c]pyridin-2-yl)-3H-
H [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6- methyloxy)pyridin-2-ylmethyl]-7- trifluoromethoxyimidazo[4,5- (6-trifluoromethoxyimidazo[4,5-
H c]pyridin-2-yl)-3H- c]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4- methyloxy)pyridin-2-ylmethyl]-7- T trifluoromethoxyimidazo[4,5- (4-trifluoromethoxyimidazo[4,5-
H
OCNF3 c]pyridin-2-yl)-3H- c]pyridin-2-yl)-3H- [l,2,3]triazolo[4,5-d]pyrimidin- [l,2,3]triazolo[4,5-d]pyrimidin-5- 5 -amine amine
N02 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-nitroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7-nitroimidazo[4,5-c]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
H 5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-nitroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-nitroimidazo[4,5-c]pyridin-2-yl)-
H d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-nitroimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-nitroimidazo[4,5-c]pyridin-2-yl)-
N02 d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
NH2 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-aminoimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7 - aminoimidazo [4,5 -c]pyridin-2 - d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-aminoimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-aminoimidazo[4,5-c]pyridin-2-
H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-aminoimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-aminoimidazo[4,5-c]pyridin-2-
H T NHN 2 d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7 -thioimidazo [4,5 -c]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (7-thioimidazo[4,5-c]pyridin-2-yl)- d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin-
Figure imgf000140_0001
5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-mioimidazo[4,5-c]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (6-thioimidazo[4,5-c]pyridin-2-yl)-
H d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-mioimidazo[4,5-c]pyridin-2- methyloxy)pyridin-2-ylmethyl]-7- yl)-3H-[l,2,3]triazolo[4,5- (4-thioimidazo[4,5-c]pyridin-2-yl)-
Figure imgf000140_0002
d]pyrimidin-5-amine 3H-[l,2,3]triazolo[4,5-d]pyrimidin- 5 -amine
Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (7-acetylimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (7 - acetylimidazo [4,5 -c]pyridin-2- d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5-
H d]pyrimidin-5 -amine
N-^ Ac 3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (6-acetylimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (6-acetylimidazo[4,5-c]pyridin-2- H d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine R3 = 5-(tetrahydrofuran-3-yl-
R2 R3 = 4-amino-3-methylbenzyl methyloxy)pyridin-2-yl)methyl
3-(4-amino-3-methylbenzyl)-7- 3-[5-(tetrahydrofuran-3-yl- (4-acetylimidazo[4,5-c]pyridin- methyloxy)pyridin-2-ylmethyl]-7- 2-yl)-3H-[l,2,3]triazolo[4,5- (4-acetylimidazo[4,5-c]pyridin-2-
H T AcN d]pyrimidin-5-amine yl)-3H-[l,2,3]triazolo[4,5- d]pyrimidin-5 -amine
Adenosine Receptor Binding: Binding Affinities at hAi Receptors
The compounds are examined in an assay measuring in vitro binding to human adenosine Ai receptors by determining the displacement of the adenosine Ai receptor selective radioligand 8-Cyclopentyl-l,3-dipropylxanthine ([3H]DPCPX) using standard techniques. See, for example, Lohse MJ, et al., (1987), 8-Cyclopentyl-l,3- dipropylxanthine (DPCPX)-a selective high affinity antagonist radioligand for Al adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol, 336(2) :204- 10, which is incorporated by reference in its entirety.
Frozen CHO-K1 cells (transfected with a human adenosine Ai recepter expression vector) are homogenized in 130 mL of 50 mM Tris HC1 buffer (pH 7.5) containing 10 mM MgCl2, and 0.1 IU /mL adenosine deaminase per pellet using a Ultra-Turrax homogeniser. The resultant homogenate is kept for immediate use in the binding.
Binding assays are performed in a total volume of 250 μΐ^, containing [3H]- DPCPX (3.0 nM), membranes and additional drugs. Total binding is determined using drug dilution buffer (50 mM Tris-HCl pH:7.5, 10 mM MgCl2, 5% DMSO). Non-specific binding is determined using 300 μΜ N6-cyclohexyladenosine (CHA). Following incubation for 90 minutes at 21 °C, assays are terminated by rapid filtration with GF/B filters (presoaked in 0.1% (w/v) polyethylenimine) using a Canberra Packard filtermate 196, washed 3 times with ice-cold Tris-HCl (pH 7.4). Filters are left to dry overnight, and Microscint-0 scintillation fluid is then added to the filters. The filters are then left for at least 2 hours before the radioactivity is assessed using a Canberra Packard TopCount microplate scintillation counter.
To determine the free ligand concentration, three vials are counted with 25 μΐ. of [3H]DPCPX containing 4 mL of Ultima-Gold MV scintillant on a Beckman LS6500 multi-purpose scintillation counter.
Data is analysed using a 4 parameter logistical equation and non-linear regression which yields affinity constants (pICso), and slope parameters:
Figure imgf000142_0001
where E is the quantity of binding and [A] is the competitor concentration. The K; is then determined using the Cheng-Prusoff equation:
K: = -
1 +
IKD ]
Figure imgf000142_0002
The compounds are examined in an assay measuring in vitro binding to human adenosine A2A receptors by determining the displacement of the adenosine A2A receptor selective radioligand 4-[2-[[6-Amino-9-(N-ethyl- -D-ribofuranuronamidosyl)-9H-purin- 2-yl]amino]ethyl]benzenepropanoic acid hydrochloride ([3H]CGS-21680) using standard techniques. See, for example, Jarvis et al., J Pharmacol Exp Ther. , 251(3):888-93, which is incorporated by reference in its entirety.
Frozen HEK-293 cells are homogenized in 65 mL of 50 mM Tris HC1 buffer (pH
7.5) containing 10 mM MgCi2, and 0.1 IU /mL adenosine deaminase per pellet using a Ultra-Turrax homogenizer. The resultant homogenate is kept for immediate use in the binding assay.
Binding assays are performed in a total volume of 250 μΕ, containing [3H]-CGS21680 (20.0 nM), membranes and additional drugs. Total binding is determined using drug dilution buffer (50 mM Tris-HCl pH 7.5, lOmM MgCl2, 5% DMSO). Non-specific binding is determined using 300 μΜ CHA. Following incubation for 90 minutes at 21 °C, assays are terminated by rapid filtration with GF/B filters (presoaked in 0.1% (w/v) polyethylenimine) using a Canberra Packard filtermate 196, washed 3 times with ice-cold Tris-HCl (pH 7.4). Filters are left to dry overnight, and Microscint-0 scintillation fluid is then added to the filters. The filters are then left for at least 2 hours before the radioactivity was assessed using a Canberra Packard TopCount microplate scintillation counter.
To determine the free ligand concentration, three vials are counted with 25 μΕ of [3H]CGS21680 containing 4 mL of Ultima-Gold MV scintillant on a Beckman LS6500 multi-purpose scintillation counter. Data is analysed using a 4 parameter logistical equation and non-linear regression which yields affinity constants (pICso), and slope parameters:
Figure imgf000143_0001
where E is the quantity of binding and [A] is the competitor concentration. The ¾ determined using the Cheng-Prusoff equation:
1 +
IKD ]
Evaluation of Potential Anti-Parkinsonian Activity In Vivo: Haloperidol-Induced Hypolocomotion Model
It has previously been demonstrated that adenosine antagonists, such as theophylline, can reverse the behavioral depressant effects of dopamine antagonists, such as haloperidol, in rodents (see, for example, Mandhane S. N. et al., Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135-141, which is incorporated by reference in its entirety). This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects. Thus, the ability of novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential
antiparkinsonian efficacy.
Female TO mice (25-30 g) are used for all experiments. Animals are housed in groups of 8 (cage size-40 cm (width) by 40 cm (length) by 20 cm (height)) under 12 hour light/dark cycle (lights on 08:00), in a temperature (20 + 2 °C) and humidity (55 + 15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
Liquid injectable haloperidol (e.g., 1 mL Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg) are diluted to a final concentration of 0.02 mg/mL using saline. Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 mL/kg.
1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Test substances are typically administered 5-60 minutes prior to testing. The animals are then placed individually into clean, clear polycarbonate cages (20 cm (width) by 40 cm (length) by 20 cm (height), with a flat perforated, Perspex lid). Horizontal locomotor activity is determined by placing the cages within a frame containing a 3 by 6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.
Evaluation of Potential Anti-Parkinsonian Activity In Vivo: 6-QHDA Model
Parkinson's disease is a progressive neurodegenerative disorder characterized by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurons in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well coordinated movement (see, e.g., Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73-94, which is incorporated by reference in its entirety). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibers of the nigrostriatal neurons.
By unilaterally lesioning the nigrostriatal pathway on only one-side of the brain, a behavioral asymmetry in movement inhibition is observed. Although unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine - sensitive neurons on the lesioned side become supersenstive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning. The ability of compounds to induce contralateral rotations in 6-OHDA lesioned rats has proven to be a sensitive model to predict drug efficacy in the treatment of Parkinson's Disease. Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hour light/dark cycle (lights on 08:00), in a temperature (20 + 2 °C) and humidity (55 + 5%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.
Ascorbic acid, desipramine, 6-OHDA and apomorphine are obtained
commercially. 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine is dissolved in warm saline, and administered in a volume of 1 mL/kg. Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds are suspended in 8% Tween and injected in a volume of 2 mL/kg.
15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to
nondopamine neurons. Animals are then placed in an anaesthetic chamber, and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilized using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site. In order to lesion the nigrostriatal pathway, the injection cannula is slowly lowered to position above the right medial forebrain bundle at -3.2 mm anterior posterior, -1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 VAL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes, yielding a final dose of 8 μg. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioral testing.
Rotational behavior is measured using an eight station rotameter system, such as one sold by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter by 15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.
To reduce stress during drug testing, rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy.
Other embodiments are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I) :
Figure imgf000147_0001
wherein
R1 is selected from H, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio, heteroarylthio, halogen, -CN, -NR5R6, -N(Ra)C(0)R4, -N(Ra)C(0)NR5R6, -N(Ra)C02R4, and -N(Ra)S02R4;
R2 is aryl or heteroaryl; aryl optionally substituted by 1-5 substituents selected from R4; or heteroaryl optionally substituted by 1-5 substituents selected from R4;
L1 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra , -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, or -(CRaRb)n-0-;
Ar3 is arylene or heteroarylene;
each R4, independently, is H, oxo, CN, halogen, -CF3, -CHF2, -CHO, -OH, -N02, -SH, -OCF3, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C02Ra, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH2)n-alkyl, -(CH2)n-alkoxy, -(CH2)n-alkenyl, -(CH2)n-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -N(Ra)Rb, -N(Ra)-alkyl, -N(Ra)-alkoxy, -N(Ra)-alkenyl, -N(Ra)-alkynyl, -N(Ra)-cycloalkyl, -N(Ra)-aryl, -N(Ra)-heteroaryl, -N(Ra)-heterocyclyl, -SOm-alkyl, -SOm-alkoxy,
-SOm-alkenyl, -SOm-alkynyl, -SOm-cycloalkyl, -SOm-aryl, -SOm-heteroaryl,
-SOm-heterocyclyl, -N(Ra)C(0)-alkyl, -N(Ra)C(0)-alkoxy, -N(Ra)C(0)-alkenyl, -N(Ra)C(0)-alkynyl, -N(Ra)C(0)-cycloalkyl, -N(Ra)C(0)-aryl, -N(Ra)C(0)-heteroaryl, -N(Ra)C(0)-heterocyclyl, -C(0)N(Ra)-alkyl, -C(0)N(Ra)-alkoxy, -C(0)N(Ra)-alkenyl, -C(0)N(Ra)-alkynyl, -C(0)N(Ra)-cycloalkyl, -C(0)N(Ra)-aryl, -C(0)N(Ra)-heteroaryl, or -C(0)N(Ra)-heterocyclyl;
L2 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra , -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, -(CRaRb)n-N(Ra)C(0)-, -N(Ra)C(0)-(CRaRb)n-, -0-, or -(CRaRb)n- 0-; each R5 and each R6 are independently H, alkyl or aryl wherein alkyl and aryl are each independently substituted by 1-3 substituents selected from R7; or R5 and R6 together with the atom to which they are attached form a heterocyclic group which is optionally substituted by 1-3 substituents selected from R7;
i is an integer selected from 0, 1, 2, 3, 4 and 5;
R7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl;
each Ra, independently, is H, halogen, Ci-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
each Rb, independently, is H, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
or Ra and Rb together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
each m, independently, is 0, 1, or 2;
each n, independently, is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein R1 is -NH2.
3. The compound of claim 2, wherein R2 is heteroaryl optionally substituted by 1-5 substituents selected from R4.
4. The compound of claim 2, wherein R2 is aryl optionally substituted by 1-5 substituents selected from R4.
5. The compound of claim 2, wherein R2 is selected from the group consisting of furyl, phenyl, thiophenyl, oxazolyl, imidazolyl, triazolyl, indolyl, pyrollyl, pyridinyl, pyrimidinyl, pyrazolyl, isoxazolyl, isothiazolyl, benzofuranyl, benzothiophenyl, thiazolyl, and thiazolyl, each of which is optionally substituted by 1-5 substituents selected from R4.
The compound of claim 1 , wherein R2 has a formula selected from the
Figure imgf000149_0001
Figure imgf000149_0002
wherein each R , independently, is fluoro, chloro, bromo, iodo, methyl, cyano, hydroxy, methoxy, trifluoromethyl, formyl, trifluoromethoxy, nitro, amino, thiol, or acetyl; and
j is an integer selected from 0, 1, 2, 3, or 4.
7. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds of Table 1.
8. A compound of formula (la):
Figure imgf000150_0001
da)
wherein:
R2 is aryl or heteroaryl; aryl optionally substituted by 1-5 substituents selected from R4; or heteroaryl optionally substituted by 1-5 substituents selected from R4;
each R4, independently, is H, oxo, CN, halogen, -CF3, -CHF2, -CHO, -OH, -N02, -SH, -OCF3, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C02Ra, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclyl, -(CH2)n-alkyl, -(CH2)n-alkoxy, -(CH2)n-alkenyl, -(CH2)n-alkynyl, -(CH2)n-cycloalkyl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)n-heterocyclyl, -N(Ra)Rb, -N(Ra)-alkyl, -N(Ra)-alkoxy, -N(Ra)-alkenyl, -N(Ra)-alkynyl, -N(Ra)-cycloalkyl, -N(Ra)-aryl, -N(Ra)-heteroaryl, -N(Ra)-heterocyclyl, -SOm-alkyl, -SOm-alkoxy,
-SOm-alkenyl, -SOm-alkynyl, -SOm-cycloalkyl, -SOm-aryl, -SOm-heteroaryl,
-SOm-heterocyclyl, -N(Ra)C(0)-alkyl, -N(Ra)C(0)-alkoxy, -N(Ra)C(0)-alkenyl, -N(Ra)C(0)-alkynyl, -N(Ra)C(0)-cycloalkyl, -N(Ra)C(0)-aryl, -N(Ra)C(0)-heteroaryl, -N(Ra)C(0)-heterocyclyl, -C(0)N(Ra)-alkyl, -C(0)N(Ra)-alkoxy, -C(0)N(Ra)-alkenyl, -C(0)N(Ra)-alkynyl, -C(0)N(Ra)-cycloalkyl, -C(0)N(Ra)-aryl, -C(0)N(Ra)-heteroaryl, or -C(0)N(Ra)-heterocyclyl;
X is =CH- or =N-;
each Y is independently -CR4=, -C(R4)2-, -N=, -NR4-, -0-, -S-, or a bond, provided that no more than two of Y are -N=, -NR4-, -0-, -S-, and provided that no more than one of Y is a bond;
L2 is a bond, -(CRaRb)n-, -C(O)-, -C(0)N(Ra , -(CRaRb)n-C(0)N(Ra)-,
-C(0)N(Ra)-(CRaRb)n-, -0-, or -(CRaRb)n-0-;
i is an integer selected from 0, 1, 2, 3, 4 and 5;
R7 is H, alkyl, alkoxyalkyl, hydroxyalkyl, cycloalkyl, cycloalkylether, or heterocyclyl; each Ra, independently, is H, halogen, Ci-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
each Rb, independently, is H, halogen, C1-C5 alkyl, C3-C8 cycloalkyl, phenyl or benzyl, each of which is optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
or Ra and Rb together with the atom to which they are attached are a 3 to 8 membered cycloalkyl optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl; or a 3 to 8 membered heterocyclo including 1, 2, 3 heteroatoms selected from O, N, or S optionally substituted with -OH, halo, -CF3, -CN, -N02, oxo, alkyl, alkoxy or cycloalkyl;
each m, independently, is 0, 1, or 2;
each n, independently, is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8, wherein each Y is independently -CR4=.
10. The compound of claim 9, wherein R2 is heteroaryl optionally substituted by 1-5 substituents selected from R4.
11. The compound of claim 9, wherein R2 is aryl optionally substituted by 1-5 substituents selected from R4.
12. The compound of claim 9, wherein R2 is selected from the group consisting of furyl, phenyl, thiophenyl, oxazolyl, imidazolyl, triazolyl, indolyl, pyrollyl, pyridinyl, pyrimidinyl, pyrazolyl, isoxazolyl, isothiazolyl, benzofuranyl,
benzothiophenyl, thiazolyl, thiabendazolyl, and thiazolyl, each of which is optionally substituted by 1-5 substituents selected from R4.
13. The compound of claim 12, wherein R2 is selected from the group consisting of furan-2-yl; 5-methyl-furan-2-yl; phenyl; 3-methoxyphenyl; 3-cyanophenyl; oxazol-2-yl; and 4-methylthiazol-2-yl.
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.
15. A method of treating a disorder comprising administering an effective dose of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need of treatment of a disorder treatable by purine receptor blocking.
16. The method of claim 15, wherein the disorder is related to hyper functioning of purine receptors.
17. The method of claim 15, wherein the subject is in need of adenosine receptor blocking.
18. The method of claim 17, wherein the adenosine receptors are A2A receptors.
19. The method of claim 18, wherein the disorder is a movement disorder.
20. The method of claim 19, wherein the movement disorder is Parkinson's disease.
21. The method of claim 20, wherein the movement disorder is drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning or post-traumatic Parkinson's disease.
22. The method of claim 19, wherein the movement disorder is progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia- Parkinsonism, spasticity or other disorders of the basal ganglia which result in dyskinesias.
23. The method of claim 15, further comprising administering to the subject an additional drug useful in the treatment of movement disorders.
24. The method of claim 23, wherein the additional drug useful in the treatment of movement disorders is a drug useful in the treatment of Parkinson's disease.
25. The method of claim 24, wherein the additional drug is L-DOPA or a dopamine agonist.
26. The method of claim 15, wherein the disorder is depression, a cognitive or memory impairment disorder, acute or chronic pain, ADHD or narcolepsy.
27. The method of claim 26, wherein the cognitive or memory impairment disorder is Alzheimer's disease.
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