NZ712079B2

NZ712079B2 - Purine derivatives as cb2 receptor agonists

Info

Publication number: NZ712079B2
Application number: NZ712079A
Authority: NZ
Inventors: Stefanie Bendels; Uwe Grether; Atsushi Kimbara; Matthias Nettekoven; Stephan Roever; Evans Mark Rogers; Gasch Tanja Schulz
Original assignee: F Hoffmann La Roche Ag
Priority date: 2013-05-02
Filing date: 2014-04-28
Publication date: 2021-06-29

Abstract

The invention relates to a compound of formula (I) wherein A and R1 to R4 are defined as in the description and in the claims. The compound of formula (I) is a CB2 receptor agonist and can be used as a medicament.

Description

Novel purine derivatives The present invention relates to organic compounds useful for y and/or prophylaxis in a mammal, and in particular to compounds that are preferential agonists of the Cannabinoid Receptor 2.

The invention es a compound of formula (I) R2 R3 R1 N N A R4 wherein A is CH2, CH2CH2 , CH2CO or absent; R1 is tert.-butyl, tert.-butylamino, 2,2-dimethylpropyloxy or halogen; R2 and R3, together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa azaspiro[3.4]octyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, substituted azetidinyl, 2,2-dioxo-2λ6-thiaazaspiro[3.3]heptyl or - azaspiro[2.4]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from halogen, hydroxyl, alkyl, yalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy and haloalkyl and n substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen, hydroxyl, alkyl and haloalkyl; and R4 is hydrogen, phenyl, enyl, alkylphenyl, haloalkylphenyl, pyridinyl, halopyridinyl, cycloalykl, alkyl, alkyloxadiazolyl, yl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl, haloalkyl-1H-pyrazolyl or cycloalkylalkyltetrazolyl; or a pharmaceutically able salt or ester thereof; provided that 2-chloro(1-pyrrolidinyl)-9H-purine; 2-chloro(phenylmethyl)(1-pyrrolidinyl)-9H-purine; 1-[2-chloro(1-methylethyl)-9H-purinyl]pyrrolidinol; and ro[1-(4-methylpiperazinyl)]purine; are excluded.

The invention also provides a process for the preparation of a compound according to the invention, comprising the reaction of a compound of formula (A) R2 R3 R1 N N H (A) in the presence of Y-A-R4 wherein Y is a leaving group and wherein A and R1 to R4 are as defined herein.

The invention also provides compound according to the invention for use as therapeutically active substance.

The ion also provides a pharmaceutical composition comprising a nd in accordance with the invention and a therapeutically inert carrier.

The invention also provides use of a compound according to the invention for the preparation of a medicament for the ent or prophylaxis of pain, atherosclerosis, agerelated r degeneration, diabetic retinopathy, glaucoma, l vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute aft rejection, chronic allograft nephropathy, ic nephropathy, glomerulonephropathy, myopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver sis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack or uveitis.

Described herein is a compound of formula (I) R2 R3 R1 N N A R4 A is CH2, CH2CH2 , CH2CO or ; R1 is tert.-butyl, tert.-butylamino, 2,2-dimethylpropyloxy or halogen; R2 and R3, together with the nitrogen atom to which they are attached, form pyrrolidinyl, tuted idinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa azaspiro[3.4]octyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, substituted azetidinyl, 2,2-dioxo-2λ6-thiaazaspiro[3.3]heptyl or halo azaspiro[2.4]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from halogen, hydroxyl, alkyl, hydroxyalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy and haloalkyl and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen, hydroxyl, alkyl and haloalkyl; and R4 is hydrogen, phenyl, enyl, alkylphenyl, haloalkylphenyl, pyridinyl, halopyridinyl, cycloalykl, alkyl, alkyloxadiazolyl, oxolanyl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl, haloalkyl-1H-pyrazolyl or lkylalkyltetrazolyl; or a ceutically acceptable salt or ester thereof.

The nd of formula (I) is particularly useful in the treatment or prophylaxis of e.g. pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic y, diabetes us, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic aft nephropathy, diabetic nephropathy, glomerulonephropathy, myopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack or s.

The compound of formula (I) is in particular useful in the treatment or prophylaxis of diabetic retinopathy, retinal vein occlusion or uveitis.

The inoid ors are a class of cell membrane ors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, termed inoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The CB1 receptor is mainly expressed in the central nervous (i.e. amygdala cerebellum, hippocampus) system and to a lesser amount in the ery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages and T-cells (Ashton, J. C. et al. Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol 2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23), 2), and in the intestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain where it is found primarily on microglia and not neurons (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).

The interest in CB2 receptor agonists has been steadily on the rise during the last decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain amo, M. Mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182-8), nflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, , 252-62), systemic fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36; Garcia- Gonzalez, E. et al. Rheumatology d) 2009, 48(9), 1050-6), liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).

Ischemia/reperfusion (I/R) injury is the principal cause of tissue damage occurring in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries, and organ lantation, as well as a major mechanism of end-organ damage complicating the course of circulatory shock of various etiologies. All these ions are characterized by a disruption of normal blood supply resulting in an icient tissue oxygenation. Re-oxygenation e.g., reperfusion is the ultimate treatment to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in further tissue damage. The damage of reperfusion injury is due in part to the inflammatory se of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as eukins as well as free radicals in response to tissue damage. The restored blood flow reintroduces oxygen within cells that damages cellular ns, DNA, and the plasma membrane.

Remote ischemic preconditioning (RIPC) represents a strategy for harnessing the body’s endogenous protective capabilities against the injury incurred by ischemia and reperfusion. It describes the intriguing phenomenon in which transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to a subsequent episode of l" ischemia reperfusion injury in a remote organ or tissue. The actual mechanism through which transient ischemia and reperfusion of an organ or tissue confers protection is currently unknown although several hypotheses have been proposed.

The humoral esis proposes that the endogenous substance (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, Angiotensin I or some other as yet unidentified humoral factor) generated in the remote organ or tissue enters the blood stream and activates its tive or in the target tissue and thereby recruiting the various intracellular ys of protection implicated in ic preconditioning.

Recent data tes that endocannabinnoids and their receptors, in particular CB2 might be involved in nditioning and contribute to prevent reperfusion injury by downregulation of the inflammatory response (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). Specifically, recent studies using CB2 tool agonists demonstrated the efficacy of this concept for reducing the I/R injury in the heart (Defer, N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27(7), 1387-96), the liver (Batkai, S. et al. Faseb J 2007, 21(8), 1788-800) and the kidney , A. et al. Exp Toxicol Pathol 2008, ), 405-10).

Moreover, over the last few years, a growing body of literature indicates that CB2 can also be of interest in sub-chronic and chronic setting. Specific upregulation of CB1 and CB2 has been shown to be associated in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, E. et al. Rheumatology d) 2009, 48(9), 1050-6; Yang, Y. Y. et al. Liver Int 2009, 29(5), 678-85) with a relevant expression of CB2 in myofibroblasts, the cells responsible for fibrosis progression.

Activation of CB2 receptor by selective CB2 agonist has in fact been shown to exert ibrotic effect in diffuse systemic sclerosis a-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and CB2 receptor has emerged as a critical target in experimental dermal fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129- 36) and in in liver pathophysiology, including fibrogenesis associated with c liver diseases (Lotersztajn, S. et al. Gastroenterol Clin Biol 2007, 31(3), 255-8; Mallat, A. et al.

Expert Opin Ther Targets 2007, 11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, , 286-9).

The compounds of the invention bind to and te the CB2 receptor and have lower CB1 or activity.

In the present description the term "alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight- chain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, the isomeric pentyls, the isomeric hexyls, the ic s and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl. A particular example of alkyl is methyl.

The term "cycloalkyl", alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a cycloalkyl ring with 3 to 6 carbon atoms. es of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and ctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclohexyl, in particular cyclohexyl.

The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, poxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. A particular "alkoxy" is y.

The terms "halogen" or "halo", alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term "halo", in combination with another group, s the substitution of said group with at least one halogen, particularly substituted with one to five halogens, particularly one to four halogens, i.e. one, two, three or four halogens. Particular "halogen" are fluorine and chlorine. In the definition of R2 and R3, fluorine is a particular halogen.

The term "haloalkyl", alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. A particular "haloalkyl" is trifluoromethyl.

The terms "hydroxyl" and "hydroxy", alone or in ation, signify the -OH group.

The term nyl", alone or in combination, signifies the -C(O)- group.

The term "oxy", alone or in combination, signifies the -O- group.

The term "amino", alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-). A ular amino is -NH-.

The term "aminocarbonyl", alone or in combination, ies the NH2-C(O)-, -NH-C(O)- or - N-C(O)- group.

The term "carbonylamino", alone or in combination, signifies the -C(O)-NH- or -C(O)-N- group. A particular carbonylamino is -C(O)-N-.

The term "sulfonyl", alone or in combination, ies the -S(O)2- group.

The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, ic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In on these salts may be prepared form addition of an nic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from c bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, ine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred ceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, romic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

"Pharmaceutically acceptable esters" means that the nd of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of sion back to the parent compounds in vivo. Examples of such compounds include logically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and yloxymethyl esters.

Additionally, any physiologically able equivalents of the compound of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compound of general formula (I) in vivo, are within the scope of this invention.

If one of the ng materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as described e.g. in "Protective Groups in Organic try" by T. W. Greene and P. G. M. Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step ng methods well known in the art. Such protecting groups can be removed at a later stage of the sis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compound of formula (I) can contain several tric centers and can be t in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the "R" or "S" configuration.

The invention is directed in particular to a compound of formula (I) wherein: A is CH2, CH2CH2 , CH2CO or absent; R1 is tert.-butyl, tert.-butylamino or methylpropyloxy; R2 and R3, together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa azaspiro[3.4]octyl or 2-oxaazaspiro[3.3]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from halogen, hydroxyl, alkyl, hydroxyalkyl, cyano and alkylcarbonylamino; and R4 is phenyl, enyl, alkylphenyl, haloalkylphenyl, pyridinyl, halopyridinyl, lkyl, alkyl, alkyloxadiazolyl, oxolanyl, alkyltetrazolyl, , alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl or haloalkyl-1H-pyrazolyl; or a pharmaceutically acceptable salt or ester thereof.

The invention further s in particular to: A compound of formula (I) wherein A is CH2; A compound of formula (I) wherein R1 is tert.-butyl or 2,2-dimethylpropyloxy; A nd of formula (I) wherein R1 is tert.-butyl; A compound of formula (I) wherein R2 and R3, together with the nitrogen atom to which they are attached, form thiazolidinyl, tuted pyrrolidinyl or substituted azetidinyl, wherein wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen, hydroxyl, hydroxyalkyl and cyano and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from halogen, yl and haloalkyl; A compound of formula (I) wherein R2 and R3, together with the nitrogen atom to which they are attached, form thiazolidinyl, substituted pyrrolidinyl or substituted azetidinyl, wherein wherein tuted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently ed from fluorine, hydroxyl, hydroxymethyl and cyano and wherein substituted azetidinyl is azetidinyl tuted with one or two substituents selected from fluoro, hydroxyl and trifluoromethyl; A compound of formula (I) wherein R2 and R3, together with the en atom to which they are attached, form thiazolidinyl, difluoropyrrolidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, cyanopyrrolidinyl, difluoroazetidinyl or (hydroxyl)(trifluoromethyl)azetidinyl; A compound of formula (I) wherein R2 and R3, together with the nitrogen atom to which they are attached, form substituted pyrrolidinyl, wherein wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from halogen and hydroxyl; A compound of formula (I) wherein R2 and R3, er with the en atom to which they are ed, form substituted pyrrolidinyl, wherein wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from fluorine and hydroxyl; A nd of formula (I) wherein R2 and R3, together with the nitrogen atom to which they are attached, form difluoropyrrolidinyl or hydroxypyrrolidinyl; A compound of formula (I) wherein R2 and R3, together with the nitrogen atom to which they are attached, form ropyrrolidinyl, hydroxypyrrolidinyl, tetrafluoropyrrolidinyl, methylcarbonylamino, thiazolidinyl, methylpiperazinyl, 2-oxa azaspiro[3.4]octyl or 2-oxaazaspiro[3.3]heptyl, (methyl)(hydroxyl)pyrrolidinyl, hyydroxyalkylpyrrolidinyl or cyanopyrrolidinyl; A compound of formula (I) wherein R4 is halophenyl, haloalkylphenyl, halopyridinyl, oxolanyl, ulfonylphenyl, pyridinyl or cycloalkyltetrazolyl; A compound of formula (I) wherein R4 is phenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridinyl, oxolanyl, methylsulfonylphenyl, nyl or cyclopropyltetrazolyl; A compound of formula (I) wherein R4 is halophenyl, haloalkylphenyl, halopyridinyl, oxolanyl, alkylsulfonylphenyl or pyridinyl; A compound of formula (I) wherein R4 is chlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridinyl, oxolanyl, sulfonylphenyl or pyridinyl; and A compound of formula (I) wherein R4 is phenyl, chlorophenyl, chlorofluorophenyl, phenyl, trifluoromethylphenyl, chloropyridinyl, oxolanyl, methylsulfonylphenyl, pyridinyl, mehtyloxadiazolyl, cyclohexyl, methyl, oxolanyl, methyltetrazolyl, methoxy, trifluoromethyl, methoxyphenyl, thietanyl, trifluoromethyl-1H-pyrazolyl or cyclopropyltetrazolyl.

The invention further relates to a compound of formula (I) ed from: -butyl[(4-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methylphenyl)methyl]purine; 2-tert-butyl[(2-chlorofluorophenyl)methyl](3,3-difluoropyrrolidin yl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purine; 2-tert-butyl[(2-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; -[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,4- oxadiazole; 2-tert-butyl(cyclohexylmethyl)(3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)ethylpurine; 2-tert-butyl(3,3-difluoropyrrolidinyl)propylpurine; 2-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,3,4- zole; 2-tert-butyl(3,3-difluoropyrrolidinyl)(oxolanyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-phenylethyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-methoxyethyl)purine; 3-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,5- oxadiazole; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl](2- chlorophenyl)ethanone; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(2- sulfonylphenyl)methyl]purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]purine; 2-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-pyridinylethyl)purine; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]pyridinylethanone; ert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; ert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol; 3-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]thietane 1,1-dioxide; 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methoxyphenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol; 1-(2-tert-butylethylpurinyl)pyrrolidinol; 1-(2-tert-butylpropylpurinyl)pyrrolidinol; 1-[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol; 1-[2-tert-butyl(2-phenylethyl)purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methylphenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl(cyclohexylmethyl)purinyl]pyrrolidinol; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[3-(trifluoromethyl)-1H-pyrazol yl]methyl]purine; 1-[2-tert-butyl[(2-chlorofluorophenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; 1-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; 1-[2-tert-butyl(oxolanyl)purinyl]pyrrolidinol; 2-[2-tert-butyl(3-hydroxypyrrolidinyl)purinyl](2-chlorophenyl)ethanone; N-{(S)[2-tert-Butyl(2-chloro-benzyl)-9H-purinyl]-pyrrolidinyl}- acetamide; N-[(S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidin tamide; N-[(S)[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide N-[(S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinyl]acetamide; ert-butyl[(2-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl(2-methoxyethyl)purinyl]oxaazaspiro[3.4]octane; 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]methylpyrrolidin- 3-ol; 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]methylpyrrolidinol; ert-butyl[(3-chloropyridinyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; 1-[2-tert-butyl(2-methoxyethyl)purinyl]methylpyrrolidinol; 2-tert-butyl[(2-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine; 2-tert-butyl[(3-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine; ert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]methylpyrrolidin N-[(S)[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide; 7-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa azaspiro[3.4]octane; N-[1-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide; 7-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa azaspiro[3.4]octane; 2-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,3,4-oxadiazole; -[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,2,4-oxadiazole; 2-tert-butyl[(1-methyltetrazolyl)methyl](3,3,4,4-tetrafluoropyrrolidin yl)purine; 3-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,2,5-oxadiazole; 2-tert-butyl(2-methoxyethyl)(3,3,4,4-tetrafluoropyrrolidinyl)purine; ert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol; 1-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol; (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; -[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol; 7-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]oxaazaspiro[3.4]octane; (3S)[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine; (3S)[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol; (3S)[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidin- 3-ol; (3S)[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; -[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; (3S)[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; (3S)[2-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidin- 3-ol; 1-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]methylpyrrolidinol; N-[(3S)[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidin yl]acetamide; 7-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane; 2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purine; 2-tert-butyl[(2-methylsulfonylphenyl)methyl](3,3,4,4-tetrafluoropyrrolidin yl)purine; -butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purin amine; N-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(5-methyl-1,3,4-oxadiazol yl)methyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazol yl)methyl]purinamine; N-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purin amine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purin- 2-amine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- methylsulfonylphenyl)methyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(3-methyl-1,2,4-oxadiazol hyl]purinamine; -[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purin yl]pyrrolidinol; (3S)[2-(tert-butylamino)[(3-chloropyridinyl)methyl]purinyl]pyrrolidin ol; (3S)[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinol; 1-[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]methylpyrrolidin 1-[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol; (3S)[2-(tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; 1-[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; 9-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)purine; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[[2- (trifluoromethyl)phenyl]methyl]purine; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2- methylsulfonylphenyl)methyl]purine; 2-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,3,4-oxadiazole; -[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] -1,2,4-oxadiazole; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol hyl]purine; (3S)[2-(tert-butylamino)(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; 1-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl] methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[(2-methylsulfonylphenyl)methyl]purinyl] methylpyrrolidinol; 1-[9-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)purinyl] methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; 1-[2-(tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]- 3-methylpyrrolidinol; N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)[[2- (trifluoromethyl)phenyl]methyl]purinamine; N-tert-butyl[(2-chlorophenyl)methyl](2-oxaazaspiro[3.3]heptanyl)purin- 2-amine; (3S)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidin 3-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,2,5-oxadiazole; N-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl](2-oxa azaspiro[3.3]heptanyl)purinamine; N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)(3,3,3-trifluoropropyl)purin amine; 6-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl]oxa ro[3.3]heptane; 3-[[2-tert-butyl(4-methylpiperazinyl)purinyl]methyl]methyl-1,2,5- oxadiazole; [(2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin rolidinyl]methanol; [(2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidin yl]methanol; (2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidine carbonitrile; (2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin rolidinecarbonitrile; 6-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.3]heptane; and 3-[[2-tert-butyl(1,3-thiazolidinyl)purinyl]methyl]methyl-1,2,5- oxadiazole.

The invention particularly also relates to a compound of formula (I) selected from: 6-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)-9H-purine; [(3S)[2-(tert-Butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinyl] acetate; [1-[2-(tert-Butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinyl] acetate; 9-Benzylchloro(3,3-difluoropyrrolidinyl)purine; (3S)[2-tert-Butyl[(1-propanyltetrazolyl)methyl]purinyl]pyrrolidin ol; 2-tert-Butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine; [(2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol; (3S)[2-tert-Butyl[(1-propyltetrazolyl)methyl]purinyl]pyrrolidinol; (2R,3S)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl] (hydroxymethyl)pyrrolidinol; 2-tert-Butyl[(3-chloropyridinyl)methyl](3,3-difluoroazetidinyl)purine; 3-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-1,3-thiazolidine; 6-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-2λ6-thia azaspiro[3.3]heptane 2,2-dioxide; -[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidine carbonitrile; -[2-tert-Butyl[[1-(cyclopropylmethyl)tetrazolyl]methyl]purin yl]pyrrolidinol; 1-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)pyrrolidinol; (3S)[2-tert-Butyl[(1-tert-butyltetrazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)azetidinol; 2-tert-Butyl[(3-chloropyridinyl)methyl](2,2-difluoroazaspiro[2.4]heptan- -yl)purine; and 1-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]methylazetidinol.

The invention further relates to a compound of formula (I) selected from: 2-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl[(2-chlorofluorophenyl)methyl](3,3-difluoropyrrolidin yl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purine; 2-tert-butyl[(2-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(oxolanyl)purine; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl](2- chlorophenyl)ethanone; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(2- sulfonylphenyl)methyl]purine; -butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; -butyl(3,3-difluoropyrrolidinyl)(2-pyridinylethyl)purine; 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-chlorofluorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; 9-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)purine; and 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[[2- (trifluoromethyl)phenyl]methyl]purine.

The ion also particularly relates to a compound of formula (I) seleceted from: 2-tert-Butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine; [(2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol; 2-tert-Butyl[(3-chloropyridinyl)methyl](3,3-difluoroazetidinyl)purine; 3-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-1,3-thiazolidine; (2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidine carbonitrile; and 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)azetidinol.

The invention also relates in particular to: The use of a compound ing of formula (I) for the preparation of a medicament for the treatment or prophylaxis of pain, sclerosis, lated macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, es mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion , acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute aft rejection, chronic allograft nephropathy, diabetic nephropathy, ulonephropathy, cardiomyopathy, heart failure, dial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, s, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ic attack or uveitis; and A compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney is, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, ic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, itis pyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack or uveitis.

Described herein is: The use of a nd of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein ion, pathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, myopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sis, thermal , burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, le sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack or uveitis; and A method for the treatment or prophylaxis of pain, atherosclerosis, lated macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver is, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, dial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis a, liver cirrhosis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's e, Parkinson's e, stroke, transient ischemic attack or uveitis, which method comprises administering an ive amount of a compound of formula (I) to a patient in need thereof.

The invention particularly relates to a nd of formula (I) for the treatment or prophylaxis of ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ia or reperfusion injury.

The invention particularly relates to a compound of formula (I) for the treatment or laxis of myocardial infarction.

The invention further particularly relates to a compound of formula (I) for the treatment or prophylaxis of age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, pathy of prematurity, ocular ischemic me, geographic atrophy or uveitis.

The ion further particularly relates to a compound of formula (I) for the treatment or prophylaxis of amyotrophic lateral sclerosis or multiple sclerosis.

Another embodiment of the invention provides a pharmaceutical composition or medicament ning a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the ion to prepare such composition and ment. In one example, the compound of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are nontoxic to recipients at the dosages and trations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of nd, but preferably ranges anywhere from about 3 to about 8.

In one example, a compound of formula (I) is formulated in an e buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

The compounds of the invention may be administered by any le means, ing oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, ulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.

Parenteral infusions e uscular, intravenous, rterial, intraperitoneal, or aneous administration.

The compounds of the present invention may be stered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, sions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more s, izing , surfactants, g agents, ating , emulsifiers, suspending agents, preservatives, idants, opaquing agents, glidants, processing aids, colorants, ners, perfuming agents, flavoring agents, diluents and other known additives to e an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition f) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art.

The substituents and s used in the ing description of the processes have the significance given herein before unless indicated to the contrary. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by ous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction ions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). We find it convenient to carry out the reactions in the presence or absence of a t. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents ed and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range n -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually e to yield the described intermediates and compounds. The reaction ce is not limited to the one displayed in the schemes, however, depending on the starting als and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.

The synthesis of the compound of a (I) can, for example, be lished according to the following schemes.

Scheme 1 Cl R2 R3 R2 R3 N N N a) b) N N N N N N N N N N N H R4 II III I a) 2-tert-Butylchloro-9H-purine II can conveniently be reacted with an amine (commercially available, or known in the art) in the presence or the absence of a base to afford intermediate III. b) Intermediate III can conveniently be reacted with an ophile (commercially available, or known in the art) in the presence or e of a base to yield title compound I. This might be the final desired compound however any protecting group either on R3 or NR2R3 can conveniently be cleaved under appropriate conditions to yield the desired final compound I.

Scheme 2 Cl R2 R3 R2 R3 N N N N a) b) N N N N F N N R1 N N R1 N N A R4 II III I a) 6-Chlorofluoro-9H-purine II is commercially available (any other suitable substituted purine serves as equal starting material) or can be accessed by methods known in the art and can conveniently be reacted with nucleophiles (1. amine 2. alcohol alternatively: 1.amine 2. amine, depending on the nature and reactivity of the respective ) to access tuted imidazopyrimidine derivatives III. The use of ting groups is optionally d depending on the nature and the reactivity of the reagents. b) Intermediate III can conveniently be reacted with an electrophile (commercially available, or known in the art) in the presence or absence of a base to yield title compound I. This might be the final d nd however any protecting group either on R4 or NR2R3 can conveniently be cleaved under appropriate conditions to yield the desired final compound I.

The invention thus also relates to a process for the preparation of a compound of formula (I) comprising the reaction of a compound of formula (A) R2 R3 R1 N N H (A) in the presence of Y-A-R4 wherein Y is a leaving group and wherein A and R1 to R4 are as defined above.

In the process of the invention, le leaving groups are for example chlorine or bromine.

The process of the invention can be carried out in the presence of a base. Examples of le bases are NaH or KOtBu.

The process of the invention can be carried out for example in NMP (N-Methyl pyrrolidone), DMF (dimethylformamide) or THF (tetrahydrofurane).

The invention is further directed to a compound of formula (I), when manufactured according to a process according to the ion.

The invention will now be illustrated by the following examples which have no limiting character.

Examples Example 1 2-tert-butyl[(4-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine N N a) 5-(2,2-Dimethyl-propionylamino)-1H-imidazolecarboxylic acid amide H N N HN N To a solution of 5-amino-1H-imidazolecarboxylic acid amide (10g, 79.36 mmol) and DMAP (291 mg, 2.38 mmol) in anhydrous pyridine (200 mL) was slowly added 2,2- dimethyl-propionyl chloride (10.74 mL, 87.30 mmol) and the reaction mixture was d at 80 °C for 8 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water (50 mL). The precipitate was filtered, washed with water (30 mL) and dried to get yield the title compound (9 g, 54 %) as ash-color solid. ): 211.4 (M+H). b) 2-tert-Butyl-1,9-dihydro-purinone N N A solution 5-(2, 2-dimethyl-propionylamino)-1H-imidazolecarboxylic acid amide (22 g, 174.6 mmol) in s KHCO3 solution (0.5N, 400 mL) was heated to reflux for 48 h.

The reaction mixture was concentrated under reduced pressure, the residue was cooled to 0 °C and pH was adjusted to 6 using 10% s HCl solution. The precipitate was filtered, washed with water and azeotroped with e to access a brown solid that was purified by column chromatography over silica gel (2-5%MeOH/DCM) to get yield the title compound (12 g, 36 %) as pale yellow solid. MS(m/e): 191.0 (M+H). c) 2-tert-Butylchloro-9H-purine N N To a solution of 2-tert-butyl-5,9-dihydro-purinone (4 g, 20.83 mmol) in CHCl3 (100 mL) was added DMF (4 mL) followed by SOCl2 (3.04 mL, 41.66 mmol) and the reaction mixture was refluxed for 3 h. Volatilities were removed in vacuo and the residue was diluted with water (50 mL), stirred for 10 min at 25 °C and filtered. The precipitate was washed with water and pentane yield the title compound (3.6 g, 82 %) as off-white solid.

MS(m/e): 211.2 (M+H). d) -Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine N N To a solution of 2-tert-butylchloro-9H-purine (970 mg, 4.62 mmol) and 3,3-difluoropyrrolidine (995 mg, 6.93 mmol) in EtOH (10 mL) was added DIPEA (2.29 mL, 13.86 mmol) and the reaction mixture was stirred at 100 °C for 16 h. The solvent was evaporated, the residue was dissolved with DCM (60 mL) and washed with water. The organic layer was dried over Na2SO4, ed and evaporated. The residue was purified by column chromatography over silica gel (25-30%EtOAc/hexane) to yield (1g, 77 %) as offwhite solid. MS(m/e): 282.2 (M+H). e) 2-tert-butyl[(4-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine To a solution of 2-tert-butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (50 mg, 0.178mmol) in dry DMF (3 mL) at 0 °C was added NaH (60% in mineral oil) (10 mg, 0.214 mmol) and the reaction mixture was stirred at 25 °C for 45 min. 1-Bromomethyl -benzene (54.7 mg, 0.267 mmol) was added to reaction mixture at 0 °C, and the reaction mixture was heated to 60 °C for 16 h. The mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 15 mL). The ed organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography over silica gel (20-30%EtOAc/hexane) to yield (54.7 mg, 61 %) as pale yellow liquid.

MS(m/e): 406.4 (M+H).

Example 2 2-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine N N Cl In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from -Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-bromomethylchloro-benzene. MS(m/e): 406.4 (M+H).

Example 3 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methylphenyl)methyl]purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-bromomethylmethyl-benzene. MS(m/e): 386.0 (M+H).

Example 4 2-tert-butyl[(2-chlorofluorophenyl)methyl](3,3-difluoropyrrolidin yl)purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-bromomethylchlorofluoro-benzene. MS(m/e): 424.0 (M+H). e 5 2-tert-butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl] methyl]purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-bromomethyltrifluoromethyl-benzene. MS(m/e): 440.0 (M+H).

Example 6 2-tert-butyl[(2-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 2-chlorochloromethyl-pyridine. MS(m/e): 407.0 (M+H).

Example 7 -[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,4- oxadiazole N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 5-chloromethylmethyl-[1,2,4]oxadiazole. MS(m/e): 378.2 (M+H). -butyl(cyclohexylmethyl)(3,3-difluoropyrrolidinyl)purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and ethyl-cyclohexane. MS(m/e): 378.2 (M+H).

Example 9 2-tert-butyl(3,3-difluoropyrrolidinyl)ethylpurine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and iodo-ethane. MS(m/e): 310.2 (M+H).

Example 10 2-tert-butyl(3,3-difluoropyrrolidinyl)propylpurine N N In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from -Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-iodo-propane. ): 324.0 (M+H).

Example 11 2-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,3,4- oxadiazole N N In analogy to the procedure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 2-chloromethylmethyl-[1,3,4]oxadiazole. MS(m/e): 378.2 (M+H).

Example 12 2-tert-butyl(3,3-difluoropyrrolidinyl)(oxolanyl)purine N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 3-bromo-tetrahydro-furan. MS(m/e): 352.0 (M+H).

Example 13 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-phenylethyl)purine N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 2-bromo-ethyl)-benzene. MS(m/e): 386.0 (M+H). e 14 2-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 5-chloromethylmethyl-1H-tetrazole. MS(m/e): 378.2 (M+H).

Example 15 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-methoxyethyl)purine N N In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-Iodomethoxy-ethane. MS(m/e): 340.0 (M+H).

Example 16 3-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,5- oxadiazole N N In analogy to the procedure described for the synthesis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 3-chloromethylmethyl-furazan. MS(m/e): 378.2 (M+H).

Example 17 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl](2-chlorophenyl)ethanone N N Cl In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from -Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 2-bromo(2-chloro-phenyl)-ethanone. MS(m/e): 434.0 (M+H).

Example 18 2-tert-butyl(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl]purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and omethylmethanesulfonyl-benzene. MS(m/e): 450.0 (M+H).

Example 19 2-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1,1,1-trifluoroiodo-propane. MS(m/e): 378.2 (M+H).

Example 20 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]purine N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 1-bromomethylmethoxy-benzene. ): 402.2 (M+H).

Example 21 2-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine N N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 3-chlorochloromethyl-pyridine. MS(m/e): 407.0 (M+H).

Example 22 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol N N a) Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester N N To a solution of 2-tert-butylchloro-9H-purine (1.2 g, 5.71 mmol) and acetic acid pyrrolidinyl ester (1.66 g, 6.85 mmol) in EtOH (7 mL) was added Et3N (2.37 mL, 17.14 mmol) at 25 °C, and the reaction e was stirred at 100 °C for 5 h. The solvent was evaporated and the residue was purified by column chromatography over silica (30- 45%EtOAc/hexane) to yield the title compound (1.1 g, 63 %) as off white solid. MS(m/e): 304.0 (M+H). b) 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol In analogy to the procedure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and omethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 386.2 (M+H). e 23 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-pyridinylethyl)purine N N In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 3-(2-bromo-ethyl)-pyridine. MS(m/e): 387.2 (M+H).

Example 24 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]pyridinylethanone N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 2-bromopyridinyl-ethanone. MS(m/e): 401.2 (M+H).

Example 25 1-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 386.2 (M+H).

Example 26 1-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / e with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 386.2 (M+H).

Example 27 3-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]thietane 1,1-dioxide N N O O In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and o-thietane 1,1-dioxide. MS(m/e): 386.2 (M+H). e 28 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and omethyltrifluoromethyl-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 420.2 (M+H).

Example 29 1-[2-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidinol N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester le 22, step a) and 5-chloromethylmethyl-[1,2,4]oxadiazole plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 358.0 (M+H).

Example 30 1-[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 5-chloromethylmethyl-1H-tetrazole plus subsequent treatment of the crude mixture / e with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 358.2 (M+H).

Example 31 1-[2-tert-butyl[(4-methoxyphenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the sis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylmethoxy-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 382.0 (M+H).

Example 32 ert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid ert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 3-chlorochloromethyl-pyridine plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 387.0 (M+H).

Example 33 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 2-chlorochloromethyl-pyridine plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 387.0 (M+H).

Example 34 1-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylmethanesulfonyl-benzene plus subsequent treatment of the crude e / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 430.0 (M+H).

Example 35 1-(2-tert-butylethylpurinyl)pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and iodo-ethane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 290.0 (M+H).

Example 36 1-(2-tert-butylpropylpurinyl)pyrrolidinol N N In analogy to the ure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and ropane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 304.0 (M+H).

Example 37 1-[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-iodomethoxy-ethane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 320.2 (M+H). e 38 1-[2-tert-butyl(2-phenylethyl)purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 2-(bromo-ethyl)-benzene plus subsequent treatment of the crude e / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 365.9 (M+H).

Example 39 1-[2-tert-butyl[(4-methylphenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylmethyl-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 365.9 (M+H).

Example 40 1-[2-tert-butyl(cyclohexylmethyl)purinyl]pyrrolidinol N N In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid ert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and bromomethyl-cyclohexane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester . MS(m/e): 358.0 (M+H).

Example 41 2-tert-butyl(3,3-difluoropyrrolidinyl)[[3-(trifluoromethyl)-1H-pyrazol yl]methyl]purine N N In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3-difluoro-pyrrolidinyl)-9H-purine (example 1, step d) and 4-bromomethyltrifluoromethyltrityl-1H-pyrazole. MS(m/e): 430.0 (M+H). e 42 1-[2-tert-butyl[(2-chlorofluorophenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1-bromomethylchlorofluoro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 404.2 (M+H).

Example 43 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 3-chloromethylmethyl-furazan plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 358.4 (M+H).

Example 44 1-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]pyrrolidin- 3-ol N N In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 4-bromomethyltrifluoromethyltrityl-1H-pyrazole plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. Subsequently the trityl-protecting group was cleaved with TFA. MS(m/e): 410.0 (M+H).

Example 45 1-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol N N F F F In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 1,1,1-trifluoroiodo-propane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 358.0 (M+H).

Example 46 1-[2-tert-butyl(oxolanyl)purinyl]pyrrolidinol N N In y to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 3-bromotetrahydrofuran plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester . MS(m/e): 332.2 (M+H).

Example 47 2-[2-tert-butyl(3-hydroxypyrrolidinyl)purinyl](2-chlorophenyl)ethanone N N In analogy to the procedure described for the sis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester (example 22, step a) and 2-bromo(2-chloro-phenyl)-ethanone plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 414.0 (M+H).

Example 48 N-{(S)[2-tert-Butyl(2-chloro-benzyl)-9H-purinyl]-pyrrolidinyl}-acetamide a) N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]-acetamide To a solution of 2-tert-butylchloro-9H-purine (600 mg, 2.857 mmol) and (S)-N- pyrrolidinyl-acetamide (402.28 mg, 3.143 mmol) in EtOH (30 mL) was added DIPEA (1.49 ml, 8.571 mmol), and the ant reaction mixture was stirred at 100 °C for 16 h.

Volatilities were ated and the residue was diluted with DCM (200 mL) and washed with water (2 x 75 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by column chromatography over silica gel (30- 40%EtOAc/hexane) to yield the title compound (660 mg, 76 %) as off white solid.

MS(m/e): 303.0 (M+H). b) [2-tert-Butyl(2-chloro-benzyl)-9H-purinyl]-pyrrolidinyl}- acetamide In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 4, step a) and 1-bromomethylchloro-benzene. MS(m/e): 427.4 (M+H).

Example 49 N-[(S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidin yl]acetamide In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 1-bromomethylchloro-benzene. MS(m/e): 427.4 (M+H).

Example 50 N-[(S)[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidin yl]acetamide Cl In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 1-bromomethylchloro-benzene. MS(m/e): 427.0 (M+H).

Example 51 N-[(S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidin yl]acetamide N F N F In y to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 1-bromomethyltrifluoromethyl-benzene. MS(m/e): 461.2 (M+H).

Example 52 N-[(S)[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidin yl]acetamide N O O In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 1-bromomethylmethanesulfonyl-benzene. MS(m/e): 471.2 (M+H).

Example 53 N-[(S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- ide le 48, step a) and 2-chlorochloromethyl-pyridine. MS(m/e): 428.2 (M+H).

Example 54 N-[(S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and rochloromethyl-pyridine. MS(m/e): 428.2 (M+H).

Example 55 N-[(S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidin- 3-yl]acetamide N O N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 2-chloromethylmethyl-[1,3,4]oxadiazole. MS(m/e): 399.0 (M+H).

Example 56 7-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane N N a) 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine N N In y to the procedure described for the synthesis of N-[(S)(2-tert-Butyl-9H-purin- 6-yl)-pyrrolidinyl]-acetamide le 48, a) the title compounds was prepared from 2- tert-butylchloro-9H-purine and 2-oxaaza-spiro [3.4] octane. MS(m/e): 288.0 (M+H). b) 7-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 1-bromomethylchloro-benzene. MS(m/e): 412.4 (M+H).

Example 57 7-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane N N In analogy to the procedure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 1-bromomethylchloro-benzene. MS(m/e): 412.2 (M+H).

Example 58 7-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane N N In analogy to the ure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and omethylchloro-benzene. MS(m/e): 412.2 (M+H).

Example 59 7-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]oxa azaspiro[3.4]octane N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 1-bromomethyltrifluoromethyl-benzene. MS(m/e): 446.0 (M+H).

Example 60 7-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]oxa azaspiro[3.4]octane N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 1-bromomethylmethanesulfonyl-benzene. MS(m/e): 456.0 (M+H). e 61 7-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane N N In analogy to the procedure described for the synthesis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 2-Chlorochloromethyl-pyridine. MS(m/e): 413.2 (M+H).

Example 62 ert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.4]octane N N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine le 56, step a) and 3-Chloromethylmethyl-furazan. MS(m/e): 384.2 (M+H).

Example 63 7-[2-tert-butyl(2-methoxyethyl)purinyl]oxaazaspiro[3.4]octane N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine le 56, step a) and 1-bromomethoxy-ethane. MS(m/e): 346.0 (M+H).

Example 64 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol N N a) Acetic acid 1-(2-tert-butyl-9H-purinyl)methyl-pyrrolidinyl ester N N In analogy to the procedure bed for the synthesis of N-[(S)(2-tert-Butyl-9H-purin- 6-yl)-pyrrolidinyl]-acetamide (example 48, a) the title compounds was prepared from 2- utylchloro-9H-purine and acetic acid 3-methyl-pyrrolidinyl ester. MS(m/e): 317.8 (M+H). b) 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 1-bromomethylchloro-benzene. MS(m/e): 400.0 (M+H).

Example 65 1-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]methylpyrrolidinol N N In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid ert-butyl-9H-purinyl)methyl- pyrrolidinyl ester (example 64, step a) and 1-bromomethylchloro-benzene. ): 400.0 (M+H).

Example 66 1-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]methylpyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 1-bromomethylchloro-benzene.

MS(m/e): 400.0 (M+H).

Example 67 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]methylpyrrolidin- 3-ol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methyl- pyrrolidinyl ester (example 64, step a) and 1-bromomethyltrifluoromethyl-benzene.

MS(m/e): 434.0 (M+H).

Example 68 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]methylpyrrolidinol N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was ed from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 2-chlorochloromethyl-pyridine. MS(m/e): 401.0 (M+H).

Example 69 ert-butyl[(3-chloropyridinyl)methyl]purinyl]methylpyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 3-chlorochloromethyl-pyridine. MS(m/e): 401.0 (M+H).

Example 70 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] pyrrolidinol N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methyl- pyrrolidinyl ester (example 64, step a) and 3-chloromethylmethyl-furazan. MS(m/e): 372.2 (M+H). e 71 1-[2-tert-butyl(2-methoxyethyl)purinyl]methylpyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 1-bromomethoxy-ethane. MS(m/e): 334.0 (M+H).

Example 72 2-tert-butyl[(2-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine F F F F a) 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H-purine F F F F In analogy to the procedure described for the synthesis of (2-tert-Butyl-9H-purin- 6-yl)-pyrrolidinyl]-acetamide (example 48, a) the title compounds was prepared from 2- tert-butylchloro-9H-purine and 3, 3, 4, 4-tetrafluoro-pyrrolidine. ): 318.0 (M+H). b) 2-tert-butyl[(2-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 1-bromomethylchloro-benzene. MS(m/e): 442.3 (M+H).

Example 73 2-tert-butyl[(3-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine F F F F In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 1-bromomethylchloro-benzene. MS(m/e): 441.2 (M+H).

Example 74 1-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]methylpyrrolidin N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methyl- pyrrolidinyl ester (example 64, step a) and 1-bromomethylmethanesulfonyl-benzene. ): 444.2 (M+H).

Example 75 N-[(S)[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide N N F H In analogy to the procedure described for the synthesis of -butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 4-bromomethyltrifluoromethyltrityl-1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. MS(m/e): 451.2 (M+H).

Example 76 ert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa ro[3.4]octane N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56 step a) and 4-bromomethyltrifluoromethyltrityl-1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. MS(m/e): 436.2 (M+H).

Example 77 N-[(S)[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and 3-bromomethyltrifluoromethyltrityl-1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. MS(m/e): 451.0 (M+H).

Example 78 ert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa azaspiro[3.4]octane N N F In analogy to the procedure described for the synthesis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56 step a) and 4-bromomethyltrifluoromethyltrityl-1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. ): 436.2 (M+H).

Example 79 2-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,3,4-oxadiazole F F F F N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 2-chloromethylmethyl-[1,3,4]oxadiazole. ): 413.8 (M+H).

Example 80 5-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,2,4-oxadiazole F F F F N N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and romethylmethyl-[1,2,4]oxadiazole. MS(m/e): 414.0 (M+H).

Example 81 2-tert-butyl[(1-methyltetrazolyl)methyl](3,3,4,4-tetrafluoropyrrolidin ine F F F F N N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 5-chloromethylmethyl-1H-tetrazole. MS(m/e): 414.2 (M+H).

Example 82 3-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 1,2,5-oxadiazole F F F F N N N N O In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine le 72, step a) and 3-chloromethylmethyl-furazan. MS(m/e): 414.2 (M+H).

Example 83 2-tert-butyl(2-methoxyethyl)(3,3,4,4-tetrafluoropyrrolidinyl)purine F F F F N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and omethoxy-ethane. MS(m/e): 376.0 (M+H).

Example 84 1-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol N N F In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 4-bromomethyltrifluoromethyltrityl- 1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. MS(m/e): 424.3 (M+H).

Example 85 1-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] pyrrolidinol N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester le 64, step a) and 3-bromomethyltrifluoromethyltrityl- 1H-pyrazole with subsequent cleavage of the trityl protecting group with TFA. MS(m/e): 424.0 (M+H).

Example 86 (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol N N F a) Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidinyl ester N N In analogy to the procedure described for the synthesis of (2-tert-Butyl-9H-purin- 6-yl)-pyrrolidinyl]-acetamide (example 48, a) the title compounds was prepared from 2- tert-butylchloro-9H-purine and acetic acid (S)-pyrrolidinyl ester. MS(m/e): 303.8 (M+H). b) (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol In analogy to the ure described for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 420.0 (M+H).

Example 87 (3S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol N N Cl In analogy to the procedure described for the sis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 386.0 (M+H).

Example 88 (3S)[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure bed for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 386.0 (M+H).

Example 89 7-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]oxaazaspiro[3.4]octane N F N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was ed from a)2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 1-bromomethoxy-ethane. MS(m/e): 384.0 (M+H).

Example 90 (3S)[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol N N In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethylmethanesulfonyl-benzene. MS(m/e): 430.2 (M+H).

Example 91 (3S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol OH Chiral N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethylmethanesulfonyl-benzene. MS(m/e): 387.2 (M+H).

Example 92 (3S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and rochloromethyl-pyridine. MS(m/e): 387.2 (M+H).

Example 93 2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine F F N F N N F In analogy to the procedure described for the synthesis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title nd was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 1,1,1-trifluoroiodo-propane. ): 414.2 (M+H).

Example 94 (3S)[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol N N O In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1-bromomethoxy-ethane. MS(m/e): 320.0 (M+H).

Example 95 (3S)[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 5-chloromethylmethyl-1H-tetrazole plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 358.2 (M+H).

Example 96 (3S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidin ol N N O In analogy to the procedure bed for the sis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 3-chloromethylmethyl-furazan plus uent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 358.2 (M+H).

Example 97 (3S)[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine le 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester le 86, step a) and 1-bromomethylchloro-benzene plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety.

MS(m/e): 386.4 (M+H).

Example 98 (3S)[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol N N In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 4-bromomethyltrifluoromethyltrityl-1H- pyrazoleplus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester . The trityl group was subsequently cleaved with TFA. MS(m/e): 410.4 (M+H).

Example 99 (3S)[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- phenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from ic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 1,1,1-trifluoroiodo-propane. MS(m/e): 358.0 (M+H).

Example 100 -[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 3-bromomethyltrifluoromethyltrityl-1H- pyrazoleplus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. The trityl group was subsequently cleaved with TFA. MS(m/e): 410.2 (M+H).

Example 101 (3S)[2-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidin ol N N N N N In y to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)Acetic acid (S)(2-tert-butyl-9H-purinyl)-pyrrolidin- 3-yl ester (example 86, step a) and 5-chloromethylmethyl-[1,2,4]oxadiazole plus uent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 358.0 (M+H).

Example 102 ert-butyl(3,3,3-trifluoropropyl)purinyl]methylpyrrolidinol N F F N N F In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from Acetic acid 1-(2-tert-butyl-9H-purinyl)methylpyrrolidinyl ester (example 64, step a) and 1, 1, 1-trifluoroiodo-propane plus subsequent treatment of the crude mixture / residue with K2CO3 in MeOH to cleave the ester moiety. MS(m/e): 372.2 (M+H). e 103 N-[(3S)[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinyl]acetamide N F F N N F In analogy to the ure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from N-[(S)(2-tert-Butyl-9H-purinyl)-pyrrolidinyl]- acetamide (example 48, step a) and trifluoroiodo-propane. MS(m/e): 399.0 (M+H).

Example 104 7-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane N N N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from a)2-tert-Butyl(2-oxaaza-spiro[3.4]octyl)-9H-purine (example 56, step a) and 3-chlorochloromethyl-pyridine. MS(m/e): 413.0 (M+H).

Example 105 2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl] methyl]purine F F N N In analogy to the procedure described for the synthesis of -butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine le 72, step a) and 1-bromomethyltrifluoromethyl-benzene. MS(m/e): 476.0 (M+H).

Example 106 2-tert-butyl[(2-methylsulfonylphenyl)methyl](3,3,4,4-tetrafluoropyrrolidin yl)purine F F N N In analogy to the procedure described for the synthesis of 2-tert-butyl[(4- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine (example 1) the title compound was prepared from 2-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-9H- purine (example 72, step a) and 1-bromomethylmethanesulfonyl-benzene. MS(m/e): 485.8 (M+H).

Example 107 -butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine N N N N a) 6-(3,3-Difluoro-pyrrolidinyl)fluoro-9H-purine N N N N To a solution of 6-chlorofluoro-9H-purine (500 mg 2.89 mmol) in tBuOH (10 mL) was added DIPEA (0.68 mL, 3.76 mmol) followed by 3, 3-difluoro-pyrrolidine hloride (415.5 mg 2.89 mmol) and the reaction mixture was heated in a sealed tube at 80 °C for 22 h. The solvent was removed under reduced pressure and the residue was purified by Combi-Flash column chromatography (40g, hexane/EtOAc 1/6) to yield the title compound (500 mg; 71 %) as brown solid MS(m/e): 244.2 (M+H). b) tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]-amine N NH N N In a sealed tube a solution of -difluoro-pyrrolidinyl)fluoro-9H-purine (500 mg, 2.058 mmol) in t-BuOH (10 mL) and tert-butyl amine (1.5 g, 20.57 mmol) was heated at 160 °C for 24 h. The reaction e was cooled to 25 °C and solvent was evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g, hexane/EtOAc 1/7) to yield the title compound (214 mg; 35 %) as a white solid.

MS(m/e): 297.2 (M+H). c) N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine To a stirred solution of 2-tert-butyl(2-oxaaza-spiro[3.3]heptyl)-7H-pyrrolo[2,3-d] pyrimidine (30 mg, 0.11 mmol) in DMF (5 mL) was added NaH (10 mg, 0.132 mmol) at 0 °C and d at 25 °C for 1 h. To this 1-bromomethylchloro-benzene (30 mg, 0.143 mmol) was added in one portion and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with NH4Cl, the solvent was removed under reduced re, the residue was dissolved in H2O (10 mL), extracted with EtOAc washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to yield the title compound (25 mg, 59 %) as off white solid. MS(m/e): 421 (M+H).

Example 108 N-tert-butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] purinamine N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). ): 455 (M+H).

Example 109 N-tert-butyl(3,3-difluoropyrrolidinyl)[(5-methyl-1,3,4-oxadiazol yl)methyl]purinamine N N N F O N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- phenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from utyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 393 (M+H).

Example 110 N-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purinamine N N F F N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine le 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 393 (M+H).

Example 111 N-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazol yl)methyl]purinamine N N F N F N O N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 393 (M+H).

Example 112 N-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purin amine N N F N N N In analogy to the procedure described for the synthesis of -butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). ): 422 (M+H).

Example 113 N-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purin amine N N N F N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 393 (M+H).

Example 114 N-tert-butyl(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl] 2-amine N N O N N In analogy to the procedure bed for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 465 (M+H).

Example 115 -butyl(3,3-difluoropyrrolidinyl)[(3-methyl-1,2,4-oxadiazol yl)methyl]purinamine N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title nd was prepared from tert-Butyl-[6-(3,3-difluoro-pyrrolidinyl)-9H-purinyl]- amine (example 107, step b). MS(m/e): 393 (M+H).

Example 116 (3S)[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]pyrrolidinol N N N N a) Acetic acid (S)(2-fluoro-9H-purinyl)-pyrrolidinyl ester N N N N In analogy to the procedure described for the synthesis of 6-(3,3-Difluoro-pyrrolidin yl)fluoro-9H-purine (example 107, step a) the title compound was prepared from 6- chlorofluoro-9H-purine and Acetic acid (S)-pyrrolidinyl ester. MS(m/e): 266.1 (M+H). b) Acetic acid (S)(2-tert-butylamino-9H-purinyl)-pyrrolidinyl ester N NH N N In analogy to the procedure described for the synthesis of tert-Butyl-[6-(3,3-difluoropyrrolidinyl )-9H-purinyl]-amine (example 107, step b) the title compound was prepared from Acetic acid (S)(2-fluoro-9H-purinyl)-pyrrolidinyl ester and tert.- amine. MS(m/e): 318.8 (M+H). c) (3S)[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl[(2- phenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 108, step b) and 1-bromomethylchloro-benzene. ): 401.3 (M+H).

Example 117 (3S)[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purinyl] pyrrolidinol N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 116, step b). ): 435.2 (M+H).

Example 118 (3S)[2-(tert-butylamino)[(3-chloropyridinyl)methyl]purinyl]pyrrolidin N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 116, step b). MS(m/e): 401.8 (M+H).

Example 119 (3S)[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinol N N HO N N N O In analogy to the procedure bed for the sis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from acetic acid (S)(2-tert-butylamino-9H-purinyl)- idinyl ester (example 116, step b). MS(m/e): 373.4 (M+H).

Example 120 1-[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol N N N N a) Acetic acid 1-(2-fluoro-9H-purinyl)methyl-pyrrolidinyl ester N NH N N In analogy to the procedure described for the synthesis of 6-(3,3-Difluoro-pyrrolidinyl)- ro-9H-purine (example 107, step a) the title compound was prepared from ro- 2-fluoro-9H-purine and Acetic acid 3-methyl-pyrrolidinyl ester. MS(m/e): 280.1 (M+H). b) Acetic acid 1-(2-tert-butylamino-9H-purinyl)methyl-pyrrolidinyl ester N NH N N In analogy to the procedure described for the synthesis of tert-Butyl-[6-(3,3-difluoropyrrolidinyl )-9H-purinyl]-amine (example 107, step b) the title compound was prepared from Acetic acid 1-(2-fluoro-9H-purinyl)methyl-pyrrolidinyl ester and tert.-butyl-amine. MS(m/e): 333.2 (M+H). c) 1-[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl[(2- phenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from Acetic acid 1-(2-tert-butylamino-9H-purinyl)methylpyrrolidinyl ester (example 120, step b) and 1-bromomethylchloro-benzene.

MS(m/e): 415.2 (M+H).

Example 121 1-[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol N N N N In analogy to the procedure described for the sis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title nd was prepared from Acetic acid 1-(2-tert-butylamino-9H-purinyl)methylpyrrolidinyl ester (example 120, step b). MS(m/e): 449.2 (M+H).

Example 122 (3S)[2-(tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol N F HO N N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was ed from acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 116, step b) plus deprotection of the trityl group with TFA.

MS(m/e): 425 (M+H).

Example 123 1-[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol N N HO N N N O In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title nd was prepared from Acetic acid 1-(2-tert-butylamino-9H-purinyl)methyl- idinyl ester (example 120, step b). MS(m/e): 387.3 (M+H).

Example 124 9-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy) purine O N N a) 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)-9H-purine O N N To a solution of 2-chloro(3,3-difluoro-pyrrolidinyl)-9H-purine (1 g, 4.12 mmol) in EtOAc (5 mL) were added o-pyran (0.75 ml, 8.23 mmol) and pTSA (39 mg; 0.21mmol) at 25 °C and the reaction mixture was heated at 50 °C for 5 h. The reaction e was diluted with EtOAc at 25 °C, washed with water, washed with saturated NaHCO3, washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40g; hexane/EtOAc 20/80) to yield 2-chloro(3,3-difluoro-pyrrolidinyl)(tetrahydropyranyl )-9H-purine (1.0 g; 74 %) as white solid. LC-MS: 344 (M+H).

A mixture of 2,2-dimethyl-propanol (1.9 g, 21.81 mmol) and NaH (60% in oil; 116 mg 2.90 mmol) was heated at 50 °C and 2-chloro(3,3-difluoro-pyrrolidinyl) (tetrahydro-pyranyl)-9H-purine (500 mg 1.45 mmol) was added. The reaction mixture was heated at 80 °C for 12 h. The mixture was quenched with water, extracted with DCM, washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure.

The residue was purified by Combi-Flash column chromatography (40g; /EtOAc /70) to yield 6-(3, 3-difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(tetrahydropyranyl )-9H-purine (250 mg; 35 %) as off white solid. LC-MS: 396 (M+H).

To a solution of 6-(3,3-difluoro-pyrrolidinyl)(2, 2-dimethyl-propoxy)(tetrahydropyranyl )-9H-purine (500 mg, 1.26 mmol) in EtOH (5 mL) was added pTSA (12 mg; 0.064 mmol) and the on mixture was heated at 80 °C for 4 h. The e was evaporated at 25 °C. The residue was dissolved in EtOAc, washed with water, saturated NaHCO3, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by Combi-Flash column tography (40g; hexane/EtOAc 20/80) to yield the title compound (350 mg; 89 %) as white solid. LC-MS: 312 (M+H). b) 9-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)purine In y to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine (example 124, step a) and 1-bromomethylchloro-benzene. ): 436 (M+H).

Example 125 -difluoropyrrolidinyl)(2,2-dimethylpropoxy)[[2-(trifluoromethyl) phenyl]methyl]purine F F O N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine (example 124, step a). MS(m/e): 470 (M+H).

Example 126 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2-methylsulfonylphenyl) methyl]purine F F O N N In y to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine le 124, step a). MS(m/e): 479.8 (M+H).

Example 127 2-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,3,4-oxadiazole F F O N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- phenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine (example 124, step a). MS(m/e): 408 (M+H).

Example 128 5-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,2,4-oxadiazole F F O N N In analogy to the ure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine (example 124, step a). MS(m/e): 408 (M+H).

Example 129 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]purine F F O N N In analogy to the procedure described for the sis of -butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine (example 124, step a). MS(m/e): 408 (M+H).

Example 130 (3S)[2-(tert-butylamino)(3,3,3-trifluoropropyl)purinyl]pyrrolidinol N N HO F N N a) Acetic acid (S)(2-fluoro-9H-purinyl)-pyrrolidinyl ester N NH N N In analogy to the ure described for the synthesis of 6-(3,3-Difluoro-pyrrolidin yl)fluoro-9H-purine (example 107, step a) the title compound was prepared from 6- fluoro-9H-purine and Acetic acid (S)-pyrrolidinyl ester. MS(m/e): 266.1 (M+H). b) Acetic acid (S)(2-tert-butylamino-9H-purinyl)-pyrrolidinyl ester N NH N N In analogy to the procedure described for the synthesis of tert-Butyl-[6-(3,3-difluoropyrrolidinyl )-9H-purinyl]-amine le 107, step b) the title compound was prepared from Acetic acid (S)(2-fluoro-9H-purinyl)-pyrrolidinyl ester and tert.- butyl-amine. MS(m/e): 277 (M+H). c) (3S)[2-(tert-butylamino)(3,3,3-trifluoropropyl)purinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from Acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 130, step b). MS(m/e): 373.3 (M+H).

Example 131 1-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl]methyl pyrrolidinol O N N In analogy to the procedure described for the sis of 9-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purine (example 124) the intermediate 1-[2-(2,2-Dimethyl-propoxy)-9H-purinyl]methyl-pyrrolidinol was prepared from acetic acid 1-(2-fluoro-9H-purinyl)methyl-pyrrolidinyl ester by protection of N1 with THP and subsequent nucleophilic substitution at C7 with 2,2- dimethyl-propanol and finally deprotection at N1 with p-TSA. LC-MS: 306.4 (M+H).

The free alcohol moiety was ted with TBDMS by reaction of 1-[2-(2,2-Dimethylpropoxy )-9H-purinyl]methyl-pyrrolidinol with tert-butyldimethylsilyl chloride and zole in DMF.

In analogy to the procedure described for the synthesis of N-tert-butyl[(2- phenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from TBDMS protected 1-[2-(2,2-Dimethyl-propoxy)-9H-purin- 6-yl]methyl-pyrrolidinol and 1-bromomethylchloro-benzene. Deprotection of the silyl protecting group with TBAF yielded the title compound. MS(m/e): 430 (M+H).

Example 132 2,2-dimethylpropoxy)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol O N N In analogy to the procedure described for the synthesis of 1-[9-[(2-chlorophenyl)methyl]- 2-(2,2-dimethylpropoxy)purinyl]methylpyrrolidinol (example 131) the title compound was prepared from the TBDMS-protected 1-[2-(2,2-Dimethyl-propoxy)-9H- 6-yl]methyl-pyrrolidinol and 1-Bromomethyltrifluoromethyl-benzene plus ge of the TBDMS group with TBAF. MS(m/e): 463.8 (M+H).

Example 133 1-[2-(2,2-dimethylpropoxy)[(2-methylsulfonylphenyl)methyl]purinyl] methylpyrrolidinol O N N O In analogy to the procedure described for the synthesis of 1-[9-[(2-chlorophenyl)methyl]- 2-(2,2-dimethylpropoxy)purinyl]methylpyrrolidinol (example 131) the title compound was prepared from the TBDMS-protected 1-[2-(2,2-Dimethyl-propoxy)-9H- 6-yl]methyl-pyrrolidinol and 1-Bromomethylmethanesulfonyl-benzene plus cleavage of the TBDMS group with TBAF. MS(m/e): 474.0 (M+H).

Example 134 1-[9-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)purinyl] methylpyrrolidinol O N N In y to the procedure described for the synthesis of 1-[9-[(2-chlorophenyl)methyl]- -dimethylpropoxy)purinyl]methylpyrrolidinol (example 131) the title compound was prepared from the TBDMS-protected 1-[2-(2,2-Dimethyl-propoxy)-9H- purinyl]methyl-pyrrolidinol and 2-Bromomethylchloro-pyridine plus cleavage of the TBDMS group with TBAF. MS(m/e): 430.8 (M+H).

Example 135 1-[2-(2,2-dimethylpropoxy)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol O N N In analogy to the procedure described for the synthesis of (2-chlorophenyl)methyl]- 2-(2,2-dimethylpropoxy)purinyl]methylpyrrolidinol (example 131) the title compound was prepared from the TBDMS-protected 1-[2-(2,2-Dimethyl-propoxy)-9H- purinyl]methyl-pyrrolidinol and 3-Chloromethylmethyl-furazan plus cleavage of the TBDMS group with TBAF. MS(m/e): 401.8 (M+H).

Example 136 tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol N F HO N N N N In y to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from Acetic acid 1-(2-tert-butylamino-9H-purinyl)methylpyrrolidinyl ester (example 120, step b) plus cleavage of the trityl group with TFA.

MS(m/e): 439.3 (M+H).

Example 137 N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)[[2-(trifluoromethyl)phenyl] methyl] purinamine N N N a) 2-Fluoro(2-oxaaza-spiro[3.3]heptyl)(tetrahydro-pyranyl)-9H-purine F N N The title compound was prepared from6-chlorofluoro(tetrahydro-pyranyl)-9H- purine and protection with THP. LC-MS: 320.3 (M+H). b) tert-Butyl-[6-(2-oxaaza-spiro[3.3]heptyl)-9H-purinyl]-amine N N N H H The title compound was prepared from 2-Fluoro(2-oxaaza-spiro[3.3]heptyl) (tetrahydro-pyranyl)-9H-purine h nucleophilic substitution with tert.butylamine and subsequent ge of the THP group with PTSA. c) N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)[[2-(trifluoromethyl)phenyl] methyl]purinamine In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine le 107) the title compound was prepared from tert-Butyl-[6-(2-oxaaza-spiro[3.3]heptyl)-9H-purin yl]-amine (example 137, step b). MS(m/e): 446.8 (M+H).

Example 138 N-tert-butyl[(2-chlorophenyl)methyl](2-oxaazaspiro[3.3]heptanyl)purin amine N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(2-oxaaza-spiro[3.3]heptyl)-9H-purin yl]-amine (example 137, step b). MS(m/e): 413 (M+H).

Example 139 -[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol N N a) 2-tert-Butylchloro(1-cyclopropyl-1H-tetrazolylmethyl)-9H-purine N N A mixture of 2-tert-butylchloro-9H-purine (200 mg, 949 µmol), NaH 60% (49.4 mg, 1.23 mmol) in DMF (8 mL) was treated with 5-(chloromethyl)cyclopropyl-1H-tetrazole (226 mg, 1.42 mmol) and stirred at 60 °C. The mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The c layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by HPLC to yield the title nd (203 mg, 64 %) as off-white solid. b) (3S)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol 2-tert-butylchloro((1-cyclopropyl-1H-tetrazolyl)methyl)-9H-purine (50 mg, 150 µmol) in acetonitrile (683 µL) was treated with DIPEA (29.1 mg, 225 µmol) and (S)- pyrrolidinol (14.4 mg, 165 µmol). The reaction mixture was stirred for 3 h at rt. 1 mL toluene was added to the reaction mixture and the solution concentrated. The residue was transferred to a separating funnel, d with citric acid 10% and extracted. The aqueous phase was extracted a second time with toluene. The combined organic phases were washed with NaHCO3 followed by NaCl. The organic ts were combined and dried over Na2SO4. Under stirring heptane was added. After 5 min product started to crystallize and the suspension was stirred overnight. The suspension was filtered, the crystals washed with heptane and dried to yield the title compound (16 mg, 28 %) as a white solid.

MS(m/e): 384.5 (M+H).

Example 140 3-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,2,5-oxadiazole F F O N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 6-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 9H-purine le 124, step a). MS(m/e): 408 (M+H).

Example 141 N-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl](2-oxa azaspiro[3.3]heptanyl)purinamine N N N H N In y to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from tert-Butyl-[6-(2-oxaaza-spiro[3.3]heptyl)-9H-purin yl]-amine le 137, step b). MS(m/e): 385.3 (M+H).

Example 142 N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)(3,3,3-trifluoropropyl)purin amine N N N In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title nd was prepared from tert-Butyl-[6-(2-oxaaza-spiro[3.3]heptyl)-9H-purin yl]-amine (example 137, step b). MS(m/e): 385.2 (M+H).

Example 143 6-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl]oxa azaspiro[3.3]heptane O N N a) 2-(2,2-Dimethyl-propoxy)(2-oxaaza-spiro[3.3]heptyl)-9H-purine O N N 2,6-Dichloro-9H-purine was N1 protected with THP in the presence of PTSA. Subsequent nucleophilic substitution first with 2-Oxaaza-spiro[3.3]heptane at C5 and second with 2,2-Dimethyl-propanol at C7 yielded the intermediate which was deprotected at N1 with PTSA to yield the title nd. b) (2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl]oxa azaspiro[3.3]heptane In analogy to the ure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from 2-(2,2-Dimethyl-propoxy)(2-oxaaza-spiro[3.3]hept yl)-9H-purine (example 143, step a). MS(m/e): 428 (M+H).

Example 144 3-[[2-tert-butyl(4-methylpiperazinyl)purinyl]methyl]methyl-1,2,5- oxadiazole N N In analogy to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title nd was prepared from 2-tert-butylchloro-9H-purine, 3-(chloromethyl) methyl-1,2,5-oxadiazole and 1-methylpiperazine. MS(m/e): 371.7 (M+H).

Example 145 [(2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidin- 2-yl]methanol N N In analogy to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from 2-tert-butylchloro-9H-purine, 3-(chloromethyl) methyl-1,2,5-oxadiazole and rrolidinylmethanol. MS(m/e): 372.7 (M+H). e 146 [(2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidin yl]methanol N N In analogy to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from 2-tert-butylchloro-9H-purine, 5-(chloromethyl) cyclopropyl-1H-tetrazole and (R)-pyrrolidinylmethanol. MS(m/e): 398.5 (M+H). e 147 (2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidine carbonitrile N N N N In y to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from -butylchloro-9H-purine, 5-(chloromethyl) cyclopropyl-1H-tetrazole and (R)-pyrrolidinecarbonitrile hydrochloride. MS(m/e): 393.6 (M+H).

Example 148 (2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidine- 2-carbonitrile N N N N In analogy to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from 2-tert-butylchloro-9H-purine, 3-(chloromethyl) -1,2,5-oxadiazole and (R)-pyrrolidinecarbonitrile hydrochloride. ): 367.5 (M+H).

Example 149 6-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.3]heptane N N In analogy to the procedure described for the synthesis of (3S)[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from 2-tert-butylchloro-9H-purine, 3-(chloromethyl) methyl-1,2,5-oxadiazole and 2-oxaazaspiro[3.3]heptane oxalate. MS(m/e): 370.5 (M+H).

Example 150 3-[[2-tert-butyl(1,3-thiazolidinyl)purinyl]methyl]methyl-1,2,5-oxadiazole N N In analogy to the procedure described for the synthesis of -[2-tert-butyl[(1- cyclopropyltetrazolyl)methyl]purinyl]pyrrolidinol (example 139) the title compound was prepared from 2-tert-butylchloro-9H-purine, 3-(chloromethyl) methyl-1,2,5-oxadiazole and thiazolidine. MS(m/e): 360.5 (M+H). Example 151 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)-9H-purine O N N To a solution of 2-chloro(3,3-difluoro-pyrrolidinyl)-9H-purine (1 g, 4.12 mmol) in EtOAc (5 mL) were added dihydro-pyran (0.75 ml, 8.23 mmol) and pTSA (39 mg; 0.21mmol) at 25 °C and the reaction mixture was heated at 50 °C for 5 h. The reaction mixture was diluted with EtOAc at 25 °C, washed with water, washed with saturated NaHCO3, washed with brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40g; hexane/EtOAc 20/80) to yield 2-chloro(3,3-difluoro-pyrrolidinyl)(tetrahydropyranyl )-9H-purine (1.0 g; 74 %) as white solid. LC-MS: 344 (M+H).

A mixture of 2,2-dimethyl-propanol (1.9 g, 21.81 mmol) and NaH (60% in oil; 116 mg 2.90 mmol) was heated at 50 °C and ro(3,3-difluoro-pyrrolidinyl) (tetrahydro-pyranyl)-9H-purine (500 mg 1.45 mmol) was added. The reaction mixture was heated at 80 °C for 12 h. The mixture was quenched with water, ted with DCM, washed with brine, dried over ous Na2SO4 and evaporated under reduced pressure.

The residue was purified by Combi-Flash column tography (40g; hexane/EtOAc /70) to yield 6-(3, 3-difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(tetrahydropyranyl )-9H-purine (250 mg; 35 %) as off white solid. LC-MS: 396 (M+H).

To a on of 6-(3,3-difluoro-pyrrolidinyl)(2, thyl-propoxy)(tetrahydropyranyl )-9H-purine (500 mg, 1.26 mmol) in EtOH (5 mL) was added pTSA (12 mg; 0.064 mmol) and the reaction mixture was heated at 80 °C for 4 h. The mixture was evaporated at 25 °C. The residue was dissolved in EtOAc, washed with water, saturated NaHCO3, brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by Combi-Flash column tography (40g; hexane/EtOAc 20/80) to yield the title compound (350 mg; 89 %) as white solid. LC-MS: 312 (M+H).

Example 152 [(3S)[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinyl] e In analogy to the procedure described for the synthesis of N-tert-butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from acetic acid (S)(2-tert-butylamino-9H-purinyl)- pyrrolidinyl ester (example 108, step b) and 3-chloromethylmethyl-furazan.

MS(m/e): 415 (M+H).

Example 153 [1-[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinyl] acetate In y to the procedure described for the synthesis of -butyl[(2- chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purinamine (example 107) the title compound was prepared from Acetic acid 1-(2-tert-butylamino-9H-purinyl)methylpyrrolidinyl ester (example 120, step b) and romethylmethyl-furazan.

MS(m/e): 428.8 (M+H).

Example 154 9-benzylchloro(3,3-difluoropyrrolidinyl)purine Cl N N To a solution of 2,6-dichloro-9H-purine (commercially available) (1g; 5.29mmol) in DMF (10 mL) was added Et3N (0.8 mL; 5.82 mmol) followed by (3,3-difluoropyrrolidine hydrochloride (0.8 g; 5.56 mmol) at 25 °C and the reaction mixture was heated at 80 °C for 12 h. The reaction e was quenched with ice-cold water and stirred it for 30 min at 0 °C. The solid was filtered; washed with cold water, and finally dried under high vaccum at 50 °C to give 2-chloro(3,3-difluoropyrrolidinyl)-9H-purine (1 g; 73 %) as light yellow solid; which was directly used for next step without further purification. LCMS : 260.2 (M+H). To a solution of crude 2-chloro(3,3-difluoro-pyrrolidinyl)-9H- purine (200 mg, 0.7 mmol) in DMF (10 mL) was added NaH (70 mg, 1.7 mmol) at 0 °C and stirred the reaction mixture at 25°C for 1 h. To this benzyl bromide (160 mg, 0.92 mmol) was added in one portion, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with NH4Cl, the t was removed under reduced re, and the residue was dissolved in H2O (10 mL), extracted with EtOAc; washed with brine, concentrated in vacuo. The crude was purified by column chromatography (SiO2; 100-200mesh; 20% EtOAc/Hexanes) to give 9-benzylchloro(3, 3- difluoropyrrolidinyl)-9H-purine (100 mg, 59 %) as off white solid. LC-MS: 349.8 (M+H).

Example 155 (3S)[2-tert-butyl[(1-propanyltetrazolyl)methyl]purinyl]pyrrolidinol N N a) -butylchloro((1-isopropyl-1H-tetrazolyl)methyl)-9H-purine N N NaH (60%, 49.4 mg, 1.23 mmol) was added to an ice cold solution of 2-tert-butyl chloro-9H-purine (CAN 7337367, 200 mg, 949 µmol) in DMF (4 mL). The reaction mixture was stirred at ambient temperature for 45 min. 5-(Chloromethyl)isopropyl-1H- tetrazole (CAN 1877395, 229 mg, 1.42 mmol) was added to the reaction e at 0 C and the reaction mixture was stirred at 60 °C for 12 h. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to give 446 mg of a brown solid which was ed by HPLC to give the title compound (218 mg, 69%) as white solid.

MS(m/e): 335.2 (M+H). b) (3S)[2-tert-butyl[(1-propanyltetrazolyl)methyl]purinyl]pyrrolidinol DIPEA (CAN 70875, 29.0 mg, 38.3 µL, 224 µmol) and rrolidinol (CAN 1002438, 14.3 mg, 13.7 µL, 164 µmol) were added to a solution of 2-tert-butyl chloro((1-isopropyl-1H-tetrazolyl)methyl)-9H-purine (50 mg, 149 µmol) in acetonitrile (679 µL). The reaction mixture was stirred overnight at ambient ature. 10% Aqueous citric acid was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (65 mg, quant.) as white solid. MS(m/e): 386.2 (M+H).

Example 156 2-tert-butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine N N a) 2-tert-butylchloro((1-cyclopropyl-1H-tetrazolyl)methyl)-9H-purine N N In y to the procedure described in example 155 a), 2-tert-butylchloro-9H-purine (CAN 7337367, 400 mg, 1.9 mmol) was reacted with 5-(chloromethyl)cyclopropyl- 1H-tetrazole (CAN 7, 452 mg, 2.85 mmol) to give the title compound (348 mg, 55%) as off-white solid. MS(m/e): 333.2 (M+H). b) -butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine In analogy to the procedure described in e 155 b), 2-tert-butylchloro((1- cyclopropyl-1H-tetrazolyl)methyl)-9H-purine (50 mg, 150 µmol) was reacted with 3,3- difluoropyrrolidine hydrochloride (CAN 1634576, 23.7 mg, 165 µmol) to give the title compound (28 mg, 46%) as white solid. MS(m/e): 404.3 (M+H).

Example 157 [(2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol N N a) 2-tert-butylchloro((3-chloropyridinyl)methyl)-9H-purine N N In analogy to the procedure described in example 155 a), 2-tert-butylchloro-9H-purine (CAN 7337367, 500 mg, 2.37 mmol) was reacted with 3-chloro omethyl)pyridine hydrochloride (CAN 1244252, 707 mg, 3.56 mmol) to give the title compound (208 mg, 26%) as off-white solid. MS(m/e): 336.4 (M+H). b) 1-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol In analogy to the procedure described in example 155 b), 2-tert-butylchloro((3- chloropyridinyl)methyl)-9H-purine (40 mg, 119 µmol) was reacted with (R)-pyrrolidin- 2-ylmethanol (CAN 688323, 13.2 mg, 12.9 µL, 131 µmol) to give the title compound (16 mg, 34%) as colorless solid. MS(m/e): 401.2 (M+H).

Example 158 (3S)[2-tert-butyl[(1-propyltetrazolyl)methyl]purinyl]pyrrolidinol N N a) (S)(2-tert-butyl-9H-purinyl)pyrrolidinol N N DIPEA (CAN 70875, 123 mg, 166 µL, 949 µmol) was added to a solution of 2-tertbutylchloro-9H-purine (CAN 7337367, 100 mg, 475 µmol) and (S)-pyrrolidinol (CAN 1002438, 74.4 mg, 71.0 µL, 854 µmol) in MeCN (2.5 mL). The reaction was stirred for 24 h at ambient temperature. 10% Citric acid was added and the mixture was washed with DCM (2 x 20 mL). The aqueous layer was basified with NaHCO3 and extracted with DCM (2 x 20 mL). The combined extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (50 mg, 80%) as white solid. MS(m/e): 262.5 (M+H). b) (3S)[2-tert-butyl[(1-propyltetrazolyl)methyl]purinyl]pyrrolidinol DBU (CAN 66742, 93.8 mg, 92.9 µL, 616 µmol) was added to a solution of (S)(2- tert-butyl-9H-purinyl)pyrrolidinol (46 mg, 176 µmol) and 5-(chloromethyl) propyl-1H-tetrazole (CAN 8481782, 84.8 mg, 528 µmol) in DMF (1 mL). The reaction was stirred for 16 h at ambient ature. Water/1N HCl (1:1), 20 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed tially with water and brine. The organic phase was dried over Na2SO4 and trated in vacuo to give the title compound (62 mg, 91%) as ite foam. ): 386.6 (M+H).

Example 159 (2R,3S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl] (hydroxymethyl)pyrrolidinol Chiral N N In analogy to the procedure described in example 155 b), 2-tert-butylchloro((3- chloropyridinyl)methyl)-9H-purine (Example 157 a, 40 mg, 119 µmol) was reacted with (2R,3S)(hydroxymethyl)pyrrolidinol (CAN 1050170, 13.9 mg, 119 µmol) to give the title compound (3 mg, 6%) as colorless solid. MS(m/e): 417.6 (M+H).

Example 160 2-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoroazetidinyl)purine F F N N In analogy to the procedure described in example 155 b), -butylchloro((3- chloropyridinyl)methyl)-9H-purine (Example 157 a, 40 mg, 119 µmol) was d with 3,3-difluoroazetidine hydrochloride (CAN 2883157, 30.8 mg, 238 µmol) to give the title compound (13 mg, 28%) as white solid. MS(m/e): 393.50 (M+H).

Example 161 3-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]-1,3-thiazolidine N N DIPEA (CAN 70875, 123 mg, 166 µL, 949 µmol) was added to a solution of 2-tertbutylchloro loropyridinyl)methyl)-9H-purine (Example 157 a, 37 mg, 110 µmol) and thiazolidine (CAN 5049, 31.0 mg, 27.4 µL, 330 µmol) in e (1 mL) and N,N-dimethylacetamide (122 µL). The reaction was d for 2.5 h at 120 °C.Water was added and the reaction mixture was extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give 39 mg of a yellow solid which was purified by flash chromatography (silica gel, 5 g, 0% to 35% EtOAc in heptane) and preparative HPLC to give the title compound (13 mg, %) as off-white solid. MS(m/e): 389.2 (M+H).

Example 162 ert-butyl[(3-chloropyridinyl)methyl]purinyl]-2λ6-thia azaspiro[3.3]heptane 2,2-dioxide O O N N DIPEA (CAN 70875, 76.9 mg, 102 µL, 595 µmol) was added to a solution of 2-tert- butylchloro((3-chloropyridinyl)methyl)-9H-purine (Example 157 a, 40 mg, 119 µmol) and 2-thiaazaspiro[3.3]heptane, 2,2-dioxide uoroacetic acid salt of CAN 12631827, 62.2 mg, 238 µmol) in dioxane (1.1 mL) and N,N-dimethylacetamide (131 µL). The reaction mixture was stirred for 16 h at 120 °C.Water was added and the reaction mixture was extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give 55 mg of a light brown solid which was purified by preparative TLC (silica gel, 1.0 mm, EtOAc) to give the title compound (27 mg, 51%) as white solid. MS(m/e): 447.2 (M+H).

Example 163 (2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidine itrile N N DIPEA (CAN 70875, 76.9 mg, 102 µL, 595 µmol) was added to a on of 2-tert- butylchloro((3-chloropyridinyl)methyl)-9H-purine (Example 157 a, 40 mg, 119 µmol) and (R)-pyrrolidinecarbonitrile hydrochloride (CAN 6756023, 47.3 mg, 357 µmol) in dioxane (623 µL). The reaction mixture was heated in the microwave oven for 30 min at 120 °C. Water was added and the mixture was extracted with EtOAc (2 x 20 mL).

The organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give 38 mg of crude productwhich was purified by preparative TLC (silica gel, 1.0 mm, 1:1, Heptanes/EtOAc) to give the title compound (3 mg, 6%) as white solid. MS(m/e): 396.2 (M+H).

Example 164 (3S)[2-tert-butyl[[1-(cyclopropylmethyl)tetrazolyl]methyl]purin yl]pyrrolidinol N N In analogy to the procedure described in example 158 b), (S)(2-tert-butyl-9H-purin yl)pyrrolidinol (Example 158 a, 40 mg, 153 µmol) was reacted with 5-(chloromethyl)- 1-(cyclopropylmethyl)-1H-tetrazole (CAN 17, 79.3 mg, 459 µmol) to give the title compound (45 mg, 74%) as white viscous oil. MS(m/e): 398.3 (M+H).

Example 165 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)pyrrolidinol OH F N N DIPEA (CAN 8-5, 46.1 mg, 61.1 µL, 357 µmol) was added to a solution of 2-tertbutylchloro ((3-chloropyridinyl)methyl)-9H-purine (Example 157 a, 30 mg, 89.2 µmol) and 3-(trifluoromethyl)pyrrolidinol hydrochloride (CAN 13341477, 34.2 mg, 178 µmol) in NMP (1 mL). The reaction mixture was stirred for 16 h at 100 °C. Water was added and the mixture was extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give 76 mg of a dark brown oil which was purified by prep. TLC (silica gel, 2.0 mm, 1:1 Heptane/EtOAc) to give the title compound (29 mg, 72%) as off-white viscous oil.

MS(m/e): 455.3 (M+H).

Example 166 (3S)[2-tert-butyl[(1-tert-butyltetrazolyl)methyl]purinyl]pyrrolidinol N N In analogy to the procedure described in example 158 b), (S)(2-tert-butyl-9H-purin yl)pyrrolidinol (Example 158 a, 40 mg, 153 µmol) was reacted with 1-tert-butyl (chloromethyl)-1H-tetrazole (CAN 754707, 88.1 mg, 459 µmol) to give the title compound (29 mg, 47%) as ite solid. MS(m/e): 400.4 (M+H). e 167 ert-butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)azetidinol HO F N N In analogy to the procedure described in example 171 a), 2-tert-butylchloro((3- pyridinyl)methyl)-9H-purine (Example 157 a, 30 mg, 89.2 µmol) was reacted with 3-(trifluoromethyl)azetidinol hydrochloride (CAN 8481921, 31.7 mg, 178 µmol) to give the title compound (26 mg, 66%) as white solid. MS(m/e): 441.3 (M+H).

Example 168 2-tert-butyl[(3-chloropyridinyl)methyl](2,2-difluoroazaspiro[2.4]heptan yl)purine N N In analogy to the ure described in example 171 a), 2-tert-butylchloro((3- chloropyridinyl)methyl)-9H-purine (Example 157 a, 29 mg, 86.3 µmol) was reacted with 1,1-difluoroazaspiro[2.4]heptane hydrochloride (CAN 12150717, 29.3 mg, 173 µmol) to give the title compound (29 mg, 78%) as off-white solid. MS(m/e): 433.3 (M+H).

Example 169 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]methylazetidinol N N In analogy to the procedure described in e 171 a), 2-tert-butylchloro((3- chloropyridinyl)methyl)-9H-purine (Example 157 a, 30 mg, 89.2 µmol) was reacted with 3-methylazetidinol hydrochloride (CAN 1246688, 22.1 mg, 178 µmol) to give the title compound (11 mg, 32%) as colorless solid. MS(m/e): 387.3 (M+H).

Example 170 Pharmacological tests The following tests were carried out in order to determine the activity of the compounds of formula I: Radioligand g assay The ty of the compounds of the invention for cannabinoid CB1 receptors was determined using ended amounts of ne preparations (PerkinElmer) of human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or 2.6 nM [3H]-CP-55,940 (Perkin Elmer) as radioligand, respectively. Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4 for CB1 receptor and 50 mM Tris, 5 mM MgCl2, 2.5 mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4 for CB2 receptor) in a total volume of 0.2 ml for 1h at 30 °C shaking. The reaction was terminated by rapid filtration through microfiltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; Packard). Bound ctivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited), with the Kd values for [3H]CP55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 receptor with affinities below 10 µM, more particularly of 1 nM to 3 µM and most particularly of 1 nM to 100 nM. cAMP Assay CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hours prior to the experiment 50.000 cells per well in a black 96 well plate with flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No. 31331), 1x HT ment, with 10 % fetal calf serum and ted at 5% CO2 and 37 °C in a humidified incubator. The growth medium was exchanged with Krebs Ringer Bicarbonate buffer with 1 mM IBMX and incubated at °C for 30 min. nds were added to a final assay volume of 100 µl and incubated for 30 min at 30 °C. Using the cAMP-Nano-TRF detection kit the assay (Roche Diagnostics) was d by the addition of 50 µl lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN3) and 50 µl detection solutions (20 µM mAb Alexa700- cAMP 1:1, and 48 µM RutheniumAHA-cAMP) and shaken for 2h at room temperature.

The time-resolved energy transfer is measured by a TRF reader (Evotec Technologies GmbH), ed with a ND:YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the emission with a delay of 100 ns and a gate of 100 ns, total re time 10s at 730 (bandwidth30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is ated as follows: FRET = T730-Alexa730-P(T645- B645) with P = Ru730-B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm, respectively. cAMP content is determined from the function of a standard curve spanning from 10 µM to 0.13 nM cAMP.

EC50 values were determined using Activity Base analysis (ID ss on, Limited). The EC50 values for a wide range of cannabinoid agonists generated from this assay were in agreement with the values published in the scientific literature.

The compounds of the invention are CB2 receptor agonists with EC50 below 1 μM and selectivity versus CB1 in the corresponding assay of at least 10 fold. Particular compound of the invention are CB2 receptor agonists with EC50 below 0.05 μM and selectivity versus CB1 in the corresponding assay of at least 500 fold.

For example, the following compounds showed the ing human EC50 values in the functional cAMP assay described above: Example EC50:CB2 EC50:CB1 Example EC50:CB2 EC50:CB1 1 0.0116 >10 86 0.0011 >10 2 0.0006 0.6766 87 0.0021 >10 3 0.0181 >10 88 0.0756 >10 4 0.0031 >10 89 0.5726 >10 0.0007 0.7406 90 0.0079 >10 6 0.0005 0.4331 91 0.0017 >10 7 0.0347 >10 92 0.0084 >10 8 0.0753 >10 93 0.0898 >10 9 0.0488 >10 94 0.4396 >10 0.0498 >10 95 0.3632 >10 11 0.0617 >10 96 0.0148 >10 12 0.0031 >10 97 0.0018 >10 13 0.0054 1.4971 98 0.0223 >10 14 0.023 >10 99 0.2276 >10 0.0235 >10 100 0.0066 >10 16 0.006 >10 101 0.3699 >10 17 0.0035 >10 102 0.1346 >10 18 0.0033 >10 103 0.2111 >10 19 0.0352 >10 104 0.1595 >10 0.0125 >10 105 0.0089 >10 21 0.0022 >10 106 0.0399 >10 22 0.0057 >10 107 0.0081 >10 23 0.0044 >10 108 0.0067 >10 24 0.0692 >10 109 0.804 >10 0.0588 >10 110 0.0183 >10 26 0.0492 >10 111 0.0147 >10 27 0.0141 >10 112 0.0079 >10 28 0.001 >10 113 0.2487 >10 29 0.4272 >10 114 0.0455 >10 0.3007 >10 115 0.195 >10 31 0.0214 >10 116 0.0121 >10 32 0.0034 >10 117 0.0072 >10 33 0.0034 >10 118 0.1521 >10 34 0.009 >10 119 0.1492 >10 0.4325 >10 120 0.1077 >10 36 0.1504 >10 121 0.0413 >10 37 0.2743 >10 122 0.1524 >10 38 0.0203 >10 123 0.5626 >10 39 0.0169 >10 124 0.0027 >10 40 0.0712 >10 125 0.0026 >10 41 0.0092 2.3294 126 0.0245 >10 42 0.0037 >10 127 0.3315 >10 43 0.0166 >10 128 0.1089 >10 44 0.0148 >10 129 0.0956 >10 45 0.0496 >10 130 0.2149 >10 46 0.1394 >10 131 0.0667 >10 47 0.1015 >10 132 0.0221 >10 48 0.1272 >10 133 0.1488 >10 49 0.3109 >10 134 0.1783 >10 50 0.5344 >10 135 0.0307 >10 51 0.0647 >10 136 0.1499 >10 52 0.2294 >10 137 0.0197 >10 53 0.1753 >10 138 0.0781 >10 54 0.3882 >10 139 0.201 >10 55 0.1378 >10 140 0.0092 >10 56 0.0558 >10 141 0.0409 >10 57 0.4665 >10 142 0.6806 >10 58 0.5058 >10 143 0.268 >10 59 0.0167 >10 144 0.2107 >10 60 0.1748 >10 145 0.0061 >10 61 0.0296 >10 146 0.0551 >10 62 0.1456 >10 147 0.1755 >10 63 0.6606 >10 148 0.0157 >10 64 0.0134 >10 149 0.1848 >10 65 0.0916 >10 150 0.0105 >10 66 0.2402 >10 151 0.0287 >10 67 0.009 >10 152 0.431 >10 68 0.0248 >10 153 0.1102 >10 69 0.0468 >10 154 0.2109 >10 70 0.0595 >10 155 0.0823 >10 71 0.6804 >10 156 0.0091 >10 72 0.0124 >10 157 0.0043 >10 73 0.1179 >10 158 0.0616 >10 74 0.0884 >10 159 0.5913 >10 75 0.2802 >10 160 1 >10 76 0.1531 >10 161 0.01259 >10 77 0.2051 >10 162 0.0701 0.3277 78 0.0175 >10 163 0.0069 >10 79 0.1162 >10 164 0.0207 >10 80 0.1793 >10 165 0.0624 4.0242 81 0.0685 3.1197 166 0.1034 >10 82 0.0492 >10 167 0.035 >10 83 0.0646 >10 168 0.0324 >10 84 0.0793 >10 169 0.0514 >10 85 0.0221 >10 Example A Film coated tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Kernel: Compound of a (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl ose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg The active ingredient is sieved and mixed with microcrystalline ose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is then mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.

Example B Capsules containing the following ingredients can be manufactured in a conventional Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg The components are sieved and mixed and filled into es of size 2.

Example C Injection solutions can have the following composition: Compound of formula (I) 3.0 mg hylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by on of acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims

Claims 1. A compound of formula (I) R2 R3 R1 N N A R4 wherein 5 A is CH2, CH2CH2 , CH2CO or absent; R1 is tert.-butyl, tert.-butylamino, 2,2-dimethylpropyloxy or halogen; R2 and R3, together with the en atom to which they are attached, form idinyl, substituted idinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa azaspiro[3.4]octyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, substituted 10 azetidinyl, 2,2-dioxo-2λ6-thiaazaspiro[3.3]heptyl or halo azaspiro[2.4]heptyl, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from halogen, hydroxyl, alkyl, hydroxyalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy and haloalkyl and wherein substituted azetidinyl is azetidinyl substituted with one 15 or two substituents selected from halogen, hydroxyl, alkyl and haloalkyl; and R4 is hydrogen, phenyl, enyl, alkylphenyl, kylphenyl, pyridinyl, halopyridinyl, cycloalykl, alkyl, alkyloxadiazolyl, oxolanyl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, lkyltetrazolyl, haloalkyl-1H-pyrazolyl or cycloalkylalkyltetrazolyl; 20 or a pharmaceutically acceptable salt or ester thereof; provided that ro(1-pyrrolidinyl)-9H-purine; 2-chloro(phenylmethyl)(1-pyrrolidinyl)-9H-purine; 1-[2-chloro(1-methylethyl)-9H-purinyl]pyrrolidinol; and 2-chloro[1-(4-methylpiperazinyl)]purine; are excluded. 2. A compound according to claim 1, wherein A is CH2. 3. A compound according to claim 1 or 2, wherein R1 is tert.-butyl or 2,2- 5 ylpropyloxy. 4. A compound according to any one of claims 1 to 3, wherein R1 is tert.-butyl. 5. A compound according to any one of claims 1 to 4, wherein R2 and R3, together with the nitrogen atom to which they are attached, form thiazolidinyl, substituted pyrrolidinyl or substituted azetidinyl, wherein wherein substituted pyrrolidinyl is 10 idinyl substituted with one or two substituents independently selected from halogen, hydroxyl, hydroxyalkyl and cyano and wherein substituted azetidinyl is inyl substituted with one or two substituents selected from halogen, hydroxyl and kyl. 6. A compound according to any one of claims 1 to 5, wherein R2 and R3, together with 15 the nitrogen atom to which they are attached, form thiazolidinyl, substituted pyrrolidinyl or tuted azetidinyl, wherein wherein substituted pyrrolidinyl is idinyl substituted with one or two tuents independently selected from fluorine, yl, hydroxymethyl and cyano and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from fluoro, hydroxyl 20 and trifluoromethyl. 7. A compound according to any one of claims 1 to 6, wherein R2 and R3, together with the nitrogen atom to which they are attached, form thiazolidinyl, difluoropyrrolidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, cyanopyrrolidinyl, difluoroazetidinyl or (hydroxyl)(trifluoromethyl)azetidinyl. 25 8. A compound according to any one of claims 1 to 7, wherein R4 is halophenyl, haloalkylphenyl, halopyridinyl, oxolanyl, alkylsulfonylphenyl, pyridinyl or cycloalkyltetrazolyl. 9. A compound according to any one of claims 1 to 8, wherein R4 is chlorophenyl, chlorofluorophenyl, oromethylphenyl, chloropyridinyl, oxolanyl, 30 methylsulfonylphenyl, pyridinyl or cyclopropyltetrazolyl. 10. A compound ing to any one of claims 1 to 9 selected from 2-tert-butyl[(4-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methylphenyl)methyl]purine; 2-tert-butyl[(2-chlorofluorophenyl)methyl](3,3-difluoropyrrolidin 5 yl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] purine; 2-tert-butyl[(2-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; 5-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,4- 10 oxadiazole; -butyl(cyclohexylmethyl)(3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)ethylpurine; -butyl(3,3-difluoropyrrolidinyl)propylpurine; 2-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,3,4- 15 oxadiazole; 2-tert-butyl(3,3-difluoropyrrolidinyl)(oxolanyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-phenylethyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-methoxyethyl)purine; 20 3-[[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]methyl]methyl-1,2,5- oxadiazole; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl](2-chlorophenyl) ethanone; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl] 25 purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]purine; 2-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; 5 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-pyridinylethyl)purine; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl]pyridinylethanone; 1-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol; ert-butyl(3,3-difluoropyrrolidinyl)purinyl]thietane 1,1-dioxide; 10 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; ert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methoxyphenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 15 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol; 1-(2-tert-butylethylpurinyl)pyrrolidinol; 1-(2-tert-butylpropylpurinyl)pyrrolidinol; 1-[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol; 20 1-[2-tert-butyl(2-phenylethyl)purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methylphenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl(cyclohexylmethyl)purinyl]pyrrolidinol; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[3-(trifluoromethyl)-1H-pyrazol yl]methyl]purine; 1-[2-tert-butyl[(2-chlorofluorophenyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidinol; 5 1-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin rolidinol; 1-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; 1-[2-tert-butyl(oxolanyl)purinyl]pyrrolidinol; 2-[2-tert-butyl(3-hydroxypyrrolidinyl)purinyl](2-chlorophenyl)ethanone; 10 N-{(S)[2-tert-Butyl(2-chloro-benzyl)-9H-purinyl]-pyrrolidinyl}- acetamide; N-[(S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidin 15 yl]acetamide; N-[(S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidin yl]acetamide; [2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidin yl]acetamide; 20 N-[(S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide; N-[(S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]acetamide N-[(S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin 25 yl]pyrrolidinyl]acetamide; 7-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]oxaazaspiro[3.4]octane; 7-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]oxa 5 azaspiro[3.4]octane; 7-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane; 7-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.4]octane; 10 7-[2-tert-butyl(2-methoxyethyl)purinyl]oxaazaspiro[3.4]octane; 1-[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]methylpyrrolidin- 15 3-ol; 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]methylpyrrolidinol; 1-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; 20 1-[2-tert-butyl(2-methoxyethyl)purinyl]methylpyrrolidinol; 2-tert-butyl[(2-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine; -butyl[(3-chlorophenyl)methyl](3,3,4,4-tetrafluoropyrrolidinyl)purine; 1-[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]methylpyrrolidin 25 [2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide; 7-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa azaspiro[3.4]octane; N-[(S)[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinyl]acetamide; 5 7-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]oxa azaspiro[3.4]octane; 2-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- oxadiazole; 5-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- 10 1,2,4-oxadiazole; 2-tert-butyl[(1-methyltetrazolyl)methyl](3,3,4,4-tetrafluoropyrrolidin yl)purine; 3-[[2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)purinyl]methyl]methyl- oxadiazole; 15 2-tert-butyl(2-methoxyethyl)(3,3,4,4-tetrafluoropyrrolidinyl)purine; 1-[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol; 1-[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl] methylpyrrolidinol; 20 (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(4-chlorophenyl)methyl]purinyl]pyrrolidinol; 7-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]oxaazaspiro[3.4]octane; (3S)[2-tert-butyl[(2-methylsulfonylphenyl)methyl]purinyl]pyrrolidinol; 25 (3S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 2-tert-butyl(3,3,4,4-tetrafluoropyrrolidinyl)(3,3,3-trifluoropropyl)purine; (3S)[2-tert-butyl(2-methoxyethyl)purinyl]pyrrolidinol; (3S)[2-tert-butyl[(1-methyltetrazolyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]pyrrolidin- 5 3-ol; (3S)[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; (3S)[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; 10 (3S)[2-tert-butyl[[4-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; (3S)[2-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl]purinyl]pyrrolidin- 3-ol; 1-[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]methylpyrrolidinol; 15 N-[(3S)[2-tert-butyl(3,3,3-trifluoropropyl)purinyl]pyrrolidin yl]acetamide; 7-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]oxa azaspiro[3.4]octane; -butyl(3,3,4,4-tetrafluoropyrrolidinyl)[[2- 20 (trifluoromethyl)phenyl]methyl]purine; -butyl[(2-methylsulfonylphenyl)methyl](3,3,4,4-tetrafluoropyrrolidin yl)purine; N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purin amine; 25 N-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(5-methyl-1,3,4-oxadiazol hyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)(3,3,3-trifluoropropyl)purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazol 5 yl)methyl]purinamine; N-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purin amine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]purin- 2-amine; 10 N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- methylsulfonylphenyl)methyl]purinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(3-methyl-1,2,4-oxadiazol yl)methyl]purinamine; -[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; 15 (3S)[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purin yl]pyrrolidinol; (3S)[2-(tert-butylamino)[(3-chloropyridinyl)methyl]purinyl]pyrrolidin (3S)[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin 20 yl]pyrrolidinol; 1-[2-(tert-butylamino)[(2-chlorophenyl)methyl]purinyl]methylpyrrolidin 1-[2-(tert-butylamino)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol; 25 (3S)[2-(tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purin yl]pyrrolidinol; 1-[2-(tert-butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)purine; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[[2- (trifluoromethyl)phenyl]methyl]purine; 5 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2- methylsulfonylphenyl)methyl]purine; 2-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] methyl-1,3,4-oxadiazole; 5-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] 10 methyl-1,2,4-oxadiazole; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]purine; -[2-(tert-butylamino)(3,3,3-trifluoropropyl)purinyl]pyrrolidinol; 1-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl] 15 methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[[2-(trifluoromethyl)phenyl]methyl]purinyl] methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[(2-methylsulfonylphenyl)methyl]purinyl] methylpyrrolidinol; 20 1-[9-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)purinyl] methylpyrrolidinol; 1-[2-(2,2-dimethylpropoxy)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinol; 1-[2-(tert-butylamino)[[3-(trifluoromethyl)-1H-pyrazolyl]methyl]purinyl]- 25 3-methylpyrrolidinol; N-tert-butyl(2-oxaazaspiro[3.3]heptanyl)[[2- (trifluoromethyl)phenyl]methyl]purinamine; N-tert-butyl[(2-chlorophenyl)methyl](2-oxaazaspiro[3.3]heptanyl)purin- 2-amine; (3S)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidin 5 3-[[6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)purinyl]methyl] -1,2,5-oxadiazole; N-tert-butyl[(3-methyl-1,2,4-oxadiazolyl)methyl](2-oxa azaspiro[3.3]heptanyl)purinamine; -butyl(2-oxaazaspiro[3.3]heptanyl)(3,3,3-trifluoropropyl)purin 10 amine; 6-[9-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)purinyl]oxa azaspiro[3.3]heptane; 3-[[2-tert-butyl(4-methylpiperazinyl)purinyl]methyl]methyl-1,2,5- oxadiazole; 15 [(2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinyl]methanol; [(2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidin yl]methanol; (2R)[2-tert-butyl[(1-cyclopropyltetrazolyl)methyl]purinyl]pyrrolidine 20 carbonitrile; (2R)[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinecarbonitrile; 6-[2-tert-butyl[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl]oxa azaspiro[3.3]heptane; 25 3-[[2-tert-butyl(1,3-thiazolidinyl)purinyl]methyl]methyl-1,2,5- oxadiazole; 6-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)-9H-purine; [(3S)[2-(tert-Butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purin yl]pyrrolidinyl] acetate; [1-[2-(tert-Butylamino)[(4-methyl-1,2,5-oxadiazolyl)methyl]purinyl] methylpyrrolidinyl] acetate; 5 9-Benzylchloro(3,3-difluoropyrrolidinyl)purine; (3S)[2-tert-Butyl[(1-propanyltetrazolyl)methyl]purinyl]pyrrolidin 2-tert-Butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine; 10 [(2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol; (3S)[2-tert-Butyl[(1-propyltetrazolyl)methyl]purinyl]pyrrolidinol; (2R,3S)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl] (hydroxymethyl)pyrrolidinol; 15 2-tert-Butyl[(3-chloropyridinyl)methyl](3,3-difluoroazetidinyl)purine; 3-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-1,3-thiazolidine; 6-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-2λ6-thia azaspiro[3.3]heptane 2,2-dioxide; (2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidine 20 carbonitrile; -[2-tert-Butyl[[1-(cyclopropylmethyl)tetrazolyl]methyl]purin yl]pyrrolidinol; 1-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)pyrrolidinol; 25 -[2-tert-Butyl[(1-tert-butyltetrazolyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl] (trifluoromethyl)azetidinol; 2-tert-Butyl[(3-chloropyridinyl)methyl](2,2-difluoroazaspiro[2.4]heptan- 5-yl)purine; and 1-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]methylazetidinol. 11. A compound according to any one of claims 1 to 10 selected from 5 2-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl[(2-chlorofluorophenyl)methyl](3,3-difluoropyrrolidin ine; 2-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]purine; 10 2-tert-butyl[(2-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; -butyl(3,3-difluoropyrrolidinyl)(oxolanyl)purine; 2-[2-tert-butyl(3,3-difluoropyrrolidinyl)purinyl](2- chlorophenyl)ethanone; 2-tert-butyl(3,3-difluoropyrrolidinyl)[(2- 15 methylsulfonylphenyl)methyl]purine; 2-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)purine; 2-tert-butyl(3,3-difluoropyrrolidinyl)(2-pyridinylethyl)purine; 1-[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidinol; 20 1-[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; 1-[2-tert-butyl[(2-chlorofluorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[[2-(trifluoromethyl)phenyl]methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(3-chlorophenyl)methyl]purinyl]pyrrolidinol; (3S)[2-tert-butyl[(2-chloropyridinyl)methyl]purinyl]pyrrolidinol; 25 (3S)[2-tert-butyl[(2-chlorophenyl)methyl]purinyl]pyrrolidinol; chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)purine; 6-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[[2- (trifluoromethyl)phenyl]methyl]purine; 5 -Butyl[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidin yl)purine; [(2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidin yl]methanol; 2-tert-Butyl[(3-chloropyridinyl)methyl](3,3-difluoroazetidinyl)purine; 10 3-[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]-1,3-thiazolidine; (2R)[2-tert-Butyl[(3-chloropyridinyl)methyl]purinyl]pyrrolidine carbonitrile; and

1.-[

2.-tert-butyl[(

3.-chloropyridinyl)methyl]purinyl] (trifluoromethyl)azetidinol. 15 12. A process for the preparation of a compound according to any one of claims 1 to 11, comprising the reaction of a compound of formula (A) R2 R3 R1 N N H (A) in the presence of Y-A-R4 wherein Y is a leaving group and n A and R1 to R4 are as defined in any one of claims 1 to 9. 20 13. A compound according to any one of claims 1 to 11 for use as therapeutically active substance. 1

4. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 11 and a therapeutically inert carrier. 1

5. Use of a compound according to any one of claims 1 to 11 for the preparation of a ment for the treatment or prophylaxis of pain, atherosclerosis, lated macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic y, diabetes 5 mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic 10 scars, keloids, itis pyrexia, liver sis or tumors, regulation of bone mass, amyotrophic lateral sclerosis, multiple sclerosis, mer's e, Parkinson's disease, stroke, transient ischemic attack or uveitis. 1

6. A compound according to any one of claims 1 to 11 and 13, substantially as herein described with reference to any example thereof. 15 1

7. A process according to claim 12, ntially as herein described with reference to any example thereof. 1

8. A pharmaceutical composition according to claim 14, substantially as herein bed with reference to any example thereof. 1

9. Use according to claim 15, substantially as herein described with reference to any 20 e thereof.