NZ622847B2 - [1,2,3]triazolo[4,5-d]pyrimidine derivatives as agonists of the cannabinoid receptor 2 agonists - Google Patents

Abstract

The disclosure relates to a [1,2,3]triazolo[4,5-D]pyrimidine derivatives of formula (I) as agonist of the cannabinoid receptor 2. An example of the derivative is 5-tert-butyl-2-(2-chloro-benzyl)-7-morpholin-4-yl-2H-[1,2,3]triazolo[4,5-d]pyrimidine.

Description

F. Hoffmann-La Roche AG, CH-4070 Basle, Switzerland Case: 30736 [1,2,3]TRIAZOLO[4,5-D]PYRIMIDINE DERIVATIVES AS AGONISTS OF THE CANNABINOID OR 2 AGONISTS The present invention relates to c compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds that are preferential agonists of the Cannabinoid Receptor 2. The compound of formula (I) is particularly useful in the ent or prophylaxis of e.g. pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney is, systemic fibrosis, acute aft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or , regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

The invention relates in particular to a compound of formula (I) R1 N N R2 R3 (I) wherein A is alkylene, hydroxyalkylene, -CH2C(O)-, -C(O)-, -SO2- or absent; R1 is hydrogen, alkyl, kyl, hydroxyl, alkoxy, koxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, (halo)(haloalkyl)phenyl, (halo)(alkoxy)phenyl, cyano, cycloalkyl, lkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, eterocyclyl, heteroaryl, haloheteroaryl, alkylheteroaryl, DP/26.10.12 (alkyl)(alkylsulfonyl)heteroaryl, (halo)(alkylamino)heteroaryl, haloalkylheteroaryl, cycloalkylheteroaryl or enzo ]oxadiazolylaminoheteroaryl, wherein heterocyclyl is a three to eight membered carbocyclic ring comprising at least one nitrogen or oxygen atom, and n heteroaryl is pyridinyl, pyrazolyl, oxadiazolyl, furazanyl, tetrazolyl, triazolyl or oxypyridinyl; R2 is alkyl, kyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkylalkoxy, haloalkoxy, alkoxy or alkylamino; R3 is halogen or -NR4R5; one of R4 and R5 is hydrogen or alkyl and the other one is alkyl or cycloalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form heterocyclyl or tuted heterocyclyl, wherein heterocyclyl is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa azaspiro[3.4]octyl, 6-oxaazaspiro[3.3]heptyl, 2-oxaaza-spiro[3.4]octyl, olidinyl, aziridinyl or dioxoisothiazolidinyl and wherein substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, carboxyl, alkoxyalkyl, cyano and arbonylamino; or a pharmaceutically acceptable salt or ester thereof.

The cannabinoid receptors are a class of cell membrane receptors belonging to the G n-coupled receptor superfamily. There are currently two known subtypes, termed Cannabinoid 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 periphery. 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), 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 or is also widely distributed in the brain where it is found primarily on microglia and not neurons l, 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 l of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain (Beltramo, M. Mini Rev Med Chem 2009, 9(1), 11-25), sclerosis (Mach, F. et al. J ndocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, , 182-8), neuroinflammation (Cabral, G. A. et al. J Leukoc Biol 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 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, pulmonary bypass and other vascular surgeries, and organ transplantation, as well as a major mechanism of end-organ damage complicating the course of circulatory shock of various etiologies. All these conditions are characterized by a tion of normal blood supply resulting in an insufficient tissue oxygenation. genation e.g., reperfusion is the ultimate ent to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a ion in which the restoration of circulation results in further tissue damage. The damage of usion injury is due in part to the inflammatory response of damaged tissues. White blood cells, carried to the area by the newly returning blood, release a host of inflammatory factors such as interleukins as well as free radicals in response to tissue damage. The ed blood flow reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma ne.

Remote ischemic preconditioning (RIPC) represents a strategy for harnessing the body’s endogenous tive capabilities against the injury ed 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 e of “lethal” 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 hypothesis 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 respective receptor in the target tissue and thereby recruiting the various intracellular pathways of protection implicated in ischemic preconditioning.

Recent data indicates that endocannabinnoids and their ors, in particular CB2 might be involved in pre-conditioning and contribute to prevent reperfusion injury by downregulation of the inflammatory response (Pacher, P. et al. Br J Pharmacol 2008, 153(2), 252-62). ically, 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 (Feizi, A. et al. Exp Toxicol Pathol 2008, 60(4-5), 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 c diseases associated with fibrosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 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 (Garcia-Gonzalez, E. et al. Rheumatology d) 2009, 48(9), 1050-6) and CB2 receptor has d 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 chronic liver diseases (Lotersztajn, S. et al. enterol 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, 153(2), 286-9).

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

In the present ption the term “alkyl”, alone or in combination, ies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or ed-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 straightchain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the ic pentyls, the ic hexyls, the isomeric s and the isomeric octyls, particularly methyl, ethyl, propyl, butyl and pentyl more particularly , ethyl, propyl, isopropyl, isobutyl, tert.-butyl and isopentyl. ular examples of alkyl are methyl, ethyl and tert.-butyl.

In the present ption the term “alkylene”, alone or in combination, signifies a straight-chain or branched-chain alkylene group with 1 to 8 carbon atoms, particularly a ht or branched-chain alkyl group with 1 to 6 carbon atoms and more ularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. es of straightchain and branched-chain C1-C8 alkylene groups are methylene or ethylene, more particularly -CH2-, -CH2CH 2- or -CH(CH3)-.

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. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. A particular example of lkyl is cyclohexyl or cyclopropyl.

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, particularly methoxy.

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

The term “halogen” or “halo”, alone or in combination, signifies fluorine, chlorine, bromine or iodine and ularly fluorine, chlorine or bromine, more particularly fluorine and chlorine. The term “halo”, in combination with another group, denotes the substitution of said group with at least one halogen, particularly substituted with one to five halogens, ularly one to four halogens, i.e. one, two, three or four halogens. ular halogens are fluorine, bromine and chlorine, more particularly fluorine and chlorine.

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

The term “haloalkoxy”, alone or in combination, denotes an alkoxy group substituted with at least one n, particularly substituted with one to five halogens, particularly one to three halogens. A particular “haloalkoxy” is trifluoromethoxy.

The term “halophenyl”, alone or in combination, denotes a phenyl group substituted with at least one halogen, particularly substituted with one to three halogens. Particular henyl” are chlorophenyl, chlorofluorophenyl, dichlorophenyl, bromophenyl and chlorodifluorophenyl.

The terms “hydroxyl” and xy”, alone or in combination, signify the -OH group.

The term “carbonyl”, alone or in combination, signifies the -C(O)- group.

The term “carboxyl” or “carboxy”, alone or in combination, signifies the -COOH group.

The term “amino”, alone or in combination, signifies the primary amino group (-NH 2), the secondary amino group (-NH-), or the tertiary amino group (-N-).

The term “sulfonyl”, alone or in combination, ies the -SO2- group.

Particular heterocyclyl groups in the definition of R1 are oxetanyl, tetrahydrofuranyl, oxo-1λ6-thietanyl and 1,1-dioxo-tetrahydro-1 λ6-thiophenyl.

Particular halopyrrolidinyl in the definition of R3 and R4 are difluoropyrrolidinyl and tetrafluoropyrrolidinyl.

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, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, ic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, ic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition 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 d to, the , potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, ary, and tertiary amines, tuted 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, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, romic acid, ic acid, phosphoric acid and methanesulfonic acid.

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

Additionally, any physiologically acceptable equivalents of the compound of l 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 starting materials or compounds of formula (I) contain one or more onal 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 Chemistry” 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 synthesis using standard methods described in the ture. 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 asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric tes 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 relates in particular to a compound of formula (I) R1 N N R2 R3 (I) wherein A is alkylene, yalkylene, -CH2C(O)-, -C(O)-, -SO2- or absent; R1 is hydrogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, , halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, ulfonylaminophenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl or haloheteroaryl, wherein heterocyclyl is a three to eight membered carbocyclic ring comprising at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridinyl, pyrazolyl, oxadiazolyl or furazanyl; R2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl or cycloalkylalkoxy; R3 is halogen or -NR4R5; one of R4 and R5 is hydrogen or alkyl and the other one is alkyl or cycloalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is morpholinyl, dinyl, piperazinyl, pyrrolidinyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, thiazolidinyl, rpholinyl, dioxothiomorpholinyl, anyl, 2-oxa azaspiro[3.4]octyl, 6-oxaazaspiro[3.3]heptyl, 2-oxaaza-spiro[3.4]octyl, isoxazolidinyl, inyl or dioxoisothiazolidinyl and wherein substituted heterocyclyl is cyclyl substituted with one to four substituents independently selected from alkyl, halogen, hydroxyl, alkoxy, hydroxyalkyl, carboxyl, alkoxyalkyl and cyano; or a ceutically acceptable salt or ester thereof.

The ion further relates in particular to the following: A nd of formua (I) wherein A is alkylene, -CH2C(O)- or absent; A compound of formua (I) wherein A is alkylene; A compound of formua (I) wherein A is methylene, ethylene or -CH(CH3)-; A compound of formua (I) wherein R1 is hydrogen, alkyl, haloalkyl, yl, alkoxy, haloalkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, cyano, cycloalkyl, lkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl or haloheteroaryl, wherein heterocyclyl is a three to eight membered carbocyclic ring sing at least one nitrogen or oxygen atom, and n heteroaryl is nyl, pyrazolyl, oxadiazolyl or furazanyl; A compound of formua (I) wherein R1 is hydrogen, alkyl, kyl, hydroxyl, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, lkyl, oxetanyl or pyridinyl; A compound of formua (I) wherein R1 is trifluoromethyl, , chlorophenyl, bromophenyl, cyanophenyl, cyclohexyl or pyridinyl; A compound of formua (I) wherein R1 is alkyl, haloalkyl, yl, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, cycloalkyl, heterocyclyl, teroaryl or alkylheteroaryl, wherein heterocyclyl is oxetanyl, and wherein heteroaryl is pyridinyl or furazanyl; A compound of formua (I) wherein R1 is alkyl, haloalkyl, hydroxyl, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, cycloalkyl, oxetanyl, pyridinyl, halopyridinyl or alkylfurazanyl; A compound of formua (I) wherein R1 is trifluoromethyl, phenyl, chlorophenyl, bromophenyl, cyanophenyl, cyclohexyl, pyridinyl, chloropyridinyl, methylfurazanyl or trifluoromethylphenyl; A compound of formua (I) wherein R2 is alkyl; A compound of formua (I) wherein R2 is tert.-butyl; A compound of formua (I) wherein R3 is -NR4R5; A compound of formua (I) wherein R4 and R5 together with the nitrogen atom to which they are ed form morpholinyl or halopyrrolidinyl; A compound of formua (I) wherein R4 and R5 together with the nitrogen atom to which they are attached form morpholinyl or difluoropyrrolidinyl; A compound of formua (I) wherein R4 and R5 er with the nitrogen atom to which they are ed form morpholinyl, halopyrrolidinyl or hydroxypyrrolidinyl; and A compound of formua (I) wherein R4 and R5 er with the nitrogen atom to which they are attached form morpholinyl, difluoropyrrolidinyl or hydroxypyrrolidinyl.

The invention also relates in particular to a compound of formua (I) selected from -Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; -tert-Butyl(2-chlorofluoro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- midine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- ethanol; -tert-Butylcyclohexylmethyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(4-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,3-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,4-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,5-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,6-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,2,2-trifluoro-ethyl)-2H- ]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-chloro-4,5-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chloro-3,6-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-(2-Bromo-benzyl)tert-butyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethoxy-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]-benzonitrile; -tert-Butyl(3,3-difluoro-pyrrolidinyl)phenethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-phenyl-ethanone; -tert-Butyl[(R)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[(S)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; and -tert-Butyl(3,3-difluoro-pyrrolidinyl)oxetanyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine.

The invention also relates in particular to a compound of formula (I) selected from -tert-Butyl(2,6-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(4-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,5-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,6-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- ]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -Butyl[2-(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[2-(3-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl[2-(4-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(R)-tetrahydro-furanyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(S)-tetrahydro-furanyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-(2-chloro-phenyl)-ethanone; -tert-Butyl(2,3-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-oxetanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- hloro-phenyl)-ethanone; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-(4-chloro-phenyl)-ethanone; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-pyridinyl-ethanone; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,3,6-trichloro-benzyl)-2H- ]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-chlorofluoromethoxy-benzyl)(3,3-difluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2,3-dichlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidin -[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-1λ6-thietanyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-tetrahydro-1λ6-thiophen yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-pyridinyl-ethanone; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,2,4]oxadiazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methanesulfonylmethyl-4H- [1,2,4]triazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; {3-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]chloro-pyridinyl}-dimethyl-amine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyl-1H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; [5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3,6-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2,3-dichloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol; (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol; [5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-3H-[1,2,3]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(4,5-dimethyl-4H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyloxy-pyridinylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S)[5-tert-Butyl(3,4-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(5-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- midinyl]-pyrrolidinol; (S)[5-tert-Butyl(2-methyl-2H-[1,2,4]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2,5-dimethyl-2H-pyrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; -tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidin -[1,2,3]triazolo[4,5-d]pyrimidine; (S){5-tert-Butyl[2-(7-nitro-benzo[1,2,5]oxadiazolylamino)-pyridin ylmethyl]-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl}-pyrrolidinol; (S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2,5-dimethyl-2H-[1,2,4]triazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (2S,3S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]hydroxymethyl-pyrrolidinol; (2S,3S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]hydroxymethyl-pyrrolidinol; -tert-Butyl(4-methyl-furazanylmethyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoro- pyrrolidinyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -Butyl(1-methyl-1H-tetrazolylmethyl)(3,3,4,4-tetrafluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)(2-oxaaza- spiro[3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(2-methanesulfonyl-benzyl)(2-oxaaza-spiro[3.3]heptyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(2-oxaaza-spiro[3.3]heptyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; (S)[2-(2-Chloro-benzyl)(2,2,2-trifluoro-ethoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-(2,2,2-Trifluoro-ethoxy)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol; (S)[2-(2-Chloro-benzyl)isopropoxy-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol; 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(1-methyl-1H-tetrazol- -ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (R)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 1-[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 7-(3,3-Difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)((S)-2,2,2-trifluoro- yl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; hloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazolylmethyl)((S)- 2,2,2-trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazolylmethyl)((S)- 2,2,2-trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)((S)-2,2,2-trifluoromethyl-ethoxy)(3,3,3- trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 2-(1-Cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidinyl)((S)- 2,2,2-trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol; (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol; (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]methyl-pyrrolidinol; (R)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]methyl-pyrrolidinol; (S)[5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; [5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- midinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3,3,3-trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]methyl-pyrrolidinol; (R)[5-tert-Butyl(3,3,3-trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]methyl-pyrrolidinol; (S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; N-{(S)[2-(2-Chloro-benzyl)(2,2-dimethyl-propoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide; [2-(3-Chloro-pyridinylmethyl)(2,2-dimethyl-propoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- ]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[2-(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; N-{(S)[2-(2-Chloro-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[2-(2-Trifluoromethyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[2-(2-Methanesulfonyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[5-tert-Butylamino(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide; and (S)[5-tert-Butylamino(1-methyl-1H-tetrazolylmethyl)-2H- ]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol.

The invention further relates in particular to a compound of formua (I) selected from 5-tert-Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; -tert-Butylcyclohexylmethyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,2,2-trifluoro-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-(2-Bromo-benzyl)tert-butyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; ert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]-benzonitrile; -tert-Butyl(3,3-difluoro-pyrrolidinyl)phenethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; and -tert-Butyl[(R)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine.

The invention also ularly relates to a compound of formua (I) selected from -tert-Butyl(4-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; -tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; and (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol.

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 ion 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 indices used in the following 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 es or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions 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 ce or absence of a t. There is no particular restriction on the nature of the solvent to be ed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described ons can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the ion. It is convenient to carry out the described reactions in a temperature range between -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 ts. However, a period of from 0.5 h to l days will usually suffice to yield the bed intermediates and compounds. The reaction sequence is not limited to the one displayed in the s, however, depending on the starting als and their respective reactivity the sequence of reaction steps can be freely d. Starting materials are either commercially available or can be ed 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.

Scheme 1 PG PG H a) b) N NH N N R2 2 c) PG X + PG N N N N N N 2 N R II III O R=CONH2, CN X=Br or Cl IV V PG PG H N R2 N N N R2 N N R2 d) e) f) N N N N N N N N O Cl R3 VIII VI VII g) N N R2 h) R1 N N R2 N A N N N N N R3 R3 IX I a) Halides II are either commercially ble or can be synthesized according to methods known in the art. These halides II are conveniently reacted with sodium azide in a suitable solvent such as acetonitrile, ethanol or DMF to afford azide derivatives III. b) Triazole derivatives IV can be prepared by a [2+3] cycloaddition of azide derivatives III with 2-cyanoacetamide in the presence of an appropriate base such as sodium methoxide or sodium de in a suitable solvent such as ol, ethanol or DMF. c) Triazole derivatives V can be obtained by acylation of IV with an acyl-halide in the presence of a base such as DIEA, DMAP, pyridine and the like. d) Triazolopyrimidine derivatives VI can be prepared by intramolecular cyclization of le derivative V in the presence of a base such as KHCO3, Na2CO3 and water either with or without a solvent such as methanol, ethanol, dioxane and toluene. e) Chlorides VII can be obtained by reaction of VI with a chlorination reagent such as POCl3, SOCl2 or (COCl)2 in the presence of an appropriate base such as N,N-diethyl aniline, ne, or pyridine. f) VII are conveniently reacted with various nucleophiles particularly amines in the presence of an appropriate base such as trietylamine, DIEA or DBU in a suitable solvent such as acetonitrile, methanol, toluene or DMF to yield triazolo-pyrimidine derivatives VIII. g) ection of VIII is done under suitable conditions, in case of PG=MPM under acidic conditons (TFA and the like), hydrogenation using Pd catalyst or oxidative cleavage (DDQ or CAN and the like) to yield IX. h) Triazole derivatives IX are iently reacted either with a halide (or sulfonate) in the presence of le base such as DIEA, DBU, K 2CO3, or Cs2CO3 particularly Ag2SO4 in a solvent such as DMF, dioxane or toluene, or alternatively with an alcohol under obu on conditions using a suitable diazodicarboxylate (DEAD, DIAD and the like) and a phosphine such as PBu3 or PPh3 in an appropriate solvent such as THF, DCM, toluene to afford final triazolo-pyrimidine derivatives I.

The ion thus also relates to a process for the preparation of a compound of formula (I) comprising the reaction of a compound of formula (A) N N R2 R3 (A) in the presence of R1-A-X and a base, or in the presence of R1-A-OH under Mitsunobu conditions, wherein A and R1 to R3 are as defined above and wherein X is halogen or SO 2.

Reaction conditions of step h) above can thus be used in the process of the invention.

The invention also relates to a compound of formula (I) when manufactured according to a process of the invention.

The invention further relates to a compound of formula (I) for use as therapeutically active substance.

The invention further s to a pharmaceutical ition comprising a nd of formula (I) and a therapeutically inert carrier.

The invention relates in ular to: The use of a compound according of formula (I) for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, ic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute aft rejection, chronic allograft nephropathy, ic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; and A compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, ma, 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, ulonephropathy, cardiomyopathy, heart failure, dial ischemia, myocardial infarction, ic sclerosis, thermal injury, burning, hypertrophic scars, keloids, itis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

The use of a compound of formula (I) for the treatment or prophylaxis of pain, in particular c pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal , g, hypertrophic scars, keloids, itis pyrexia, liver cirrhosis or tumors is also described herein.

The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of chronic pain, in particular chronic pain, sclerosis, regulation of bone mass, mation, ia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial tion, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors is a further aspect of the invention.

The invention also relates to a compound of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, tion of bone mass, inflammation, ia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.

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

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

Also described herein is the use of a compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, 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, ulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial tion, systemic sis, thermal injury, g, hypertrophic scars, keloids, gingivitis pyrexia, liver sis or tumors, regulation of bone mass, neurodegeneration, , transient ischemic attack or uveitis.

Also described herein is a method for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, ma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver e, liver is, lung is, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, myopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, itis pyrexia, liver cirrhosis or , tion of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, which method comprises stering an effective amount of a compound of formula (I) to a patien in need f.

A method for the treatment or laxis of pain, in particular chronic pain, atherosclerosis, tion of bone mass, inflammation, ia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, dial infarction, systemic sclerosis, ulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver sis or tumors, which method comprises administering an effective amount of a compound of formula (I) is also described herein.

Another embodiment of the invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as s of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds 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 non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.

The pH of the formulation depends mainly on the particular use and the concentration of compound, 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 r embodiment, the compounds of formula (I) are 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 eration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual t, the cause of the disorder, the site of delivery of the agent, the method of administration, the ling of administration, and other factors known to medical practitioners.

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

Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered 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 , and further active .

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 ce of Pharmacy. Philadelphia: Lippincott, ms & s, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing , surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, sing aids, colorants, ners, perfuming agents, flavoring agents, diluents and other known ves to provide 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 invention will now be illustrated by the following examples which have no limiting character.

Examples Abbreviations MS = mass ometry; CAN = ceric ammonium nitrate; Ac = acetyl; DIEA = N,N- diisopropylethylamine; DBU = 1,8-Diazabicyclo[5.4.0]undecene; DMF = dimethylformamide; HPLC = LC = high performance liquid chromatography; THF = tetrahydrofurane; TFA = trifluoroacetic acid; Ph = phenyl; DCM = dichloromethane; MPM = p-methoxyphenylmethyl; DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone; PMB = p-methoxy-benzyl; DIPEA= ropylethylamine.

Chiral separation of 1-(3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl) -pyrrolidinol (example 124, step a) yielded the respective enantiopure R and S derivatives. However, the unequivocal stereochemical assignment is g. Therefore, the stereochemical assignment for enantiopure examples 124-133 has not been made.

Example 1 -tert-Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5d]pyrimidine N N Cl N O a) 5-Amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide N NH2 A mixture of 1-(chloromethyl)methoxybenzene (20.0 g, 128 mmol) and sodium azide (12.5 g, 192 mmol) in acetonitrile (255 mL) was refluxed for 5 h under N2 atmosphere.

The mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude domethyl)methoxybenzene. The residue was used for the next reaction without further purification.

A mixture of the above crude e, 2-cyanoacetamide (10.8 g, 128 mmol) and sodium ethanolate (8.71 g, 128 mmol) in ethanol (256 mL) was refluxed for 21 h under N2 atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to afford 5-amino(4- methoxybenzyl)-1H-1,2,3-triazolecarboxamide as pale-orange solid (26.5 g, 84% for 2 steps). MS(m/e): 248.1 (MH+). b) -Butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one N N A mixture of 5-amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide (10.0 g, 40.4 mmol) and pivaloyl de (7.47 mL, 60.7 mmol) in pyridine (20.2 mL) was stirred at 80 °C for 2 h under N2 atmosphere. Then, to the reaction mixture was added 8 M sodium hydroxide aq. (15.2 mL, 121 mmol) and methanol (20.2 mL). After being stirred at 80 °C for 1 h, the reaction mixture was poured into 1M HCl aq. , extracted with diethyl ether, washed with 2M HCl aq., water and brine, dried over Na2SO4 and concentrated in vacuo to afford the mixture of crude ethoxybenzyl)pivalamido-1H-1,2,3-triazole carboxamide and N-(4-cyano(4-methoxybenzyl)-1H-1,2,3-triazolyl)pivalamide. The residue was used for the next reaction without further purification.

A mixture of the above crude residue and KHCO3 (12.1 g, 121 mmol) in H2O (242 mL) was refluxed for 18 h. The reaction e was poured into 1M HCl aq., extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 10% to 70% EtOAc in e) to afford 5-tert-butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (4.44 g, 35% for 2 steps). MS(m/e): 314.2 (MH+). c) ert-Butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine N N A mixture of 5-tert-butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)- one (50.0 mg, 160 µmol) and N,N-diethylaniline (50.8 µL, 319 µmol) in POCl3 (1000 µL, .9 mmol) was refluxed for 4 h under N2 atmosphere. The reaction mixture was trated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butylchloro(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.

A e of the above crude residue, morpholine (28.0 µL, 320 µmol) and DIEA (55.9 µL, 320 µmol) in acetonitrile (250 µL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini 5um C18 110A 75 x 30mm. mobile phase: water (0.05% Et3N): acetonitrile 45:55% to 5:95%. WL: 280 nm Flow: 30 mL/min.) to afford the title compound as white solid (47.7 mg, 78% for 2 steps). MS(m/e): 383.4 (MH+). d) 5-tert-Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine A mixture of 4-(5-tert-butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin yl)morpholine (49.0 mg, 128 µmol) and TFA (1000 µL) was refluxed for 8 h under N2 here. The reaction mixture was concentrated in vacuo to afford crude to 5-tert- butylmorpholinyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.

A mixture of the portion of above residue (85.3 µmol), momethyl)chlorobenzene (22.1 µL, 171 µmol) and DBU (25.7 µL, 171 µmol) in DMF (500 µL) was stirred at the room temperature overnight. The on mixture was directly purified by preparative HPLC (column: Gemini 5um C18 110A 75 x 30mm. mobile phase: water (0.05% Et3N): acetonitrile 65:35% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title nd as white solid (8.0 mg, 24%). MS(m/e): 387.4 (MH+). -tert-Butyl(2-chlorofluoro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5-d] pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(2-chloro-benzyl)- 7-morpholinyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step d), the title compound was prepared from 5-tert-butylmorpholinyl-3H-[1,2,3]triazolo[4,5-d] dine and 1-(bromomethyl)chlorofluorobenzene and isolated as white solid (5.1 mg, 30%). MS(m/e): 405.4 (MH+).

Example 3 -tert-Butyl(3,3-difluoro-pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d] pyrimidine N N a) 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methoxy-benzyl)-3H-[1,2,3]triazolo [4,5-d]pyrimidine N N In analogy to the ure described for the synthesis of 4-(5-tert-butyl(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)morpholine (example 1, step c), the title compound was ed from 5-tert-butylchloro(4-methoxybenzyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride and isolated as white solid (5.1 mg, 30%). MS(m/e): 405.4 (MH+). b) 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine A mixture of 5-tert-butyl(3,3-difluoro-pyrrolidinyl)(4-methoxy-benzyl)-3H-[1,2,3] triazolo [4,5-d]pyrimidine (264 mg, 656 µmol) and TFA (5.00 mL) was ed for 8 h under N2 atmosphere. The reaction mixture was concentrated in vacuo to afford crude to 5- tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further cation.

A mixture of the portion of above residue (41.0 µmol), iodoethane (6.63 µL, 82.0 µmol) and DBU (12.4 µL, 82.0 µmol) in DMF (250 µL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini 5um C18 110A 75 x 30mm. mobile phase: water (0.05% Et3N): acetonitrile 60:40% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (4.2 mg, 33%). ): 311.3 (MH+).

Example 4 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-ethyl)-2H-[1,2,3]triazolo [4,5-d]pyrimidine N N O N In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-bromomethoxyethane and isolated as light-yellow gum (4.5 mg, 32%). MS(m/e): 341.3 (MH+).

Example 5 ert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- ethanol N N OH N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromoethanol and isolated as white solid (1.9 mg, 14%).

MS(m/e): 327.3 (MH+).

Example 6 -tert-Butylcyclohexylmethyl(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3]triazolo [4,5-d]pyrimidine N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and (bromomethyl)cyclohexane and isolated as white solid (6.1 mg, 39%). MS(m/e): 379.4 (MH+).

Example 7 -tert-Butyl(3-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3]triazolo [4,5-d]pyrimidine N N Cl N F In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and momethyl)chlorobenzene and isolated as white solid (4.8 mg, 29%). MS(m/e): 407.4 (MH+).

Example 8 -tert-Butyl(4-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3]triazolo [4,5-d]pyrimidine N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)chlorobenzene and isolated as white solid (5.1 mg, 31%). MS(m/e): 407.4 (MH+).

Example 9 5-tert-Butyl(2,3-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N Cl N In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine le 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as white solid (5.5 mg, 30%). MS(m/e): 441.4 (MH+).

Example 10 -tert-Butyl(2,4-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2,4-dichlorobenzene and isolated as white solid (5.3 mg, 29%). MS(m/e): 441.4 (MH+).

Example 11 -tert-Butyl(2,5-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N In analogy to the ure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (4.6 mg, 25%). MS(m/e): 441.4 (MH+).

Example 12 -tert-Butyl(2,6-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N Cl N F In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3-dichlorobenzene and ed as white solid (5.8 mg, 32%). MS(m/e): 441.4 (MH+).

Example 13 -Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)chlorofluorobenzene and isolated as colorless gum (5.5 mg, 32%). MS(m/e): 425.4 (MH+). e 14 5-tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N F N In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-chloro(chloromethyl)fluorobenzene and isolated as white solid (5.4 mg, 31%). MS(m/e): 425.4 (MH+).

Example 15 -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N N N In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)pyridine hydrobromide and isolated as white gum (5.0 mg, 33%). MS(m/e): 374.4 (MH+). e 16 -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N N N In analogy to the ure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(chloromethyl)pyridine hydrochloride and isolated as ess gum (2.2 mg, 14%). MS(m/e): 374.4 (MH+). e 17 -tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 4-(bromomethyl)pyridine hydrobromide and isolated as orange solid (4.1 mg, 27%). MS(m/e): 374.4 (MH+).

Example 18 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,2,2-trifluoro-ethyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine F F F N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2,2,2-trifluoroethyl trifluoromethanesulfonate and isolated as yellow solid (3.0 mg, 20%).MS(m/e): 365.3 (MH+).

Example 19 5-tert-Butyl(2-chloro-4,5-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N F F In analogy to the ure bed for the sis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)chloro-4,5-difluorobenzene and isolated as colorless gum (6.2 mg, 34%). MS(m/e): 443.4 (MH+).

Example 20 -tert-Butyl(2-chloro-3,6-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N F F N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)chloro-1,4-difluorobenzene and isolated as white solid (7.0 mg, 38%). MS(m/e): 443.4 (MH+).

Example 21 2-(2-Bromo-benzyl)tert-butyl(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Br N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and o(bromomethyl)benzene and isolated as colorless gum (6.9 mg, 37%). MS(m/e): 451.3 (MH+).

Example 22 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H-[1,2,3] lo[4,5-d]pyrimidine F F N N F N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(trifluoromethyl)benzene and isolated as colorless gum (8.5 mg, 47%). MS(m/e): 441.4 (MH+).

Example 23 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-benzyl)-2H-[1,2,3]triazolo [4,5-d]pyrimidine N N O N In y to the procedure described for the sis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(chloromethyl)methoxybenzene and ed as colorless gum (6.6 mg, 40%). ): 403.4 (MH+).

Example 24 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethoxy-benzyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine F F F N N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(trifluoromethoxy)benzene and isolated as light-yellow gum (7.3 mg, 39%). MS(m/e): 457.4 (MH+).

Example 25 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl methyl]-benzonitrile N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and momethyl)benzonitrile and isolated as white solid (6.1 mg, 37%). MS(m/e): 398.3 (MH+).

Example 26 -tert-Butyl(3,3-difluoro-pyrrolidinyl)phenethyl-2H-[1,2,3]triazolo[4,5-d] pyrimidine N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and (2-bromoethyl)benzene and isolated as light-yellow gum (7.3 mg, 46%). ): 387.4 (MH+).

Example 27 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] phenyl-ethanone N N F In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromophenylethanone and isolated brown gum (0.8 mg, 5%). MS(m/e): 401.4 (MH+).

Example 28 -tert-Butyl[(R)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N To a solution of 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3]triazolo[4,5-d] pyrimidine (41.3 µmol), (S)(2-chlorophenyl)ethanol (12.9 mg, 82.6 µmol) and PPh3 (21.7 mg, 82.6 µmol) in THF(250 µL) was added DEAD (13.1 µL, 82.6 µmol) at 0 °C.

After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by ative HPLC (column: Gemini 5um C18 110A 75 x 30mm. mobile phase: water (0.05% Et3N): itrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.5 mg, 20%). MS(m/e): 421.4 (MH+). e 29 -tert-Butyl[(S)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N In analogy to the procedure described for the synthesis of 5-tert-butyl[(R)(2-chlorophenyl )-ethyl](3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine (example 28), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidin- 1-yl)-3H-[1,2,3]triazolo[4,5-d] pyrimidine and (R)(2-chlorophenyl)ethanol and isolated as white solid (3.7 mg, 21%). ): 421.4 (MH+).

Example 30 -Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N F N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)chlorofluorobenzene and isolated as light-yellow gums (4.9 mg, 28%). MS(m/e): 425.3 (MH+).

Example 31 -tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H-[1,2,3] triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the sis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)chlorofluorobenzene and isolated as yellow gum (4.0 mg, 23%). MS(m/e): 425.3 (MH+).

Example 32 -Butyl(3,3-difluoro-pyrrolidinyl)oxetanyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine N N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-bromooxetane and isolated as light-brown solid (2.8 mg, %). MS(m/e): 339.3 (MH+).

Example 33 5-tert-Butyl(2,6-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N F Cl N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and momethyl)-1,3-dichlorofluorobenzene and isolated as white solid. MS(m/e): 459.2 (MH+).

Example 34 -tert-Butyl(2-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(bromomethyl)chloropyridine hydrobromide and ed as light yellow gum. MS(m/e): 408.3 (MH+).

Example 35 -tert-Butyl(4-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 4-chloro(chloromethyl)pyridine and isolated as light yellow gum. MS(m/e): 408.3 (MH+).

Example 36 -tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N N In analogy to the ure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-chloro(chloromethyl)pyridine and isolated as light brown gum. MS(m/e): 408.3 (MH+).

Example 37 -tert-Butyl(2,5-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] lo[4,5-d]pyrimidine and 2,5-dichloro(chloromethyl)pyridine and isolated as light yellow gum. MS(m/e): 442.3 (MH+).

Example 38 -tert-Butyl(3,6-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and chloro(chloromethyl)pyridine and isolated as light brown gum. MS(m/e): 442.3 (MH+).

Example 39 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N N N N In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(bromomethyl)methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS(m/e): 379.3 (MH+).

Example 40 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazolylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N O N In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1,2,4-oxadiazole and ed as light yellow gum. MS(m/e): 379.3 (MH+).

Example 41 -tert-Butyl[2-(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine Cl N N F In analogy to the procedure described for the synthesis of -butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)chlorobenzene and isolated as light yellow gum. MS(m/e): 421.3 (MH+).

Example 42 -tert-Butyl[2-(3-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine Cl N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)chlorobenzene and isolated as light yellow gum. MS(m/e): 421.3 (MH+).

Example 43 -tert-Butyl[2-(4-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)chlorobenzene and ed as white solid. ): 421.3 (MH+).

Example 44 -tert-Butyl(2,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2,4-dichloropyridine hydrobromide and ed as light green solid. MS(m/e): 442.3 (MH+).

Example 45 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(R)-tetrahydro-furanyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N A mixture of 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidine (11.6 mg, 41.1 µmol), (S)-tetrahydrofuranol (7.24 mg, 6.6 µl, 82.2 µmol) and triphenylphosphine (21.6 mg, 82.2 µmol) were combined with THF (250 µl) to give a light yellow solution.To the solution was added DEAD (14.3 mg, 13.0 µl, 82.2 µmol) at 0 °C. The on mixture was stirred at r.t. for 4 h. The crude material was purified by preparative HPLC on reversed phase g with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 3.1 mg (21 %) of the title nd as colorless gum. MS(m/e): 353.3 (MH+).

Example 46 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(S)-tetrahydro-furanyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N F In analogy to the procedure described for the synthesis of 5-tert-Butyl(3,3-difluoropyrrolidinyl )(R)-tetrahydro-furanyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 45) the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and (R)-tetrahydrofuranol as colorless gum. MS(m/e): 353.3 (MH+).

Example 47 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] (2-chloro-phenyl)-ethanone N N Cl N A mixture of 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3]triazolo[4,5- midine (11.6 mg, 41.1 µmol), 2-bromo(2-chlorophenyl)ethanone (11.5 mg, 7.19 µl, 49.3 µmol) and DIPEA (10.6 mg, 14.4 µl, 82.2 µmol) were combined with DCM (250 µl) to give a light yellow solution. The reaction mixture was stirred at r.t. for 4 h and purified by preparative HPLC on ed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.9 mg (11 %) of the title compound as yellow gum. MS(m/e): 435.3 (MH+).

Example 48 -tert-Butyl(2,3-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N Cl F N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichlorofluorobenzene and isolated as white solid. MS(m/e): 459.3 (MH+).

Example 49 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- ]triazolo[4,5-d]pyrimidine N N S N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(methylsulfonyl)benzene and isolated as white solid. MS(m/e): 451.3 (MH+).

Example 50 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and romoethyl)pyridine hydrobromide and isolated as colorless gum. MS(m/e): 388.3 (MH+).

Example 51 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-oxetanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N F In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(iodomethyl)methyloxetane and isolated as white solid.

MS(m/e): 367.3 (MH+).

Example 52 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] (3-chloro-phenyl)-ethanone N N In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl(3,3-difluoropyrrolidinyl )-[1,2,3]triazolo[4,5-d]pyrimidinyl](2-chloro-phenyl)-ethanone (example 47), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidin- 1-yl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromo(3-chlorophenyl)ethanone and isolated as yellow solid. ): 435.3 (MH+).

Example 53 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] (4-chloro-phenyl)-ethanone Cl N N In analogy to the procedure described for the synthesis of ert-Butyl(3,3-difluoropyrrolidinyl )-[1,2,3]triazolo[4,5-d]pyrimidinyl](2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidin- 3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromo(4-chlorophenyl)ethanone and isolated as light yellow solid. MS(m/e): 435.3 (MH+).

Example 54 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] pyridinyl-ethanone N O N N In analogy to the procedure described for the synthesis of 2-[5-tert-Butyl(3,3-difluoro- pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl](2-chloro-phenyl)-ethanone (example 47), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidin- 3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromo(pyridinyl)ethanone hydrobromide and isolated as light yellow solid. MS(m/e): 402.3 (MH+).

Example 55 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,3,6-trichloro-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N Cl Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3,4-trichlorobenzene and isolated as light red solid. ): 475.2 (MH+).

Example 56 5-tert-Butyl(2-chlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N Cl N F N F N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 1-(bromomethyl)chloro(trifluoromethyl)benzene and isolated as white solid. ): 475.3 (MH+).

Example 57 -tert-Butyl(2-chlorofluoromethoxy-benzyl)(3,3-difluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N Cl N O F N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine le 3, step b), the title nd was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)chlorofluoromethoxybenzene and isolated as white solid. MS(m/e): 455.3 (MH+).

Example 58 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N F In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(2-bromoethyl)pyridine hydrobromide and isolated as light yellow gum. MS(m/e): 388.3 (MH+).

Example 59 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 4-(2-bromoethyl)pyridine hydrobromide and ed as white solid. MS(m/e): 388.3 (MH+).

Example 60 -tert-Butyl(2,3-dichlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine FF N N F N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloro(trifluoromethyl)benzene and isolated as white solid. MS(m/e): 509.3 (MH+).

Example 61 -tert-Butyl(3,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N Cl N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- idinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3,4-dichloropyridine hydrobromide and isolated as light yellow gum. MS(m/e): 442.3 (MH+). e 62 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-1λλλλ6-thietanyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N S N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-bromo-thietane 1,1-dioxide and ed as white solid.

MS(m/e): 387.3 (MH+).

Example 63 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-tetrahydro-1λλλλ6-thiophen- 3-yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-bromo-tetrahydro-thiophene 1,1-dioxide and ed as white solid. MS(m/e): 401.3 (MH+).

Example 64 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl] pyridinyl-ethanone O N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-bromo(pyridinyl)ethanone romide and isolated as brown solid. MS(m/e): 402.3 (MH+). e 65 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazolylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N O N N N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 2-(chloromethyl)methyl-1,3,4-oxadiazole and isolated as colorless gum. MS(m/e): 379.3 (MH+).

Example 66 -tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 4-(bromomethyl)chloropyridine hydrobromide and isolated as yellow gum. MS(m/e): 408.3 (MH+).

Example 67 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,2,4]oxadiazolylmethyl)- 2,3]triazolo[4,5-d]pyrimidine N N N N N N In analogy to the ure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] lo[4,5-d]pyrimidine and 3-(chloromethyl)methyl-1,2,4-oxadiazole and isolated as yellow gum. MS(m/e): 379.3 (MH+).

Example 68 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-tetrazole and isolated as white solid. MS(m/e): 379.3 (MH+).

Example 69 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] lo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-1,2,4-triazole hydrochloride and isolated as colorless gum. MS(m/e): 378.3 (MH+).

Example 70 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methanesulfonylmethyl-4H- ]triazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N S N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(iodomethyl)methyl(methylsulfonyl)-4H-1,2,4- triazole and isolated as white solid. MS(m/e): 456.3 (MH+). e 71 tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]chloro-pyridinyl}-dimethyl-amine N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(bromomethyl)chloro-N,N-dimethylpyridinamine hydrobromide and isolated as light yellow gum. MS(m/e): 451.4 (MH+).

Example 72 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyl-1H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N F F F N N N F a) 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyltrityl-1H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F N N F N N N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and momethyl)(trifluoromethyl)trityl-1H-pyrazole and used in the consecutive step t further purification. b) 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyl-1H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine The crude 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyltrityl-1H- pyrazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine and ylsilane in TFA was stirred at r.t. for 3 h.The reaction mixture was concentrated in vacuo and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield the title compound as white solid. MS(m/e): 431.3 (MH+).

Example 73 (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N a) (S)[5-tert-Butyl(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol N N OH In analogy to the procedure described for the synthesis of 4-(5-tert-Butyl(4- methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine (example 1, step c) the title compound was prepared from 5-tert-Butyl(4-methoxybenzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one after chlorination with POCl3 and philic tution with (S)-pyrrolidinol as light green viscous oil which was used in the consecutive step without further purification. b) Trifluoro-acetic acid (S)(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)- pyrrolidinyl-ester N N F O F O A mixture of (S)[5-tert-Butyl(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol and triethylsilane in TFA was heated to 70 °C for 22h and evaporated to dryness. The residue was used without further purification in the consecutive step. c) (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine le 3, step b), the title nd was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 3-(bromomethyl)methyl- 1,2,5-oxadiazole. After completion of the substitution reaction methanol was added and the mixture was stirred for 1 h at room temperature and uently subjected to purification with ative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing ons the title compound was isolated as light-yellow gum. MS(m/e): 359.3 (MH+).

Example 74 (S)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N O N In analogy to the procedure described for the sis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)methyl- 1,2,4-oxadiazole and isolated as brown gum. MS(m/e): 359.3 (MH+). e 75 (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N Cl N N N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 3-chloro (chloromethyl)pyridine and isolated as light yellow gum. MS(m/e): 388.3 (MH+).

Example 76 [5-tert-Butyl(3,6-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N Cl N N N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methyl- furazanylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and chloro (chloromethyl)pyridine and isolated as light yellow gum. MS(m/e): 422.3 (MH+).

Example 77 (S)[5-tert-Butyl(2-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N Cl N N N In y to the ure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 3-(bromomethyl) chloropyridine hydrobromide and isolated as light brown gum. MS(m/e): 388.3 (MH+).

Example 78 (S)[5-tert-Butyl(2,3-dichloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol N N Cl N Cl N In analogy to the procedure described for the sis of (S)[5-tert-Butyl(4-methyl- furazanylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 1-(bromomethyl)-2,3- dichlorobenzene and isolated as light brown gum. MS(m/e): 421.3 (MH+).

Example 79 (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]-pyrrolidinol F F N N F N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl 1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title nd was ed from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 1-(bromomethyl) (trifluoromethyl)benzene and isolated as light yellow gum. MS(m/e): 421.3 (MH+).

Example 80 (S)[5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol N N S N O N OH In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 1-(bromomethyl) (methylsulfonyl)benzene and isolated as white solid. MS(m/e): 431.3 (MH+).

Example 81 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-pyrazolylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole and isolated as light yellow gum. MS(m/e): 391.3 (MH+). e 82 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-3H-[1,2,3]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-1,2,3-triazole hydrochloride and isolated as light yellow solid. MS(m/e): 378.3 (MH+).

Example 83 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(4,5-dimethyl-4H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole and isolated as light yellow solid. MS(m/e): 392.3 (MH+).

Example 84 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyloxy-pyridinylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N O N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine le 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 3-(chloromethyl)methylpyridine 1-oxide and isolated as light yellow gum. MS(m/e): 404.3 (MH+).

Example 85 (S)[5-tert-Butyl(3,4-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N Cl N Cl N N In y to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methyl- furazanylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was ed from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 2-(bromomethyl)-3,4- dichloropyridine hydrobromide and isolated as white solid. MS(m/e): 422.2 (MH+).

Example 86 [5-tert-Butyl(5-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 3-(chloromethyl)methyl- 1,2,4-oxadiazole and isolated as light yellow gum. MS(m/e): 359.5 (MH+).

Example 87 (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N O N N N OH In analogy to the procedure bed for the sis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 2-(chloromethyl)methyl- 1,3,4-oxadiazole and isolated as light yellow gum. MS(m/e): 359.5 (MH+).

Example 88 (S)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N In analogy to the ure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title nd was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)methyl- 1H-tetrazole and isolated as yellow gum. MS(m/e): 359.3 (MH+).

Example 89 (S)[5-tert-Butyl(2-methyl-2H-[1,2,4]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N OH In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)methyl- 1H-1,2,4-triazole hydrochloride and isolated as light yellow gum. ): 358.2 (MH+).

Example 90 (S)[5-tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- ]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)methyl- 1H-1,2,3-triazole hydrochloride and isolated as light yellow gum. MS(m/e): 358.3 (MH+).

Example 91 (S)[5-tert-Butyl(2,5-dimethyl-2H-pyrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N OH In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from oro-acetic acid (5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)-1,3- dimethyl-1H-pyrazole and isolated as light yellow gum. MS(m/e): 371.3 (MH+).

Example 92 -tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N N In analogy to the ure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and oromethyl)cyclopropyl-1H-tetrazole and isolated as red gum. MS(m/e): 405.3 (MH+).

Example 93 (S){5-tert-Butyl[2-(7-nitro-benzo[1,2,5]oxadiazolylamino)-pyridin ylmethyl]-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl}-pyrrolidinol N N O N N NH N N N A mixture of (S)(5-tert-butyl((2-chloropyridinyl)methyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl)pyrrolidinol (5.70 mg, 14.7 µmol) (example 75), 7- nitrobenzo[c][1,2,5]oxadiazolamine (3.18 mg, 17.6 µmol), Pd2(dba)3 (1.35 mg, 1.47 µmol), xantphos (2.55 mg, 4.41 µmol) and Cs2CO3 (9.58 mg, 29.4 µmol) in dioxane (500 µl) was heated to 120 °C (microwave) and d for 20 min. The crude material was filtered, concentrated and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 3.1 mg (40 %) of the title compound was isolated as red solid.

MS(m/e): 532.4 (MH+).

Example 94 [5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N In y to the ure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl) ropyl-1H-tetrazole and isolated as light yellow gum. MS(m/e): 385.3 (MH+).

Example 95 (S)[5-tert-Butyl(2,5-dimethyl-2H-[1,2,4]triazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol N N N N N N N In analogy to the procedure described for the synthesis of (S)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 73), the title compound was prepared from oro-acetic acid (S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl-ester and 5-(chloromethyl)-1,3- dimethyl-1H-1,2,4-triazole and isolated as colorless gum. MS(m/e): 372.3 (MH+).

Example 96 -tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -butyl(3,3-difluoropyrrolidinyl)-3H-[1,2,3] triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole and isolated as light yellow gum. MS(m/e): 392.3 (MH+).

Example 97 (2S,3S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]hydroxymethyl-pyrrolidinol N N N N N N N a) )[5-tert-Butyl(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d] dinyl]hydroxymethyl-pyrrolidinol N N In analogy to the procedure described for the synthesis of 4-(5-tert-Butyl(4- methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine (example 1, step c) the title compound was prepared from 5-tert-Butyl(4-methoxybenzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one after chlorination with POCl3 and nucleophilic substitution with (2S,3S)Hydroxymethylmethyl-pyrrolidinol as light yellow gum.

MS(m/e): 413.4 (MH+). b) Trifluoro-acetic acid (2S,3S)(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl) (2,2,2-trifluoro-acetoxymethyl)-pyrrolidinyl ester N N F F F O A mixture of (2S,3S)[5-tert-Butyl(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]hydroxymethyl-pyrrolidinoland triethylsilane in TFA was heated to 70 °C for 22h and evaporated to dryness. The residue was used without r purification in the utive step. c) (2S,3S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]hydroxymethyl-pyrrolidinol In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from oro-acetic acid (2S,3S)(5-tert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)(2,2,2-trifluoro-acetoxymethyl)-pyrrolidinyl ester and 5-(chloromethyl)cyclopropyl-1H-tetrazole. After completion of the substitution reaction methanol was added and the mixture was stirred for 1 h at room temperature and subsequently subjected to purification with preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions the title compound was isolated as yellow solid.

MS(m/e): 415.4 (MH+). e 98 (2S,3S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]hydroxymethyl-pyrrolidinol N N N N N OH In analogy to the procedure described for the sis of (2S,3S)[5-tert-Butyl(1- cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] hydroxymethyl-pyrrolidinol (example 97), the title compound was prepared from Trifluoro-acetic acid (2S,3S)(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl) (2,2,2-trifluoro-acetoxymethyl)-pyrrolidinyl ester and 3-(bromomethyl)methyl-1,2,5- oxadiazole and isolated as white solid. MS(m/e): 389.3 (MH+).

Example 99 -tert-Butyl(4-methyl-furazanylmethyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N F F F F a) 5-tert-Butyl(4-methoxy-benzyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine N N F F F In y to the procedure described for the synthesis of 4-(5-tert-Butyl(4- methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine (example 1, step c) the title compound was prepared from 5-tert-Butyl(4-methoxybenzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one after chlorination with POCl3 and nucleophilic tution with 3,3,4,4-Tetrafluoro-pyrrolidine as purple oil and ised in the consecutive step without further purification. b) 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine N N F F F A mixture of 5-tert-Butyl(4-methoxy-benzyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and triethylsilane in TFA was heated to 70 °C for 22h and evaporated to s. The residue was used without further purification in the consecutive step. c) 5-tert-Butyl(4-methyl-furazanylmethyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS(m/e): 415.3 (MH+).

Example 100 -tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N O N F F F F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1,2,4-oxadiazole and isolated as light yellow gum. MS(m/e): 415.3 (MH+).

Example 101 -tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N O N N N F F F F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)methyl-1,3,4-oxadiazole and ed as white solid. MS(m/e): 415.3 (MH+).

Example 102 -tert-Butyl(1-methyl-1H-tetrazolylmethyl)(3,3,4,4-tetrafluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N N F F F F In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-tetrazole and isolated as light yellow solid. MS(m/e): 415.3 (MH+).

Example 103 -tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N F F F F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS(m/e): 428.3 (MH+).

Example 104 -tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N F F F F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 5-tert-Butyl(3,3,4,4-tetrafluoro-pyrrolidinyl)-3H- ]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-1,2,3-triazole hydrochloride and isolated as yellow gum. MS(m/e): 414.3 (MH+).

Example 105 -tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N a) 5-tert-Butyl(4-methoxy-benzyl)(2-oxaaza-spiro[3.3]heptyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine N N In analogy to the procedure described for the synthesis of 4-(5-tert-Butyl(4- methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine (example 1, step c) the title compound was prepared from 5-tert-Butyl(4-methoxybenzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one after chlorination with POCl3 and nucleophilic tution with 2-oxaaza-spiro[3.3]heptane and used in the consecutive step without further purification. b) [1-(5-tert-Butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)chloromethyl-azetidinyl]- methanol N N A mixture of 6-(5-tert-butyl(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin yl)oxaazaspiro[3.3]heptane (361 mg, 915 µmol) and palladium (II) chloride (81.1 mg, 458 µmol) in MeOH (3.00 mL) was stirred at r.t. for 9 h under H2 (1 atm, balloon) atmosphere. After replacement of H2 with N2, the reaction e was filtered with cotton, concentrated in vacuo and used in the consecutive step without further purification. c) 5-tert-Butyl(2-oxaaza-spiro[3.3]heptyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine N N A mixture of (1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl) (chloromethyl)azetidinyl)methanol (284 mg, 915 µmol) and potassium tert-butoxide (205 mg, 1.83 mmol) in THF (3.00 mL) at 0 °C was stirred to room ature and stirred at room temperature for 20 h.The reaction mixture was filetered and concentrated in vacuo and used without further cation. d) 5-tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl(2-oxaaza-spiro[3.3]heptyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and oromethyl)cyclopropyl-1H-tetrazole and isolated as white solid. MS(m/e): 397.3 (MH+).

Example 106 -tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N N N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from -Butyl(2-oxaaza-spiro[3.3]heptyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hloride and isolated as white solid. MS(m/e): 384.3 (MH+).

Example 107 -tert-Butyl(2-methanesulfonyl-benzyl)(2-oxaaza-spiro[3.3]heptyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N S N O N O In analogy to the procedure bed for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl(2-oxaaza-spiro[3.3]heptyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(methylsulfonyl)benzene and isolated as white solid. MS(m/e): 443.3 (MH+).

Example 108 -tert-Butyl(3-chloro-pyridinylmethyl)(2-oxaaza-spiro[3.3]heptyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl(2-oxaaza-spiro[3.3]heptyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro(chloromethyl)pyridine and isolated as light brown gum. MS(m/e): 400.3 (MH+).

Example 109 (S)[2-(2-Chloro-benzyl)(2,2,2-trifluoro-ethoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N O Cl N OH a) 3-(4-Methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-diol N N OH N N A mixture of 5-Amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide (example 1, step a) , 30.7 mmol), diethyl ate (4.72 g, 39.9 mmol) and sodium ethoxide (3.76 g, 55.3 mmol) in ethanol (97.1 mL) was heated to reflux over night. The solid was filtered, washed with EtOH and dried to give 3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidine-5,7(4H,6H)-dione (8.542 g, 15.6 mmol, 50.9 % yield) which was used in the consecutice step without further purification. MS(m/e): 272.0 (MH+). b) 5,7-Dichloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine N N Cl N N A mixture of 3-(4-Methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-diol (example 109, a) and N,N-diethyl aniline (2.73 mL) at 0 °C was treated with POCl3 (44.4 mL) and heated to 120 °C for 4 h. The excess POCl3 was removed by distillation and the residue was poured into 100 mL water / ice and extracted with DCM. The combined organic layers were dried with MgSO4, filtered and evaporated. The title compound was used in the consecutive step without further cation. c) (S)[5-Chloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol N N Cl N N A mixture of chloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 109, b) (2.95 g), (S)-pyrrolidinol (1.82 g, 20.9 mmol) and DIPEA (9.83 g, 76.1 mmol) in DCM was stirred at room temperature for 30 min. The mixture was poured into water, extracted with DCM and the combined organic layers were dried with MgSO4, red and evaporated to yield the crude title compound which was used in the consecutive step without further purification. MS(m/e): 361.3 (MH+). d) (S)[3-(4-Methoxy-benzyl)(2,2,2-trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N O N F N N A mixture of 2,2,2-trifluoroethanol (936 mg, 9.35 mmol) in THF was treated with NaH for 1 h at room temperature. (S)[5-Chloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol (example 109, c) was added and the mixture was stirred at 100 °C for 2 h. The on mixture was poured into 1 M HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield the crude title compound which was used in the consecutive step without further purification. MS(m/e): 425.4 (MH+). e) (S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidin ol H F N N O N F N N (S)[3-(4-Methoxy-benzyl)(2,2,2-trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol (example 109, d) in 4.57 mL TFA was heated to 80 °C over night and ated. The residue was treated with 1M NaOH and washed with EtOAc. The combined organic layer was evaporated to yield the crude titel compound which was used in the utive step without further purification. MS(m/e): 305.2 (MH+). f) (S)[2-(2-Chloro-benzyl)(2,2,2-trifluoro-ethoxy)-2H-[1,2,3]triazolo[4,5- midinyl]-pyrrolidinol In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- midinyl]-pyrrolidinol and 1-(bromomethyl)chlorobenzene. MS(m/e): 429.4 (MH+).

Example 110 (S)[5-(2,2,2-Trifluoro-ethoxy)(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol F F N N O F N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol and 1-(bromomethyl)(trifluoromethyl)benzene.

MS(m/e): 463.4 (MH+). e 111 (S)[2-(2-Chloro-benzyl)isopropoxy-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol N N O OH a) Trifluoro-acetic acid (S)(5-isopropoxy-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)- pyrrolidinyl ester N N O N N F O F O In analogy to the procedure described for the synthesis of (S)[5-(2,2,2-Trifluoroethoxy )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was ed from (S)[5-Chloro(4-methoxy-benzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol le 108, c) through nucleophilic tution with iso-propanol and subsequent cleavage of the 4-methoxy benzyl group with TFA and used crude in the subsequent step. b) (S)[2-(2-Chloro-benzyl)isopropoxy-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from Trifluoro-acetic acid (S)(5-isopropoxy-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl ester and 1-(bromomethyl) chlorobenzene. MS(m/e): 389.3 (MH+). e 112 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(1-methyl-1H-tetrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N O N N N N N a) 5-Chloro(3,3-difluoro-pyrrolidinyl)(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidine N N Cl In analogy to the procedure described for the synthesis of (S)[5-Chloro(4-methoxybenzyl )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, c) the title compound was prepared from 5,7-Dichloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidine and 3,3-difluoro-pyrrolidine and used in the consecutive step without further purification. b) 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)-3H-[1,2,3]triazolo[4,5- d]pyrimidine N N O In analogy to the procedure described for the sis of (S)[5-(2,2,2-Trifluoroethoxy )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was ed from 5-Chloro(3,3-difluoro-pyrrolidinyl)(4-methoxybenzyl 1,2,3]triazolo[4,5-d]pyrimidine (example 112, a) h nucleophilic tution with 2,2-dimethylpropanol and subsequent cleavage of the 4-methoxy benzyl group with TFA and used crude in the subsequent step. c) 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(1-methyl-1H-tetrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-tetrazole.

MS(m/e): 409.4 (MH+).

Example 113 (R)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N a) (3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol N N In analogy to the ure described for the synthesis of 4-(5-tert-Butyl(4- methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7yl)morpholine /example 1c) the title compound was prepared from 3-benzyltert-butylchloro-triazolo[4,5-d]pyrimidine and (R)-pyrrolidinol and isolated as white foam. MS(m/e): 352.4 (MH+). b) (R)(5-tert-butyl((1-methyl-1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl)pyrrolidinol (R)(3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol was hydrogenated over Pd/C and the resulting (R)(5-tert-Butyl-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl)-pyrrolidinol was reacted in analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro-pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5- midine (example 3, step b) with 5-(chloromethyl)methyl-1H-tetrazole. MS(m/e): 359.3 (MH+).

Example 114 1-[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N a) 1-(3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol In analogy to the procedure described for the synthesis of (3-Benzyltert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol le 113, a) the title compound was prepared from 3-benzyltert-butylchloro-triazolo[4,5-d]pyrimidine and pyrrolidin- 3-ol and isolated as light yellow oil. b) ert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) 1-(3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)methyl-1H-tetrazole and isolated as light yellow oil. MS(m/e): 359.3 (MH+).

Example 115 7-(3,3-Difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)((S)-2,2,2-trifluoro methyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F F F N N O F N a) 7-(3,3-Difluoro-pyrrolidinyl)((S)-2,2,2-trifluoromethyl-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidine F F N N O In analogy to the procedure described for the synthesis of 7-(3,3-Difluoro-pyrrolidinyl)- -(2,2-dimethyl-propoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 112, b) the title compound was ed from 5-Chloro(3,3-difluoro-pyrrolidinyl)(4-methoxy- benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 112, a) through nucleophilic substitution with (S)-1,1,1-Trifluoro-propanol and subsequent ge of the 4- methoxy benzyl group with TFA and used crude in the subsequent step. b) 7-(3,3-Difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)((S)-2,2,2-trifluoro -ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(trifluoromethyl)benzene.

MS(m/e): 497.4 (MH+).

Example 116 7-(3,3-Difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)((S)-2,2,2-trifluoro methyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F N N O O F S N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)(methylsulfonyl)benzene.

MS(m/e): 507.4 (MH+).

Example 117 2-(3-Chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N F F N N O Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro(chloromethyl)pyridine. MS(m/e): 464.4 (MH+).

Example 118 7-(3,3-Difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazolylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F N N O N N N O N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine le 3, step b), the title compound was prepared from -Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)methyl-1,3,4-oxadiazole.

MS(m/e): 435.4 (MH+).

Example 119 7-(3,3-Difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazolylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F N N O N N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1,2,4-oxadiazole.

MS(m/e): 435.4 (MH+).

Example 120 7-(3,3-Difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F N N O N N N N N In analogy to the procedure described for the synthesis of -butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl-1H-tetrazole.

MS(m/e): 435.3 (MH+).

Example 121 7-(3,3-Difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N F F N N O In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and momethyl)methyl-1,2,5-oxadiazole.

MS(m/e): 435.3 (MH+).

Example 122 7-(3,3-Difluoro-pyrrolidinyl)((S)-2,2,2-trifluoromethyl-ethoxy)(3,3,3- trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine F F N N O F N F N F In analogy to the procedure described for the sis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-bromo-1,1,1-trifluoropropane. MS(m/e): 435.3 (MH+).

Example 123 2-(1-Cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidinyl)((S)- 2,2,2-trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine N N F F N N N O In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)- 3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)cyclopropyl-1H-tetrazole.

MS(m/e): 461.4 (MH+).

Example 124-a and Example 124-b [5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol and (R)[5-tert-Butyl(2-chloro-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol N N N Cl N Cl N N N N N N N OH OH a) 1-(3-Benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)methyl-pyrrolidin- 3-ol N N In analogy to the procedure described for the synthesis of (R)(3-Benzyltert-butyl-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol (example 113, a) the title compound was prepared from 3-benzyltert-butylchloro-triazolo[4,5-d]pyrimidine and 3-Methylpyrrolidinol and subjected to tion by chiral HPLC to yield (S)(3-benzyltert- butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)methylpyrrolidinol and (3- benzyltert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)methylpyrrolidinol. The enatiopure intermediates where ed with 39 % and 36 % yield. b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol and (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 1-(bromomethyl)- robenzene. MS(m/e): 401.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently d with 1-(bromomethyl)- 2-chlorobenzene. MS(m/e): 401.4 (MH+).

Example 125-a and Example 125-b (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]methyl-pyrrolidinol and (R)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol F F N N F F N N F N F N N N N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 1-(bromomethyl)- 2-(trifluoromethyl)benzene. MS(m/e): 435.4 (MH+).

In y to the procedure described for the synthesis of (5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 1-(bromomethyl)- 2-(trifluoromethyl)benzene. MS(m/e): 435.4 (MH+).

Example 126-a and Example 126-b [5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]methyl-pyrrolidinol and (R)[5-tert-Butyl(2-methanesulfonyl-benzyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol N N N N O O S N S N O N O N N N N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) [5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 1-(bromomethyl)- 2-(methylsulfonyl)benzene. ): 445.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 1-(bromomethyl)- 2-(methylsulfonyl)benzene. MS(m/e): 445.4 (MH+). e 127-a and Example 127-b (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(3-chloropyridinylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol N N N N N N Cl N Cl N N N N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) [5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 3-chloro omethyl)pyridine. MS(m/e): 402.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- razolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol le 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 3-chloro (chloromethyl)pyridine. MS(m/e): 402.4 (MH+).

Example 128-a and Example 128-b (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(5-methyl- [1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methylpyrrolidinol N N N N N N N N N O N N O N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 2-(chloromethyl)- 5-methyl-1,3,4-oxadiazole. MS(m/e): 373.4 (MH+).

In analogy to the ure bed for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently d with 2-(chloromethyl)- 5-methyl-1,3,4-oxadiazole. MS(m/e): 373.4 (MH+).

Example 129-a and Example 129-b [5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(3-methyl- [1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl- pyrrolidinol N N N N N N N N N N N N O O N N N N OH OH In analogy to the ure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)- 3-methyl-1,2,4-oxadiazole. ): 373.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)- 3-methyl-1,2,4-oxadiazole. MS(m/e): 373.4 (MH+).

Example 130-a and Example 130-b (S)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(1-methyl-1H- olylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol N N N N N N N N N N N N N N N N N N N N OH OH In y to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] -pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)- 1-methyl-1H-tetrazole. ): 373.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)- 1-methyl-1H-tetrazole. MS(m/e): 373.4 (MH+).

Example 131-a and Example 131-b (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(4-methylfurazanylmethyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidin ol O O N N N N N N N N N N N N N N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol le 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 3-(bromomethyl)- 4-methyl-1,2,5-oxadiazole. MS(m/e): 373.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 3-(bromomethyl)- 4-methyl-1,2,5-oxadiazole. MS(m/e): 373.4 (MH+).

Example 132-a and Example 132-b (S)[5-tert-Butyl(3,3,3-trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- yl-pyrrolidinol and (R)[5-tert-Butyl(3,3,3-trifluoro-propyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidinol N N N N F N F N F N N F N F N F N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and uently reacted with o-1,1,1- trifluoropropane. ): 373.4 (MH+).

In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol le 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 3-bromo-1,1,1- trifluoropropane. MS(m/e): 373.4 (MH+).

Example 133-a and Example 133-b (S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and (R)[5-tert-Butyl(1-cyclopropyl- 1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]methyl-pyrrolidin- 3-ol N N N N N N N N N N N N N N N N N N OH OH In analogy to the procedure described for the synthesis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol (example 113, b) (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently reacted with 5-(chloromethyl)- 1-cyclopropyl-1H-tetrazole. MS(m/e): 399.4 (MH+).

In analogy to the procedure described for the sis of (R)(5-tert-butyl((1-methyl- 1H-tetrazolyl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)pyrrolidinol le 113, b) (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol was hydrogenated and subsequently d with 5-(chloromethyl)- 1-cyclopropyl-1H-tetrazole. MS(m/e): 399.4 (MH+).

Example 134 N-{(S)[2-(2-Chloro-benzyl)(2,2-dimethyl-propoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide N N O Cl N a) N-{(S)[5-Chloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- idinyl}-acetamide N N Cl In y to the procedure described for the synthesis of (S)[5-Chloro(4-methoxy- benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, c) the title compound was prepared from 5,7-Dichloro(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5- d]pyrimidine and Pyrrolidinyl-acetamide and used in the consecutive step without further purification. b) N-{(S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinyl}-acetamide N N O CF3 N N In analogy to the ure described for the synthesis of (S)[5-(2,2,2-Trifluoroethoxy )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was prepared from N-{(S)[5-Chloro(4-methoxy-benzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide (example 134, a) through nucleophilic substitution with 2,2,2-trifluoro-ethanol and subsequent cleavage of the 4- methoxy benzyl group with TFA and used crude in the subsequent step. c) N-{(S)[2-(2-Chloro-benzyl)(2,2-dimethyl-propoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N-{(S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- midinyl]-pyrrolidinyl}-acetamide and 1-(bromomethyl)chlorobenzene.

MS(m/e): 458.4 (MH+).

Example 135 [2-(3-Chloro-pyridinylmethyl)(2,2-dimethyl-propoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide N N O Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was ed from N-{(S)[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide and 3-chloro(chloromethyl)pyridine.

MS(m/e): 459.4 (MH+).

Example 136 tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine F F N N NH F N a) tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- amine H H N N N In analogy to the procedure described for the synthesis of [5-(2,2,2-Trifluoroethoxy )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was ed from 5-Chloro(3,3-difluoro-pyrrolidinyl)(4-methoxy- benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 112, a) through nucleophilic substitution with tert-butylamine and subsequent cleavage of the 4-methoxy benzyl group with TFA and used crude in the subsequent step. b) tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine and 1-(bromomethyl) uoromethyl)benzene. MS(m/e): 456.4 (MH+).

Example 137 tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine N N O NH S N O N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine and 1-(bromomethyl) (methylsulfonyl)benzene. MS(m/e): 466.4 (MH+).

Example 138 tert-Butyl-[2-(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine N N NH Cl N In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H- ]triazolo[4,5-d]pyrimidinyl]-amine and 3-chloro(chloromethyl)pyridine.

MS(m/e): 423.3 (MH+).

Example 139 tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine N N NH N N N N N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl hyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine and oromethyl)methyl-1H-tetrazole.

MS(m/e): 394.4 (MH+).

Example 140 tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine N N N N NH In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)-3H- ]triazolo[4,5-d]pyrimidinyl]-amine and 3-(bromomethyl)methyl-1,2,5- zole. MS(m/e): 394.4 (MH+).

Example 141 N-{(S)[2-(2-Chloro-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide N N O Cl N N F a) N-{(S)[5-((S)-2,2,2-Trifluoromethyl-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinyl}-acetamide H F N N O N F In analogy to the procedure described for the synthesis of (S)[5-(2,2,2-Trifluoroethoxy 1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was prepared from N-{(S)[5-Chloro(4-methoxy-benzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide (example 134, a) through nucleophilic substitution with (S)-1,1,1-Trifluoro-propanol and subsequent ge of the 4-methoxy benzyl group through hydrogenation and used crude in the subsequent step. b) N-{(S)[2-(2-Chloro-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoro- pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N-{(S)[5-((S)-2,2,2-Trifluoromethyl-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide and 1-(bromomethyl) benzene. MS(m/e): 484.4 (MH+).

Example 142 [2-(2-Trifluoromethyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- ]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide F F N N O F N N F In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N-{(S)[5-((S)-2,2,2-Trifluoromethyl-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide and 1-(bromomethyl) (trifluoromethyl)benzene. MS(m/e): 518.5 (MH+).

Example 143 N-{(S)[2-(2-Methanesulfonyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide N N O O S N O N N F In analogy to the procedure described for the sis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N-{(S)[5-((S)-2,2,2-Trifluoromethyl-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide and momethyl) (methylsulfonyl)benzene. MS(m/e): 528.5 (MH+).

Example 144 N-{(S)[5-tert-Butylamino(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]-pyrrolidinyl}-acetamide N H N N Cl N a) N-[(S)(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinyl]- acetamide H H N N N In analogy to the procedure described for the synthesis of (S)[5-(2,2,2-Trifluoro- ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 108, e) the title compound was prepared from N-{(S)[5-Chloro(4-methoxy-benzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide (example 134, a) through nucleophilic substitution with tert-butylamine and subsequent cleavage of the 4-methoxy benzyl group through hydrogenation and used crude in the subsequent step. b) N-{(S)[5-tert-Butylamino(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin rrolidinyl}-acetamide In y to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from N-[(S)(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl)-pyrrolidinyl]-acetamide and 1-(bromomethyl)chlorobenzene.

MS(m/e): 443.4 (MH+).

Example 145 (S)[5-tert-Butylamino(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol N N N N N N N N OH a) (S)(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl)-pyrrolidinol H H N N N In analogy to the uere described for the synthesis of d) (S)[3-(4-Methoxybenzyl )(2,2,2-trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 109, d) the title nd was prepared from (S)[5-Chloro(4-methoxybenzyl )-3H-[1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol (example 109, c) and tert- butyl amine, subsequent cleavage of the PMB protecting group and used in the utive step without further purification. b) (S)[5-tert-Butylamino(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol In analogy to the procedure described for the synthesis of 5-tert-butyl(3,3-difluoropyrrolidinyl )ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title nd was prepared from (S)(5-tert-Butylamino-3H-[1,2,3]triazolo[4,5- d]pyrimidinyl)-pyrrolidinol and 5-(chloromethyl)methyl-1H-tetrazole. MS(m/e): 374.3 (MH+).

Example 146 Pharmacological tests The ing tests were d out in order to determine the activity of the compounds of formula I: Radioligand binding assay The affinity of the compounds of the ion for cannabinoid CB1 receptors was determined using recommended amounts of membrane preparations (PerkinElmer) of human embryonic kidney (HEK) cells expressing the human CNR1 or CNR2 receptors in conjunction with 1.5 or 2.6 nM P-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 radioactivity was analyzed for Ki using nonlinear regression analysis (Activity Base, ID Business Solution, Limited), with the Kd values for 55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 or with affinities below 10 µM, more ularly of 1 nM to 3 µM and most particularly of 1nM to 100 nM.

The compounds according to formula I have an activity in the above assay (Ki) particularly of 0.5 nM to 10 µM, more particularly of 0.5 nM to 3 µM and most particularly of 0.5 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 supplement, with 10 % fetal calf serum and incubated at 5% CO2 and 37°C in a humidified incubator. The growth medium was exchanged with Krebs Ringer onate buffer with 1 mM IBMX and incubated at °C for 30 min. Compounds 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 stopped by the addition of 50 µl lysis t (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), equipped with a ND:YAG laser as excitation . 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 exposure time 10s at 730 (bandwidth 30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is calculated 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 0.1 nM cAMP.

EC 50 values were ined using Activity Base analysis (ID ss Solution, 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.

All compounds are CB2 agonists with EC50 below 3 uM, particularly below 1uM, more particularly below 0.5 uM, and selectivity versus CB1 in the corresponding assay of at least 10 fold.

For e, the ing compounds showed the following human EC50 values in the functional cAMP assay bed above: human human human human Example CB2 EC50 CB2 EC50 Example CB2 EC50 CB2 EC50 [µM] [µM] [µM] [µM] 1 0.0033 >10 79 0.0004 >10 2 0.0022 >10 80 0.0103 >10 3 0.0185 >10 81 0.0094 >10 4 0.008 >10 82 0.0028 >10 0.0647 >10 83 0.0061 >10 6 0.0005 0.306 84 0.094 >10 7 0.0041 >10 85 0.0102 >10 8 0.0065 >10 86 0.0522 >10 9 0.0034 >10 87 0.2578 >10 0.0041 >10 88 0.0521 >10 11 0.0012 >10 89 0.3715 >10 12 0.0015 >10 90 0.0407 >10 13 0.001 >10 91 0.1244 >10 14 0.0005 0.065 92 0.005 1.576 0.0007 0.21 93 0.2695 >10 16 0.0039 >10 94 0.2514 >10 17 0.0008 >10 95 0.2574 >10 18 0.0014 >10 96 0.0226 >10 19 0.0022 >10 97 0.1445 >10 0.0002 0.034 98 0.2108 >10 21 0.0001 0.183 99 0.0009 >10 22 0.0002 >10 100 0.0046 >10 23 0.0002 0.086 101 0.0157 >10 24 0.0004 >10 102 0.0063 >10 0.0001 0.205 103 0.0209 >10 26 0.0013 0.386 104 0.0101 >10 27 0.0009 >10 105 0.1103 >10 28 0.0002 0.134 106 0.0627 >10 29 0.0008 0.098 107 0.0084 >10 0.0007 nd 108 0.0052 0.3625 31 0.0005 nd 109 0.1066 >10 32 0.019 nd 110 0.06 >10 33 0.0012 >10 111 0.2654 >10 34 0.0005 >10 112 0.0309 >10 0.0005 0.6416 113 1.6631 >10 36 0.0002 0.0203 114 0.1644 >10 37 0.0009 >10 115 0.0312 >10 38 0.0011 0.0986 116 0.0231 >10 39 0.0002 >10 117 0.0212 >10 40 0.0043 >10 118 0.4409 >10 41 0.0005 0.4975 119 0.4393 >10 42 0.0106 >10 120 0.0694 >10 43 0.022 >10 121 0.0075 >10 44 0.0002 0.4545 122 0.0084 >10 45 0.0076 >10 123 0.0493 >10 46 0.0028 >10 124-a 0.0025 >10 47 0.0006 >10 124-b 0.0068 >10 48 0.0055 >10 125-a 0.0004 0.3978 49 0.0004 0.1498 125-b 0.0037 >10 50 0.0015 >10 126-a 0.0106 >10 51 0.0009 >10 126-b 0.024 >10 52 0.013 >10 127-a 0.0051 0.7573 53 0.0072 >10 127-b 0.0119 0.6091 54 0.0065 >10 128-a 0.0702 >10 55 0.0087 >10 128-b 0.7891 >10 56 0.0126 >10 129-a 0.1968 >10 57 0.0036 >10 129-b 0.3164 >10 58 0.0043 >10 130-a 0.1718 >10 59 0.0035 >10 130-b 0.7985 >10 60 0.0127 >10 131-a 0.0102 >10 61 0.0026 >10 131-b 0.0614 >10 62 0.0058 >10 132-a 0.0181 >10 63 0.004 >10 132-b 0.0698 >10 64 0.0024 >10 133-a 0.1255 >10 65 0.0186 >10 133-b 0.5466 >10 66 0.0004 0.2337 134 0.6818 >10 67 0.0013 1.6275 135 0.6056 >10 68 0.0023 >10 136 0.035 >10 69 0.0011 >10 137 0.0053 >10 70 0.0336 >10 138 0.054 >10 71 0.0014 0.105 139 0.0281 >10 72 0.0118 >10 140 0.0061 >10 73 0.0071 >10 141 1.15 >10 74 0.0613 >10 142 1.11 >10 75 0.0046 >10 143 1.73 >10 76 0.0059 >10 144 1.95 >10 77 0.0155 >10 145 1.09 >10 78 0.006 >10 β-Arrestin translocation PathHunter™ (DiscoveRx) PathHunter™ β-arrestin CHO-K1 CNR1 cell line (catalog number #93-0200C2) and the βarrestin CHO-K1 CNR2 cell line og number #93-0706C2) were purchased from DiscoveRx Corporation. The cell line was engineered to express the β-galactosidase EA fragment fused to β-arrestin and the ProLink complementary e fused to the target receptor. The PathHunter™ protein complementation assay (DiscoveRx Corporation #93- 0001) was performed according to the manufacturer’s protocol. Assay plates were seeded containing 7500 (CNR1) and 10000 (CNR2) cells in 384 well plates (Corning Costar #3707, white, clear bottom) in 20µL cell plating reagent 2 (Discoverx #93-0563R2A).

After incubation at 37 °C (5% CO2, 95% relative humidity) overnight, 5 µl of test compound was added (1% final DMSO tration) and the incubation continued at 30 °C for 90 min. Detection reagent (12 µl) was then added and the incubation continued at room temperature for 60 min. Plates were then analyzed for a chemiluminescent signal using a Victor 3V reader (Perkin Elmer).

Example A Film coated tablets containing the following ingredients can be manufactured in a conventional : Ingredients Per tablet Kernel: Compound of formula (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 ium stearate 1.5 mg 4.5 mg (Kernel ) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 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 red with an aq. on / suspension of the above mentioned film coat.

Example B Capsules containing the following ingredients can be manufactured in a tional manner: 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 capsules of size 2.

Example C Injection solutions can have the following composition: Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for ion 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 addition of acetic acid. The volume is ed 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 (22)

Claims

1. A compound of formula (I) R1 N N R2 R3 (I) wherein 5 A is ne, hydroxyalkylene, -CH2C(O)-, -C(O)-, -SO2- or ; R1 is hydrogen, alkyl, haloalkyl, hydroxyl, alkoxy, haloalkoxy, , halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, (halo)(haloalkyl)phenyl, (halo)(alkoxy)phenyl, cyano, lkyl, 10 cycloalkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl, haloheteroaryl, alkylheteroaryl, (alkyl)(alkylsulfonyl)heteroaryl, (alkylamino)heteroaryl, haloalkylheteroaryl, cycloalkylheteroaryl or nitrobenzo [1,2,5]oxadiazolylaminoheteroaryl, wherein heterocyclyl is a three to 15 eight membered carbocyclic ring comprising at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridinyl, pyrazolyl, oxadiazolyl, furazanyl, tetrazolyl, triazolyl or oxypyridinyl; R2 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkylalkoxy, haloalkoxy, alkoxy or alkylamino; 20 R3 is halogen or -NR4R5; one of R4 and R5 is hydrogen or alkyl and the other one is alkyl or cycloalkyl; or R4 and R5 together with the nitrogen atom to which they are attached form heterocyclyl or substituted heterocyclyl, wherein heterocyclyl is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxaazaspiro[3.3]heptyl, azetidinyl, 25 thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa azaspiro[3.4]octyl, 6-oxaazaspiro[3.3]heptyl, 5-aza-spiro[3.4]octyl, isoxazolidinyl, inyl or dioxoisothiazolidinyl and wherein tuted cyclyl is heterocyclyl substituted with one to four substituents independently selected from alkyl, halogen, yl, alkoxy, hydroxyalkyl, carboxyl, alkoxyalkyl, cyano and alkylcarbonylamino; or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1, wherein A is alkylene, -CH2C(O)- or absent. 5

3. A compound according to claim 1 or 2, wherein A is alkylene.

4. A compound according to any one of claims 1 to 3, wherein A is methylene, ethylene or -CH(CH3)-.

5. A compound according to any one of claims 1 to 4, wherein R1 is alkyl, haloalkyl, hydroxyl, alkoxy, , halophenyl, alkoxyphenyl, kylphenyl, 10 haloalkoxyphenyl, cyanophenyl, cycloalkyl, heterocyclyl, haloheteroaryl or alkylheteroaryl, wherein heterocyclyl is oxetanyl, and wherein heteroaryl is pyridinyl or nyl.

6. A compound according to any one of claims 1 to 5, wherein R1 is alkyl, haloalkyl, hydroxyl, alkoxy, , halophenyl, phenyl, haloalkylphenyl, 15 haloalkoxyphenyl, cyanophenyl, cycloalkyl, oxetanyl, pyridinyl, halopyridinyl or urazanyl.

7. A compound according to any one of claims 1 to 6, wherein R1 is trifluoromethyl, phenyl, phenyl, bromophenyl, cyanophenyl, cyclohexyl, pyridinyl, chloropyridinyl, methylfurazanyl or trifluoromethylphenyl. 20

8. A compound according to any one of claims 1 to 7, wherein R2 is alkyl.

9. A compound according to any one of claims 1 to 8, wherein R2 is tert.-butyl.

10. A compound according to any one of claims 1 to 9, wherein R3 is -NR4R5.

11. A compound according to any one of claims 1 to 10, wherein R4 and R5 er with the nitrogen atom to which they are attached form morpholinyl, halopyrrolidinyl 25 or hydroxypyrrolidinyl.

12. A nd according to any one of claims 1 to 11, wherein R4 and R5 together with the en atom to which they are attached form morpholinyl, difluoropyrrolidinyl or hydroxypyrrolidinyl.

13. A nd according to any one of claims 1 to 12 selected from 5-tert-Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 5-tert-Butyl(2-chlorofluoro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- 5 d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)ethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 10 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 5-tert-Butylcyclohexylmethyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- 15 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(4-chloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,3-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 20 5-tert-Butyl(2,4-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,5-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,6-dichloro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- 25 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- ]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,2,2-trifluoro-ethyl)-2H- 10 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chloro-4,5-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chloro-3,6-difluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 15 romo-benzyl)tert-butyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methoxy-benzyl)-2H- 20 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-trifluoromethoxy-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]-benzonitrile; 25 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)phenethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-phenyl-ethanone; 5-tert-Butyl[(R)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[(S)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5 5-tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)oxetanyl-2H-[1,2,3]triazolo[4,5- 10 d]pyrimidine; 5-tert-Butyl(2,6-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 15 5-tert-Butyl(4-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,5-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- 20 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,6-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- ]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 25 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazol yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[2-(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[2-(3-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl[2-(4-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5 5-tert-Butyl(2,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(R)-tetrahydro-furanyl-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(S)-tetrahydro-furanyl-2H- 10 [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-(2-chloro-phenyl)-ethanone; 5-tert-Butyl(2,3-dichlorofluoro-benzyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 15 -Butyl(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-oxetanylmethyl)-2H- 20 [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-(3-chloro-phenyl)-ethanone; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-(4-chloro-phenyl)-ethanone; 25 ert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-pyridinyl-ethanone; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,3,6-trichloro-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-chlorofluoromethoxy-benzyl)(3,3-difluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-pyridinyl-ethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2,3-dichlorotrifluoromethyl-benzyl)(3,3-difluoro-pyrrolidin 10 yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,4-dichloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- ]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-1λ6-thietanyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 15 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(1,1-dioxo-tetrahydro-1λ6-thiophen yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidinyl]- 1-pyridinyl-ethanone; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazol 20 ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methyl-[1,2,4]oxadiazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 25 -Butyl(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(5-methanesulfonylmethyl-4H- [1,2,4]triazolylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; {3-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]chloro-pyridinyl}-dimethyl-amine; 5 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-trifluoromethyl-1H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- 10 d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3,6-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 15 (S)[5-tert-Butyl(2-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2,3-dichloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- idinol; [5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 20 7-yl]-pyrrolidinol; (S)[5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-pyrazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 25 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(3-methyl-3H-[1,2,3]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(4,5-dimethyl-4H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2-methyloxy-pyridinylmethyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S)[5-tert-Butyl(3,4-dichloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 5 (S)[5-tert-Butyl(5-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- 10 d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2-methyl-2H-[1,2,4]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 15 (S)[5-tert-Butyl(2,5-dimethyl-2H-pyrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidin yl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (S){5-tert-Butyl[2-(7-nitro-benzo[1,2,5]oxadiazolylamino)-pyridin 20 yl]-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl}-pyrrolidinol; [5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; (S)[5-tert-Butyl(2,5-dimethyl-2H-[1,2,4]triazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol; 25 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,5-dimethyl-2H-[1,2,4]triazol ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (2S,3S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]hydroxymethyl-pyrrolidinol; (2S,3S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]hydroxymethyl-pyrrolidinol; 5-tert-Butyl(4-methyl-furazanylmethyl)(3,3,4,4-tetrafluoro-pyrrolidinyl)- 2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5 5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)(3,3,4,4-tetrafluoro-pyrrolidin 10 -[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-methyl-3H-[1,2,3]triazolylmethyl)(3,3,4,4-tetrafluoropyrrolidinyl )-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 15 5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(4,5-dimethyl-4H-[1,2,4]triazolylmethyl)(2-oxaazaspiro [3.3]heptyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(2-methanesulfonyl-benzyl)(2-oxaaza-spiro[3.3]heptyl)-2H- 20 [1,2,3]triazolo[4,5-d]pyrimidine; -Butyl(3-chloro-pyridinylmethyl)(2-oxaaza-spiro[3.3]heptyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; (S)[2-(2-Chloro-benzyl)(2,2,2-trifluoro-ethoxy)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 25 (S)[5-(2,2,2-Trifluoro-ethoxy)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol; (S)[2-(2-Chloro-benzyl)isopropoxy-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl]- pyrrolidinol; 7-(3,3-Difluoro-pyrrolidinyl)(2,2-dimethyl-propoxy)(1-methyl-1H-tetrazol- 5-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; (R)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 5 1-[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinol; 7-(3,3-Difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)((S)-2,2,2-trifluoro- 10 1-methyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 2-(3-Chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(5-methyl-[1,3,4]oxadiazolylmethyl)((S)- 2,2,2-trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 15 7-(3,3-Difluoro-pyrrolidinyl)(3-methyl-[1,2,4]oxadiazolylmethyl)((S)- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)((S)-2,2,2- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)((S)-2,2,2- 20 trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 7-(3,3-Difluoro-pyrrolidinyl)((S)-2,2,2-trifluoromethyl-ethoxy)(3,3,3- trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 2-(1-Cyclopropyl-1H-tetrazolylmethyl)(3,3-difluoro-pyrrolidinyl)((S)- trifluoromethyl-ethoxy)-2H-[1,2,3]triazolo[4,5-d]pyrimidine; 25 (S)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol; (R)[5-tert-Butyl(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol; (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]methyl-pyrrolidinol; (R)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]methyl-pyrrolidinol; 5 (S)[5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(2-methanesulfonyl-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- 10 d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(3-chloro-pyridinylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; 15 [5-tert-Butyl(5-methyl-[1,3,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(3-methyl-[1,2,4]oxadiazolylmethyl)-2H-[1,2,3]triazolo[4,5- 20 d]pyrimidinyl]methyl-pyrrolidinol; [5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(1-methyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; 25 (S)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(4-methyl-furazanylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (S)[5-tert-Butyl(3,3,3-trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]methyl-pyrrolidinol; [5-tert-Butyl(3,3,3-trifluoro-propyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin yl]methyl-pyrrolidinol; 5 (S)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; (R)[5-tert-Butyl(1-cyclopropyl-1H-tetrazolylmethyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol; N-{(S)[2-(2-Chloro-benzyl)(2,2-dimethyl-propoxy)-2H-[1,2,3]triazolo[4,5- 10 d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[2-(3-Chloro-pyridinylmethyl)(2,2-dimethyl-propoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-trifluoromethyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; 15 tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(2-methanesulfonyl-benzyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[2-(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(1-methyl-1H-tetrazolylmethyl)-2H- 20 [1,2,3]triazolo[4,5-d]pyrimidinyl]-amine; tert-Butyl-[7-(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- ]triazolo[4,5-d]pyrimidinyl]-amine; N-{(S)[2-(2-Chloro-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; 25 N-{(S)[2-(2-Trifluoromethyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[2-(2-Methanesulfonyl-benzyl)((S)-2,2,2-trifluoromethyl-ethoxy)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinyl}-acetamide; N-{(S)[5-tert-Butylamino(2-chloro-benzyl)-2H-[1,2,3]triazolo[4,5- d]pyrimidinyl]-pyrrolidinyl}-acetamide; and (S)[5-tert-Butylamino(1-methyl-1H-tetrazolylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol. 5

14. A compound according to any one of claims 1 to 13 selected from 5-tert-Butyl(2-chloro-benzyl)morpholinyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 5-tert-Butylcyclohexylmethyl(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 10 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)pyridinylmethyl-2H- ]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(2,2,2-trifluoro-ethyl)-2H- ]triazolo[4,5-d]pyrimidine; 2-(2-Bromo-benzyl)tert-butyl(3,3-difluoro-pyrrolidinyl)-2H-

15 [1,2,3]triazolo[4,5-d]pyrimidine; 2-[5-tert-Butyl(3,3-difluoro-pyrrolidinyl)-[1,2,3]triazolo[4,5-d]pyrimidin ylmethyl]-benzonitrile; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)phenethyl-2H-[1,2,3]triazolo[4,5- d]pyrimidine; 20 5-tert-Butyl[(R)(2-chloro-phenyl)-ethyl](3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(4-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- 25 [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3,3-difluoro-pyrrolidinyl)(4-methyl-furazanylmethyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; 5-tert-Butyl(3-chloro-pyridinylmethyl)(3,3-difluoro-pyrrolidinyl)-2H- [1,2,3]triazolo[4,5-d]pyrimidine; and (S)[5-tert-Butyl(2-trifluoromethyl-benzyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin- 7-yl]-pyrrolidinol. 5 15. A s for the preparation of a compound according to any one of claims 1 to 14 comprising the reaction of a compound of formula (A) N N R2 R3 (A) in the presence of R1-A-X and a base, or in the presence of R1-A-OH under Mitsunobu conditions, wherein A and R1 to R3 are defined according to any one of 10 claims 1 to 12 and wherein X is halogen or SO2.

16. A compound according to any one of claims 1 to 14, when manufactured according to a process of claim 15.

17. A compound according to any one of claims 1 to 14 for use as therapeutically active substance. 15

18. A pharmaceutical composition comprising a compound in ance with any one of claims 1 to 14 and a therapeutically inert carrier.

19. The use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, 20 inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, ic fibrosis, acute aft ion, chronic aft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, g, rophic scars, 25 s, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.

20. A compound according to any one of claims 1 to 14 for the treatment or prophylaxis of pain, atherosclerosis, age-related r degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, iareperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart e, myocardial 5 ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis a, liver cirrhosis or tumors, regulation of bone mass, egeneration, stroke, transient ischemic attack or s.

21. A s according to claim 15 substantially as herein described with reference to any example thereof. 10

22. A pharmaceutical composition according to claim 18 substantially as herein described with reference to any example thereof.