NZ715085B2 - Novel triazolo[4,5-d]pyrimidine derivatives - Google Patents

Novel triazolo[4,5-d]pyrimidine derivatives Download PDF

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NZ715085B2
NZ715085B2 NZ715085A NZ71508514A NZ715085B2 NZ 715085 B2 NZ715085 B2 NZ 715085B2 NZ 715085 A NZ715085 A NZ 715085A NZ 71508514 A NZ71508514 A NZ 71508514A NZ 715085 B2 NZ715085 B2 NZ 715085B2
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New Zealand
Prior art keywords
methyl
triazolo
difluoropyrrolidinyl
chlorophenyl
pyrimidine
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NZ715085A
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NZ715085A (en
Inventor
Uwe Grether
Atsushi Kimbara
Matthias Nettekoven
Stephan Roever
Evans Mark Rogers
Sebastien Schmitt
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F Hoffmann La Roche Ag
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Priority to NZ756513A priority Critical patent/NZ756513B2/en
Priority claimed from PCT/EP2014/068640 external-priority patent/WO2015032769A1/en
Publication of NZ715085A publication Critical patent/NZ715085A/en
Publication of NZ715085B2 publication Critical patent/NZ715085B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

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

Description

Novel triazolo[4,5-d]pyrimidine derivatives The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in ular to nds that are preferential agonists of the Cannabinoid Receptor 2.
The invention provides a nd of formula (I) wherein R1 is haloalkyl, enyl, alkoxyphenyl, alkyl-1,2,5-oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl; R2 is alkylamino, cycloalkylamino, alkyloxetanylamino, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl; R3 and R4 are independently selected from en, halogen, hydroxyl, alkylcarbonylamino and alkyl, provided that R3 and R4 are not both hydrogen at the same time; and n is 1 or 2; or a pharmaceutically acceptable salt or ester thereof; provided that (S)[3-(4-Methoxy-benzyl)(2,2,2-trifluoro-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol is excluded.
Also described is a compound of formula (I) wherein R1 is haloalkyl, halophenyl, alkoxyphenyl, alkyl-1,2,5-oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl; R2 is cycloalkyl, isopropyl, alkenyl, dinyl, alkylamino, azetidinyl, pyrrolidinyl, cycloalkylamino, alkyloxetanylamino, morpholinyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkylsulfonyl; R3 and R4 are independently ed from hydrogen, halogen, hydroxyl, arbonylamino and alkyl, provided that R3 and R4 are not both hydrogen at the same time; and n is 1 or 2; or a pharmaceutically acceptable salt or ester thereof; ed that (S)[3-(4-Methoxy-benzyl)(2,2,2-trifluoro-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol is excluded.
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 e, ischemiareperfusion 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, itis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
The cannabinoid receptors are a class of cell membrane receptors belonging to the G n-coupled receptor superfamily. There are currently two known es, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The CB1 receptor is mainly sed 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 erally, 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), 8; Centonze, D., et al. Curr Pharm Des 2008, , 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain where it is found primarily on microglia and not s (Cabral, G. A. et al. Br J Pharmacol 2008, 153(2): 240-51).
The st in CB2 receptor agonists has been steadily on the rise during the last decade (currently 30-40 patent applications/year) due to the fact that several of the early compounds have been shown to have beneficial effects in pre-clinical models for a number of human diseases including chronic pain amo, M. Mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, F. et al. J Neuroendocrinol 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, I. et al. Br J Pharmacol 2008, 153(2), 182-8), 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, , 252-62), systemic fibrosis (Akhmetshina, A. et al. tis Rheum 2009, 60(4), 1129-36; Garcia- Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), ), liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), ).
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 disruption of normal blood supply resulting in an insufficient tissue oxygenation. Re-oxygenation e.g., reperfusion is the ultimate treatment to restore normal tissue oxygenation. However the absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in further tissue damage. The damage of reperfusion injury is due in part to the inflammatory 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 restored blood flow oduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.
Remote ic preconditioning (RIPC) represents a gy for harnessing the body’s endogenous protective capabilities against the injury incurred by ischemia and reperfusion. It describes the intriguing phenomenon in which ent non-lethal ischemia and reperfusion of one organ or tissue confers resistance to a subsequent episode 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 ine, bradykinin, opioids, CGRP, nnabinoids, ensin I or some other as yet unidentified humoral factor) generated in the remote organ or tissue enters the blood stream and activates its tive receptor in the target tissue and thereby recruiting the various intracellular pathways of cardioprotection implicated in ischemic preconditioning.
Recent data indicates that nnabinnoids and their receptors, 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). Specifically, recent studies using CB2 tool agonists demonstrated the efficacy of this concept for reducing the I/R injury in the heart (Defer, N. et al. Faseb J 2009, 23(7), 0), the brain , 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 l Pathol 2008, 60(4-5), ).
Moreover, over the last few years, a growing body of literature indicates that CB2 can also be of interest in sub-chronic and chronic setting. Specific upregulation of CB1 and CB2 has been shown to be associated in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, E. et al. Rheumatology (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 ssion.
Activation of CB2 or by selective CB2 agonist has in fact been shown to exert anti-fibrotic effect in diffuse ic sclerosis (Garcia-Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6) and CB2 receptor has emerged as a critical target in experimental dermal fibrosis (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129- 36) and in in liver pathophysiology, including fibrogenesis associated with chronic liver diseases sztajn, S. et al. Gastroenterol Clin Biol 2007, 31(3), 255-8; Mallat, A. et al.
Expert Opin Ther Targets 2007, 11(3), 403-9; Lotersztajn, S. et al. Br J Pharmacol 2008, 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 description the term "alkyl", alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or 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, yl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric s and the isomeric octyls. Particular examples of alkyl are methyl, ethyl, n-propyl, isopropyl, n.- butyl, isobutyl, tert.-butyl, and neopentyl.
The term "cycloalkyl", alone or in combination, ies a cycloalkyl ring with 3 to 8 carbon atoms and particularly a lkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, eptyl and cyclooctyl. Particular es of "cycloalkyl" are cyclopropyl and cyclobutyl.
The term "alkenyl", alone or in combination, ies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1- propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.
The term "alkynyl", alone or in ation, ies a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. A particular example of alkynyl group is propinyl.
The term "alkoxy", alone or in combination, signifies a group of the formula O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Particular "alkoxy" are methoxy, ethoxy, n-propyloxy, isopropyloxy, isobutyloxy, tert.- butyloxy and neopentyloxy.
The terms "halogen" or "halo", alone or in combination, ies fluorine, chlorine, bromine or iodine and particularly ne, 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 ns, particularly one to four halogens, i.e. one, two, three or four halogens. Particular "halogen" are fluorine, chlorine and bromine.
The term "haloalkyl", alone or in combination, denotes an alkyl group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. Particular "haloalkyl" are oromethyl, trifluoroethyl and trifluoropropyl.
The term "haloalkyloxy" or "haloalkoxy", alone or in combination, denotes an alkyloxy group substituted with at least one halogen, particularly substituted with one to five halogens, particularly one to three halogens. ular "haloalkyloxy" are trifluoroethyloxy, trifluoropropyloxy, fluoroethyloxy, roethyloxy and difluoropropyloxy.
The terms "hydroxyl" and "hydroxy", alone or in combination, signify the -OH group.
The term "oxy", alone or in combination, signifies the -O- group.
The term "amino", alone or in combination, signifies the primary amino group (-NH2), the secondary amino group (-NH-), or the tertiary amino group (-N-). A particular amino is -NH-.
The term "sulfonyl", alone or in combination, ies the -S(O)2- group.
The term "sulfanyl", alone or in ation, signifies the -S- group.
The term "pharmaceutically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not ically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, c acid, oxalic acid, maleic acid, malonic acid, ic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an nic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion ge resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, ne, N-ethylpiperidine, piperidine, polyamine resins. The compound of formula (I) can also be present in the form of zwitterions. Particularly red pharmaceutically acceptable salts of compounds of formula (I) are the salts of hloric acid, romic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
"Pharmaceutically acceptable esters" means that the compound of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as ymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
Additionally, any physiologically able equivalents of the compound of general formula (I), similar to the metabolically labile esters, which are e 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) n one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups (as bed 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 applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using rd methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl ate (Teoc), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).
The compound of a (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 reoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the "R" or "S" configuration.
The invention relates in particular to: A compound of formula (I) wherein R1 is enyl, alkoxyphenyl, 1,2,5- oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl; A compound of formula (I) wherein R1 is halophenyl, haloalkylphenyl or alkylsulfonylphenyl; A compound of formula (I) wherein R1 is phenyl, trifluoromethylphenyl or methylsulfonylphenyl; A compound of formula (I) n R3 and R4 are independently selected from hydrogen, halogen and hydroxyl; A compound of formula (I) wherein one of R3 and R4 is hydrogen and the other one is hydroxyl, or wherein R3 and R4 are both halogen at the same time; and A nd of formula (I) wherein one of R3 and R4 is hydrogen and the other one is hydroxyl, or wherein R3 and R4 are both fluorine at the same time.
Also described is: A compound of formula (I) wherein R2 is cycloalkyl, isopropyl, alkylamino, alkoxy, haloalkyloxy or alkylsulfanyl; A compound of formula (I) wherein R2 is cyclobutyl, isopropyl, tert.-butylamino, pentyloxy, isopropyloxy, trifluoroethyloxy, trifluoropropyloxy, ethylsulfanyl or tert.- ulfanyl.
The invention further relates in particular to a compound of formula (I) selected from: 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5- d]pyrimidinamine; 3-[(2-chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- midinamine; N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(3-methyloxetan yl)triazolo[4,5-d]pyrimidinamine; N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(2,2- dimethylpropyl)triazolo[4,5-d]pyrimidinamine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(oxetan yl)triazolo[4,5-d]pyrimidinamine; 3-[(2-chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine; (3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol; N-tert-butyl(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinamine; N-[(3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; N-tert-butyl(3,3-difluoropyrrolidinyl)[[2- (trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- sulfonylphenyl)methyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazol hyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazol yl)methyl]triazolo[4,5-d]pyrimidinamine; N-[(3S)[5-(tert-butylamino)[(3-chloropyridinyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; (3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol; (3S)[5-(tert-butylamino)[(1-methyltetrazolyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]methylpyrrolidinol; (3R)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin- 7-yl]methylpyrrolidinol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2- trifluoroethoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1,1,1-trifluoropropan- 2-yloxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](2,2-difluoroethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)ethoxytriazolo[4,5- d]pyrimidine; -butoxy[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- midine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- fluoroethoxy)triazolo[4,5-d]pyrimidine; chlorophenyl)methyl](cyclopropylmethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl]cyclobutyloxy(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(oxetan yloxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(3-methyloxetan hoxy]triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2R)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](2,2-difluoropropoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan riazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)prop ynoxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1-methoxypropan yloxy)triazolo[4,5-d]pyrimidine; 1-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]oxymethylpropanol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propoxytriazolo[4,5- d]pyrimidine; (3S)[3-[(2-chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3S)[5-(2,2,2-trifluoroethoxy)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3S)[3-[(2-chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]pyrrolidinol; (3S)[3-[(2-methylsulfonylphenyl)methyl]propanyloxytriazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3S)[3-[(1-methyltetrazolyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinol; 7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]triazolo[4,5-d]pyrimidine; 7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2- sulfonylphenyl)methyl]triazolo[4,5-d]pyrimidine; 3-[[7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)triazolo[4,5-d]pyrimidin- 3-yl]methyl]methyl-1,2,5-oxadiazole; 7-(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 7-(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 2-[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan triazolo[4,5-d]pyrimidinyl]methyl]methyl-1,3,4-oxadiazole; -[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]methyl]methyl-1,2,4-oxadiazole; 7-(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]methyl]methyl-1,2,5-oxadiazole; 7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxy(3,3,3- trifluoropropyl)triazolo[4,5-d]pyrimidine; 3-[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; N-[(3S)[3-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[5-(2,2-dimethylpropoxy)[(4-methyl-1,2,5-oxadiazol yl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[(2-chlorophenyl)methyl][(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfanyltriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2- trifluoroethylsulfanyl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfanyltriazolo[4,5-d]pyrimidine; 5-tert-butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfonyltriazolo[4,5-d]pyrimidine; ylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfonyltriazolo[4,5-d]pyrimidine; (2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfanylethanol; 1-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfanylpropanol; -butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfanyl)triazolo[4,5-d]pyrimidine; -butylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfonyl)triazolo[4,5-d]pyrimidine; 1-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfonylpropanol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfonyl)triazolo[4,5-d]pyrimidine; and N-[(3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinyl]acetamide.
Also described in particular is a compound of formula (I) ed from: 3-[(2-chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine; -cyclopropyl(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan yltriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl]cyclopropyl(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; cyclopropyl(3,3-difluoropyrrolidinyl)triazolo[4,5-d]pyrimidin yl]methyl]methyl-1,2,5-oxadiazole; (3S)[3-[(2-chlorophenyl)methyl]propenyltriazolo[4,5-d]pyrimidin yl]pyrrolidinol; 3-[(2-chlorophenyl)methyl]-5,7-di(piperidinyl)triazolo[4,5-d]pyrimidine; tidinyl)[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)pyrrolidin yltriazolo[4,5-d]pyrimidine; 4-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]morpholine; (3S)[3-[(2-chlorophenyl)methyl]morpholinyltriazolo[4,5-d]pyrimidinyl]- 3-methylpyrrolidinol; (3S)methyl[5-morpholinyl[[2- (trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol; (3S)[3-[(3-chloropyridinyl)methyl]morpholinyltriazolo[4,5-d]pyrimidin- 7-yl]methylpyrrolidinol; (3S)methyl[3-[(3-methyl-1,2,4-oxadiazolyl)methyl]morpholin yltriazolo[4,5-d]pyrimidinyl]pyrrolidinol; (3R)[3-[(2-chlorophenyl)methyl]morpholinyltriazolo[4,5-d]pyrimidinyl]- 3-methylpyrrolidinol; (3R)methyl[5-morpholinyl[[2- (trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol; (3R)methyl[3-[(2-methylsulfonylphenyl)methyl]morpholinyltriazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3R)methyl[3-[(3-methyl-1,2,4-oxadiazolyl)methyl]morpholin yltriazolo[4,5-d]pyrimidinyl]pyrrolidinol.
The invention further relates in ular to a nd of formula (I) selected from: N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidinamine; chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropoxy)triazolo[4,5-d]pyrimidine; (3S)[3-[(2-chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinol; -difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfanyltriazolo[4,5-d]pyrimidine; and -tert-butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine.
Also described is a compound of formula (I) selected from: 3-[(2-chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- midine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan yltriazolo[4,5-d]pyrimidine.
In the definition of R2, haloalkyloxy is in particular trifluoroethyloxy, trifluoropropyloxy, difluoroethyloxy, fluoroethyloxy or difluoropropyloxy, and in particular trifluoropropyloxy, difluoroethyloxy, fluoroethyloxy or difluoropropyloxy.
Abbreviations: In the present description the ing abbreviations are used: MS = mass spectrometry; EI = electron ionization; ESI = electrospray; NMR = nuclear magnetic resonance; DBU = 1,8-Diazabicyclo[5.4.0]undecen; DCM = dichloromethane; DEAD = diethyl azodicarboxylate; DIAD = diisopropyl azodicarboxylate ; DIPEA = diisopropylethyl amine; DMA = ylacetamide; DMF = dimethylformamide; DMSO = yl-sulfoxide; dppf = 1,1'- bis(diphenylphosphino)ferrocene; HATU = 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)- 1,1,3,3-tetramethylisouronium hexafluorophosphate(V); HBTU = O-benzotriazole- N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate; HPLC = LC = high performance liquid chromatography; m-CPBA = meta-chloroperoxybenzoic acid; NMP = N- methylpyrrolidine; PMB = para-methoxy benzyl; TBTU = O-(benzotriazolyl)- N,N,N’,N’-tetramethyl-uronium-tetrafluoroborate; TBME = methyl tert-butylether, TFA = trifluoroacetic acid ; THF = tetrahydrofuran; tlc = thin layer chromatography; CAN = CAS Registry .
The ation of compounds of a (I) of the present invention may be carried out in tial or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the following schemes. The skills required for carrying out the reactions and purifications of the ing 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 examples or by analogous s. 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 presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not al to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to . The time ed for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the described intermediates and nds. The reaction sequence is not d to the one yed in the schemes, however, depending on the ng materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially ble or can be prepared by methods analogous to the methods given below, by methods described in references cited in the description or in the examples, or by methods known in the art.
Unless otherwise indicated, R1 to R4 and n have in the following schemes the same g as described above.
Scheme 1 R2 = cycloalkyl, isopropyl or alkenyl; A = CH2. a) b) c) II III X=Br or Cl IV d) e) f) VI VII I a) Halides II are either commercially available or can be synthesized according to methods known in the art. These halides II are conveniently reacted with sodium azide in a le solvent such as acetonitrile, ethanol or DMF to afford azide tives III. Alternative preferred ions involve the use of ts like DMA, NMP or DMSO, even more preferred are NMP and DMSO. In polar aprotic solvents like NMP and DMSO, the alkylations can usually be conducted at lower temperature than for example in itrile, often at room temperature to 40°C (this is the case for example for BnCl, 1-chloro (chloromethyl)benzene or PMB-Cl ; this depends of course on the reactivity of the Halides II) and hence provide a better process safety window (caution organic azides are of course know to be potentially dangerous and process safety has always to be carefully assessed).
The addition of water can be beneficial as it increases the solubility of sodium azide and provided more robust kinetic profiles as it helps to dissolves hard clumps of NaN3. It can also lead to a better filterability of the final azide reaction mixture. Filtration of the reaction mixture might be required for e when the following cycloaddition is performed in a continuous mode in small channels reactors. The azide is not isolated and its solution is best introduced in the next step. This also avoids its isolation which can also lead to safety issues. b) Triazole derivatives IV can be prepared by a [3+2] ddition of azide derivatives III with oacetamide in the presence of an appropriate base such as sodium methoxide or sodium ethoxide in a suitable solvent such as methanol, ethanol or DMF.
Alternative preferred conditions involve reacting the azide with 2-cyanoacetamide in solvents like NMP or DMSO, in the presence of sodium ide. The batch process is usually performed at room temperature to 50°C, preferably between room temperature and 40°C (caution, process safety has always to be carefully assessed). The ddition process is also amendable to continuous mode (for a relevant literature example, see Org.
Process Res. Dev., 2009, 13 (6), pp 1401–1406) and in this case the on temperature can be increased above 50°C, for example (but not limited to) between 50°C and 90°C, ably between 60°C and 70°C. c) Triazole IV can conveniently be reacted with an riate acid chloride (commercially available or known in the art) in the presence of a base (pyridine, DIPEA, NEt3 and the like) in the presence or absence of a solvent (DCM, DMF and the like) to access triazole deivatives V. d) Cyclisation of triazole V is can conveniently be done under basic conditions. It proved advantageous to perform this reaction under aqueous conditions in the ce of a base.
Suitable bases are NaHCO3 or KHCO3 and the like. This gave access to lopyrimidine derivatives VI. 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, lutidine, or pyridine. Alternative preferred conditions involve the use of the Vislmeier t as chlorinating agent. It can also be ted in situ by reacting oxalyl chloride with DMF. The chlorination can be performed for example in in acetonitrile, DCM or AcOEt, preferably in DCM. These conditions allow for mild reaction temperature and for example, avoid the quench of excess POCl3 upon work-up. The crude product can be introduced in the next step. f) VII are conveniently reacted with various nucleophiles particularly amines in the presence of an appropriate base such as triethylamine, DIPEA or DBU in a suitable solvent such as itrile, methanol, toluene or DMF to yield triazolo-pyrimidine derivatives I.
These tives can be the final compounds, however preferably when R1-A is a substituted benzyl group such as p-methoxy benzyl, these groups can be cleaved with TFA, CAN, enation and the like to access derivatives wherein R1-A is replaced with H. The benzyl group can be cleaved under standard hydrogenolysis conditions also for example in the ce of acids.
The triazole derivatives wherein R1-A has been replaced with H is conveniently reacted either with a halide (or sulfonate) in the presence of suitable base such as DIPEA, DBU, K2CO3, or Cs2CO3 in a solvent such as DMF, dioxane or toluene, or alternatively with an alcohol under Mitsunobu reaction conditions using suitable diazodicarboxylate (DEAD, DIAD and the like) and ine such as PBu3 or PPh3 in an appropriate solvent such as THF, DCM, toluene to afford final triazolopyrimidine tives I.
Scheme 2 R2 is as defined above but not cycloalkyl nor isopropyl, nor alkenyl; A = CH2. a) b) IV VIII IX c) d) X I a) Triazole IV can conveniently be reacted with diethyl carbonate (or any other le C1-fargment, commercially available or known in the art) in the presence of a base (NaOEt and the like) in the presence or absence of a solvent (ethanol, dioxane and the like) to access triazolopyrimidine derivative VIII. b) Chlorides IX can be obtained by reaction of VIII with a chlorination reagent such as POCl3, SOCl2 or 2 in the presence of an appropriate base such as N,N-diethyl aniline, lutidine, or pyridine. Alternative preferred conditions involve the use of the Vislmeier reagent as chlorinating agent. It can also be generated in situ by ng oxalyl chloride with DMF. The chlorination can be performed for example in in acetonitrile, DCM or AcOEt, ably in DCM. The crude t can be uced in the next step. c) Nucleophilic substitution of chloride IX with an appropriate amine can be performed in the presence of absence of a base (DIPEA, NEt3 and the like) and a solvent (DCM, dioxane, DMF and the like to access triazolopyrimidine X. d) Nucleophilic substitution of triazolopyrimidine X with an appropriate amine, sulfide or alcohol can be performed in the presence or absence of a base (DBU, DIPEA, NaH, Cs2CO3 and the like) and a solvent (DCM, THF, dioxane, DMF and the like to access triazolopyrimidine I.
These derivatives can be the final compounds, however preferably when R1-A is a substituted benzyl group such as p-methoxy , these groups can be d with TFA, CAN, hydrogenation and the like to access derivatives wherein R1-A has been replaced with H. The benzyl group can be cleaved under standard hydrogenolysis conditions also for example in the presence of acids.
The triazole derivatives wherein R1-A has been replaced with H is conveniently d either with a halide (or sulfonate) in the presence of le base such as DIPEA, DBU, K2CO3 or Cs2CO3 in a solvent such as DMF, dioxane or toluene, or alternatively with an alcohol under Mitsunobu reaction conditions using suitable diazodicarboxylate (DEAD, DIAD and the like) and phosphine such as PBu3 or PPh3 in an appropriate solvent such as THF, DCM, toluene to afford final triazolopyrimidine derivatives I.
The compounds of formula I n R2 is a sulfur containing group as defined above (e.g. a sulfanyl) can be be conveniently oxidized with m-CPBA to afford a sulfone of formula I.
The invention also relates to a process for the preparation of a compound of a (I) comprising one of the following steps: (a) the reaction of a compound of formula (A1) N N R (A1) in the presence of a compound of formula (A2) (CH2)n R R (A2) n R2 is isopropyl, cycloalkyl or alkenyl and R1, R3, R4 and n are as defined above; (b) the reaction of a compound of formula (B) H 2 N N R (CH2)n R R in the presence of R1CH2X wherein X is a halogen, a yl or a sulfonate group, wherein R2 is isopropyl, cycloalkyl or alkenyl and wherein R3 to R4 and n are as defined above; or (c) the on of a compound of formula (C) N N Cl (CH2)n R R in the presence of R2-H wherein R2 is piperidinyl, alkylamino, azetidinyl, pyrrolidinyl, cycloalkylamino, alkyloxetanylamino, linyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, xetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl and wherein R1, R3, R4 and n are as defined above.
Step (a) is preferably carried out in the presence of an appropriate base such as triethylamine, DIPEA or DBU.
Step (a) is preferably carried out in a suitable solvent such as acetonitrile, methanol, toluene or DMF.
Step (b) is preferably carried out in the presence of a suitable base such as DIPEA, DBU, K2CO3 or Cs2CO3.
Step (b) is preferably d out in a solvent such as DMF, dioxane or toluene.
When X is a hydroxyl group, step (b) can be d out under obu reaction conditions using suitable diazodicarboxylate (e.g. DEAD, DIAD) and phosphine such as PBu3 or PPh3. The reaction can be done in an appropriate solvent such as THF, DCM or toluene.
Step (c) can be carried out in the presence or absence of a base (e.g. DBU, DIPEA, NaH or Cs2CO3).
Step (c) can be carried out in the presence of a solvent (DCM, THF, dioxane, DMF).
Another embodiment of the invention provides a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or excipient, as well as a method of using the compounds of the ion to prepare such composition and medicament. In one example, the nd of formula (I) may be formulated by mixing at ambient temperature at the riate pH, and at the desired degree of , with physiologically acceptable carriers, i.e., carriers that are ic 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 acetate buffer, at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
Compositions are formulated, dosed, and administered in a fashion tent with good medical ce. Factors for consideration in this context include the particular disorder being treated, the ular mammal being d, the clinical condition of the individual t, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
The compounds of the invention may be administered by any suitable means, including oral, l (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, ulmonary, intradermal, intrathecal and al and intranasal, and, if desired for local ent, intralesional administration. eral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The nds of the t invention may be stered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components tional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking , and further active agents.
A typical ation is prepared by mixing a compound of the present invention and a r 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 ry Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring , diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition f) or aid in the cturing of the pharmaceutical product (i.e., medicament).
The invention also relates in particular 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, diabetic pathy, 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 infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or , regulation of bone mass, neurodegeneration, , transient ischemic attack or uveitis; A compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes us, mation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung is, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart e, myocardial ischemia, myocardial infarction, ic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, ent ischemic attack or uveitis; and Also described is: The use of a compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related r degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft pathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver sis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; A method for the treatment or prophylaxis of pain, atherosclerosis, lated macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion , acute liver e, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft pathy, diabetic nephropathy, glomerulonephropathy, myopathy, heart failure, dial ischemia, myocardial tion, 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, which method ses administering an effective amount of a compound of formula (I) to a patient in need thereof.
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 ular ischemia or reperfusion injury.
Also described is a compound of formula (I), when manufactured according to a process according to the invention.
The term "comprising" as used in this specification and claims means sting at least in part of". When interpreting statements in this specification and claims which include the term "comprising", other features besides the es prefaced by this term in each statement can also be present. Related terms such as "comprise" and "comprises" are to be interpreted in similar manner.
In the description in this ication reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into ce the invention as defined in the appended claims.
In this specification where reference has been made to patent specifications, other al documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such nts, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.
The invention will now be illustrated by the following examples which have no limiting character.
Examples Example 1 3-[(2-Chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine a) o(2-chlorobenzyl)-1H-1,2,3-triazolecarboxamide A mixture of 1-(bromomethyl)chlorobenzene (5 g, 24.3 mmol) and sodium azide (2.37 g, 36.5 mmol) in acetonitrile (48.7 mL) was refluxed for 3 h under N2 atmosphere. Then, the e 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 1-(azidomethyl)chlorobenzene. The residue was used for the next reaction without further purification. A mixture of the above crude residue, 2-cyanoacetamide (1.82 g, 21.7 mmol) and sodium ethanolate (1.47 g, 21.7 mmol) in ethanol (43.3 mL) was refluxed for 3 h under N2 atmosphere. The mixture was trated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to the title compound as pale-orange solid (5.10 g, 94% for 2 steps). MS(m/e): 252.1 (MH+). b) 1-[(2-Chlorophenyl)methyl](cyclobutanecarbonylamino)triazolecarboxamide A mixture of 5-Amino(2-chlorobenzyl)-1H-1,2,3-triazolecarboxamide (1.1 g, crude) and utanecarbonyl chloride (777 mg, 748 µl, 6.56 mmol) in pyridine (30 mL) was heated to 80 °C for 5 h. After cooling to room temperature HCl (50 mL, 1M) was carefully added and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried with MgSO4, filtered and ated to dryness. The residue was used in the consecutive step without further purification. MS(m/e): 333.7 (MH+). c) 3-[(2-Chlorophenyl)methyl]cyclobutyl-6H-triazolo[4,5-d]pyrimidinone A mixture of 1-[(2-chlorophenyl)methyl](cyclobutanecarbonylamino)triazole carboxamide (1.37 g, crude) and KHCO3 (2.96 g, 29.6 mmol) in water (60 mL) was heated to reflux overnight. After cooling to room temperature NaHCO3 aq. (50 mL, 1N) was added and the mixture was extracted with TBME (3 x 125 mL). The combined organic layers were dried with MgSO4 and ated to dryness. The residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product ning fractions 182 mg (14 %) of the title compound was isolated as white solid. MS(m/e): 357.2 (MH+). d) 3-[(2-Chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine A e of 3-[(2-chlorophenyl)methyl]cyclobutyl-6H-triazolo[4,5-d]pyrimidinone (185 mg, 0.586 mmol), POCl3 (2.7 g, 17.6 mmol) and N,N-diethylaniline (0.21 g, 1.41 mmol) at 0 °C was heated to 120 °C for 4 h. The mixture was evaporated, the residue poured into ice/water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried with MgSO4 and evaporated. The residue was taken up in acetonitrile (10 mL) and fluoropyrrolidine hydrochloride (295 mg, 2.05 mmol) and DIPEA (379 mg, 2.93 mmol) was added and the mixture was stirred for 2 days at room temperature. After evaporation of the mixture the residue was subjected to purification by preparative HPLC on reversed phase g with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 50 mg (21 %) of the title compound was isolated as light yellow solid. MS(m/e): 405.2 (MH+).
Example 2 -Cyclopropyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo [4,5-d]pyrimidine a) 5-Amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide N NH2 O A mixture of 1-(chloromethyl)methoxybenzene (20 g, 128 mmol) and sodium azide (12.5 g, 192 mmol) in acetonitrile (250 mL) was refluxed for 5 h under N2 here.
The mixture was filtered and concentrated in vacuo. The residue was diluted with DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)methoxybenzene. The e was used for the next reaction without further purification.
A mixture of the above crude residue, 2-cyanoacetamide (10.8 g, 128 mmol) and sodium ethanolate (8.71 g, 128 mmol) in ethanol (250 mL) was refluxed for 21 h under N2 atmosphere. The mixture was trated 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) 5-(Cyclopropanecarbonylamino)[(4-methoxyphenyl)methyl]triazolecarboxamide A mixture of 5-amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide (1 g, crude) and ropanecarbonyl chloride (1.27 g, 12.1 mmol) in pyridine (8 mL) was heated to 80 °C for 3 h. The mixture was evaporated and methanol (8 mL) and NaOH aq. (1.5 mL) was added and heated to 80 °C for 1 h. The mixture was cooled and poured into HCl aq. (50 mL, 1M) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried with MgSO4 an evaporated to yield the crude title compound which was used in the consecutive step without further purification. MS(m/e): 316.5 (MH+). c) 5-Cyclopropyl[(4-methoxyphenyl)methyl]-6H-triazolo[4,5-d]pyrimidinone A mixture of 5-(cyclopropanecarbonylamino)[(4-methoxyphenyl)methyl]triazole carboxamide (1g, crude) and KHCO3 aq. (2.36 g, 23.6 mmol) in 46 mL water was heated to reflux ght. After cooling to room ature the mixture was filtered and the light yellow solid dried. The filtrate was extracted with DCM (3 x 125 mL) and the combined c layers were dried with MgSO4 and evaporated. This e was combined with the light yellow solid to yield the title compound as light yellow solid.
MS(m/e): 298.5 (MH+). d) 5-Cyclopropyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo [4,5-d]pyrimidine A mixture of 5-cyclopropyl[(4-methoxyphenyl)methyl]-6H-triazolo[4,5-d]pyrimidin one (0.32 g, crude), POCl3 (4.95 g, 32.3 mmol) and N,N-diethylaniline (0.385 g, 2.58 mmol) was heated to 120 °C for 4 h. The mixture was evaporated, the residue poured into ice/water (100 mL) and extracted with DCM (2 x 200 mL). The combined c layers were dried with MgSO4 and evaporated. The residue was taken up in acetonitrile (15 mL) and 3,3-difluoropyrrolidine hydrochloride (847 mg, 5.9 mmol) and DIPEA (693 mg, 5.36 mmol) was added and the mixture was stirred for 2 days at room temperature. After ation of the mixture the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 160 mg (39 %) of the title compound was isolated as light yellow solid. MS(m/e): 387.2 (MH+).
Example 3 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)isopropyl-triazolo[4,5- d]pyrimidine a) 1-(2-Chloro-benzyl)isobutyrylamino-1H-[1,2,3]triazolecarboxylic acid amide A mixture of 5-amino(2-chlorobenzyl)-1H-1,2,3-triazolecarboxamide (1 g, crude) and isobutyryl chloride (1.27 g, 12.1 mmol) in pyridine (8 mL) was heated to 80 °C for 3 h. The mixture was evaporated and methanol (8 mL) and NaOH aq. (1.5 mL) was added and heated to 80 °C for 1 h. The mixture was cooled and poured into HCl aq. (50 mL, 1M) and extracted with ethyl acetate (3 x 100 mL). The combined c layers were dried with MgSO4 an evaporated to yield the crude title compound as light yellow solid which was used in the consecutive step without further purification. MS(m/e): 322.5 (MH+). b) 3-[(2-Chlorophenyl)methyl]isopropyl-6H-triazolo[4,5-d]pyrimidinone A mixture of 1-(2-chloro-(benzyl)isobutyrylamino-1H-[1,2,3]triazolecarboxylic acid amide (1.37 g, crude) and KHCO3 (4.37 g, 43.6 mmol) in water (50 mL) was heated to 120 °C ght. After cooling to room temperature with mixture was ed and the residue dried to yield the crude title compound as white powder. MS(m/e): 304.5 (MH+). c) 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)isopropyl-triazolo[4,5- d]pyrimidine A e of 3-[(2-chlorophenyl)methyl]isopropyl-6H-triazolo[4,5-d]pyrimidinone (0.74 g, crude), POCl3 (8.97 g, 58.5 mmol) and ethylaniline (0.698 g, 4.68 mmol) was heated to 120 °C for 2 h. The mixture was evaporated, the residue poured into ice/water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried with MgSO4 and evaporated. The residue was taken up in acetonitrile (10 mL) and 3,3-difluoropyrrolidine hydrochloride (1.53 g, 10.6 mmol) and DIPEA (1.25 g, 9.68 mmol) was added and the mixture was stirred for 2 days at room temperature. After evaporation of the mixture the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing ons 154 mg (20 %) of the title compound was isolated as yellow oil. MS(m/e): 393.2 (MH+).
Example 4 3-[(2-Chlorophenyl)methyl]cyclopropyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine a) 5-Cyclopropyl(3,3-difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidine A mixture of opropyl(3,3-difluoropyrrolidinyl)(4-methoxybenzyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine (example 2) (0.16 g, 0.41 mmol) and TFA (2 mL) was heated to 80 °C for 2h. The mixture was evaporated and the residue was poured into NaHCO3 aq. (20 mL, 1M) and extracted with ethyl acetate (3 x 20 mL). The ed organic layers were dried with MgSO4, filtered and evaporated to yield the crude title compound as orange solid which was used in the consecutive step without further purification. MS(m/e): 267.1 (MH+). b) 3-[(2-Chlorophenyl)methyl]cyclopropyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine A mixture of 5-cyclopropyl(3,3-difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidine (55 mg, crude), 1-(bromomethyl)chlorobenzene (85 mg, 0.413 mmol) and DBU (94 mg, 0.62 mmol) in DMF (3 mL) was heated to 80 °C for 12 h. After cooling to room temperature the e was subjected to cation by preparative HPLC on reversed phase eluting with a nt formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 8.1 mg (10 %, 2 steps) of the title compound was isolated as dark green solid. MS(m/e): 391.2 (MH+).
Example 5 3-[[5-Cyclopropyl(3,3-difluoropyrrolidinyl)triazolo[4,5-d]pyrimidin yl]methyl]methyl-1,2,5-oxadiazole In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] cyclopropyl(3,3-difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 4) the title compound was prepared from 5-cyclopropyl(3,3-difluoropyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)methyl-1,2,5-oxadiazole as light brown solid. MS(m/e): 363.2 (MH+).
Example 6 -[3-[(2-Chlorophenyl)methyl]propenyltriazolo[4,5-d]pyrimidin yl]pyrrolidinol a) 3-[(2-Chlorophenyl)methyl](1-hydroxymethyl-ethyl)-6H-triazolo[4,5- d]pyrimidinone A mixture of 5-Amino(2-chlorobenzyl)-1H-1,2,3-triazolecarboxamide (3 g, 11.9 mmol) and 1-chloromethyloxopropanyl acetate (5.89 g, 35.8 mmol) in pyridine (20 mL) was heated to 80 °C and stirred for 3 h. After cooling to room temperature the mixture was ated and poured into HCl aq. (50 mL, 1M) and extracted with ethyl e (3 x 100 mL). The combined organic layers were dried with MgSO4, filtered and evaporated. KHCO3 (9.79 g, 97.8 mmol) and water (150 mL) was added and the mixture was heated to 120 °C for 24 h. After cooling to room temperature the mixture was extracted with DCM (2 x 200 mL). The combined organic layers were dried with MgSO4, filtered and evaporated to yield 1.4 g (4.47 mmol, 37 %) of the title compound as yellow oil. MS(m/e): 361.2 (MH+). b) (3S)[3-[(2-Chlorophenyl)methyl]propenyltriazolo[4,5-d]pyrimidin yl]pyrrolidinol A mixture of 3-[(2-chlorophenyl)methyl](1-hydroxymethyl-ethyl)-6H-triazolo[4,5- d]pyrimidinone (1.18 g, 3.7 mmol) and NaH (193 mg, suspension in oil, 4.82 mmol) and (bromomethyl)benzene (951 mg, 5.56 mmol) in DMF (20 mL) at 0 °C was stirred to room temperature and continued for 4 h. The mixture was poured into HCl aq. (20 mL, 1M) and extracted with DCM (3 x 100 mL). The combined organic layers were dried with MgSO4, filtered and evaporated. POCl3 (28.2 g, 184 mmol) and N,N-diethylamine (1.32 g, 8.83 mmol) was added at 0 °C and the mixture was heated to 120 °C for 4 h. The mixture was ated and poured into ice / water (100 mL) and extracted with DCM (2 x 200 mL). The combined organic layers were dried with MgSO4, filtered and ated to yield 2.5 g of the crude chlorinated ediate. 205 mg of the crude intermediate were dissolved in acetonitrile (5 mL) and DIPEA (148 mg, 1.15 mmol) and (S)-pyrrolidinol (37.5 mg, 0.43 mmol) were added and the mixture was stirred at room temperature for 6 h.
The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product ning fractions 20 mg (0.054 mmol) of the title compound was isolated as light green solid. MS(m/e): 371.2 (MH+).
Example 7 3-[(2-Chlorophenyl)methyl]-5,7-di(piperidinyl)triazolo[4,5-d]pyrimidine a) Chlorophenyl)methyl]-4H-triazolo[4,5-d]pyrimidine-5,7-dione A mixture of 5-amino(2-chlorobenzyl)-1H-1,2,3-triazolecarboxamide (8 g, 25.4 mmol), sodium ethoxide (4.5 g, 66.1 mmol) and diethyl carbonate (4.51 g, 38.1 mmol) in ethanol (60 mL) was heated to reflux overnight. After cooling to room temperature the mixture was filtered and the precipitate was filtered, washed with ethanol and dried to yield 10 g (25.2 mmol, 99 %) of the title compound as white solid. MS(m/e): 278.0 (MH+). b) 3-[(2-chlorophenyl)methyl]-5,7-di(piperidinyl)triazolo[4,5-d]pyrimidine A mixture of 3-[(2-chlorophenyl)methyl]-4H-triazolo[4,5-d]pyrimidine-5,7-dione (146 mg, 0.368 mmol), POCl3 (1.98 g, 13 mmol) and N.N-diethylaniline (110 mg, 0.736 mmol) was heated to 120 °C for 3 h. After cooling to room temperature the e was poured into ice / water (25 mL) and ted with ethyl acetate (2 x 25 mL). The combined organic layers were evaporated to yield crude 5,7-dichloro[(2- chlorophenyl)methyl]triazolo[4,5-d]pyrimidine which was used in the consecutive step without r purification.
A mixture of crude 5,7-dichloro[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidine (86 mg) and piperidine (186 mg, 2.19 mmol) in chloroform (1 mL) was d at room temperature for 1 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 27 mg (0.065 mmol) of the title nd was isolated as white solid. MS(m/e): 412.2 (MH+).
Example 8 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5- midinamine a) 5-Chloro[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine A mixture of 5,7-dichloro[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidine (1.7 g, 5.4 mmol), DIPEA (3.49 g, 27 mmol) and 3,3-difluoropyrrolidine hydrochloride (1.09 g, 7.57 mmol) in DCM (0.4 mL) was stirred at 0 °C for 3 h. Isolute was added and the absorbed mixture was subjected to purification by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing ons 421 mg (1.09 mmol, 20 %) of the title compound as yellow oil. MS(m/e): 385.1 (MH+). b) 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5- d]pyrimidinamine A mixture of 5-chloro[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine (27 mg, 0.07 mmol), DIPEA (90 mg, 0.7 mmol) and ethylamine (16 mg, 0.35 mmol) in DMF (1 mL) was stirred at 110 °C overnight and evaporated to dryness. The residue was subjected to purification by ative HPLC on reversed phase g with a gradient formed from acetonitrile, water and formic acid.
After evaporation of the product containing fractions 13.8 mg (50 %) of the title compound was isolated. MS(m/e): 394.2 (MH+).
Example 9 -(Azetidinyl)[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo [4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and azetidine. MS(m/e): 406.2 (MH+).
Example 10 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)pyrrolidin yltriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and pyrrolidine. MS(m/e): 420.3 (MH+).
Example 11 3-[(2-Chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and cyclobutylamine. MS(m/e): 420.3 (MH+).
Example 12 -Butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine In analogy to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2-methylpropanamine. MS(m/e): 422.3 (MH+).
Example 13 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(3-methyloxetan yl)triazolo[4,5-d]pyrimidinamine In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 3-methyloxetanamine. MS(m/e): 436.3 (MH+).
Example 14 4-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]morpholine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title nd was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and morpholine. ): 436.3 (MH+).
Example 15 N-tert-Butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine In analogy to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and tert-butyl-methyl-amine. MS(m/e): 436.3 (MH+). e 16 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(2,2-dimethylpropyl) triazolo[4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2,2-dimethylpropanamine.
MS(m/e): 436.3 (MH+).
Example 17 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(oxetanyl)triazolo [4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and oxetanamine hydrochloride.
MS(m/e): 422.2 (MH+).
Example 18 3-[(2-Chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and N-methylcyclobutanamine hydrochloride. MS(m/e): 434.3 (MH+).
Example 19 (3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol a) 3-[(4-methoxyphenyl)methyl]-4H-triazolo[4,5-d]pyrimidine-5,7-dione A mixture of 5-amino(4-methoxybenzyl)-1H-1,2,3-triazolecarboxamide (7.6 g, 30.7 mmol), sodium ethoxide (3.76 g, 55.3 mmol) and diethyl carbonate (4.72 g, 39.9 mmol) in ethanol (97.1 mL) was heated to reflux overnight. After cooling to room temperature the e was filtered and the precipitate was washed with ethanol to yield after drying 8.54 g (51 %) of the title nd as white solid. MS(m/e): 272.0 (MH+). b) (3S)[5-Chloro[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol A mixture of 3-[(4-methoxyphenyl)methyl]-4H-triazolo[4,5-d]pyrimidine-5,7-dione (5.2 g, 9.52 mmol), POCl3 (73 g, 476 mmol) and N.N-diethylamine (2.56 g, 1.7 mmol) was heated to 120 °C for 4 h. The mixture was evaporated and the residue poured into ice / water (100 mL) and extracted with DCM (2 x 600 mL). The combined c layers were dried with MgSO4, filtered and evaporated to yield crude 5,7-dichloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine which was used in the consecutive step without further purification.
A mixture of the crude 5,7-dichloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidine (2.95 g), DIPEA (9.83 g, 76.1 mmol) and (S)-pyrrolidinol (1.82 g, 20.9 mmol) in DCM (150 mL) was d at room temperature for 30 min. The mixture was poured into water (150 mL) and extracted with DCM (2 x 125 mL). The combined organic layers were dried with MgSO4, ed and evaporated to yield the crude title compound as dark brown foam which was used in the consecutive step without further cation.
MS(m/e): 361.3 (MH+). c) (3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from (3S)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol and 2-methylpropanamine. MS(m/e): 398.5 (MH+).
Example 20 N-tert-Butyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo [4,5-d]pyrimidinamine a) 5-Chloro(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidine In analogy to the procedure described for the synthesis of (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) the title nds was ed from the crude 5,7-dichloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine and 3,3-difluoropyrrolidine hydrochloride as light brown solid. MS(m/e): 381.3 (MH+). b) N-tert-Butyl(3,3-difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinamine In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from 5-chloro(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine and tert-butylamine as light yellow foam. MS(m/e): 418.5 (MH+).
Example 21 N-[(3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide a) N-[(3S)[5-Chloro[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinyl]acetamide In analogy to the procedure bed for the sis of (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) the title nds was prepared from the crude 5,7-dichloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine and (S)-N-(pyrrolidinyl)acetamide as light brown solid. MS(m/e): 402.4 (MH+). b) N-[(3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from N-[(3S)[5-chloro[(4-methoxyphenyl)methyl]triazolo [4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and tert-butylamine as light yellow foam.
MS(m/e): 439.5 (MH+).
Example 22 N-tert-Butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] triazolo[4,5-d]pyrimidinamine a) -Butyl(3,3-difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine N-tert-butyl(3,3-Difluoropyrrolidinyl)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinamine (example 20) was hydrogenated over Pd/C in methanol to yield the title compound which was used in the utive step without further purification. b) N-tert-Butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] triazolo[4,5-d]pyrimidinamine A mixture of N-tert-butyl(3,3-difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidin amine (25 mg, 0.08 mmol), NEt3 (14.6 mg, 0.144 mmol) and 1-(bromomethyl) (trifluoromethyl)benzene (26.8 mg, 0.112 mmol) in 2 mL DMF was stirred at room temperature for 5 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product ning fractions 5.2 mg (14 %) of the title compound was isolated. MS(m/e): 456.4 (MH+).
Example 23 N-tert-Butyl(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl] triazolo[4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-tert-butyl(3,3- ropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and 1-(bromomethyl) (methylsulfonyl)benzene. MS(m/e): 466.4 (MH+).
Example 24 N-tert-Butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)triazolo [4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-tert-butyl(3,3- ropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and 3-chloro (chloromethyl)pyridine. MS(m/e): 423.3 (MH+).
Example 25 -Butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]triazolo [4,5-d]pyrimidinamine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-tert-butyl(3,3- difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and oromethyl) methyl-1H-tetrazole. MS(m/e): 394.4 (MH+).
Example 26 N-tert-Butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazolyl)methyl] triazolo[4,5-d]pyrimidinamine In y to the procedure described for the sis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-tert-butyl(3,3- difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and 3-(bromomethyl) methyl-1,2,5-oxadiazole. MS(m/e): 394.4 (MH+).
Example 27 N-[(3S)[5-(tert-Butylamino)[(3-chloropyridinyl)methyl]triazolo[4,5-d] pyrimidinyl]pyrrolidinyl]acetamide a) N-[(3S)[5-(tert-Butylamino)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidin yl]acetamide N-[(3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinyl]acetamide (example 21) was hydrogenated over Pd/C in methanol to yield the title compound which was used in the consecutive step without further purification. b) N-[(3S)[5-(tert-Butylamino)[(3-chloropyridinyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- ropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from )[5-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 3-chloro (chloromethyl)pyridine. MS(m/e): 444.4 (MH+). e 28 (3S)[5-(tert-Butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol a) (3S)[5-(tert-Butylamino)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol (3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol (example 19) was hydrogenated over Pd/C in methanol to yield the title compound which was used in the consecutive step without further purification. b) (3S)[5-(tert-Butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- ropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from (3S)[5-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 1-(bromomethyl)chlorobenzene.
MS(m/e): 402.3 (MH+).
Example 29 (3S)[5-(tert-Butylamino)[(1-methyltetrazolyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol In analogy to the procedure bed for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3S)[5-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 5-(chloromethyl)methyl-1H- tetrazole. MS(m/e): 374.3 (MH+).
Example 30 -[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]methylpyrrolidinol a) (3S)[5-Chloro[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]methylpyrrolidinol In analogy to the procedure described for the synthesis of (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol le 19, step b) the title compounds was prepared from the crude 5,7-dichloro[(4-methoxyphenyl) methyl]triazolo[4,5-d]pyrimidine and ylpyrrolidinol. The two enantiomers were separated by preparative HPLC on chiral phase. MS(m/e): 375.4 (MH+). b) (3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]methylpyrrolidinol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from (3S)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and tert-butylamine. MS(m/e): 412.3 (MH+).
Example 31 (3R)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin methylpyrrolidinol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from (3R)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol (isolated as described in example 30) and tertbutylamine.
MS(m/e): 412.3 (MH+).
Example 32 -[3-[(2-Chlorophenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] -pyrrolidinol a) (3S)[3-[(4-Methoxyphenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from (3S)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and morpholine. MS(m/e): 426.4 (MH+). b) (3S)Methyl(5-morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol (3S)[3-[(4-methoxyphenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol (0.45 g, 1 mmol) in TFA (3.87 mL) was heated to 80 °C for 4h and evaporated. The crude product was used in the consecutive step without further purification. MS(m/e): 306.2 (MH+). c) (3S)[3-[(2-Chlorophenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from (3S)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) chlorobenzene. MS(m/e): 430.3 (MH+).
Example 33 (3S)Methyl[5-morpholinyl[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5- midinyl]pyrrolidinol In analogy to the procedure bed for the synthesis of N-tert-butyl(3,3- ropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3S)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) (trifluoromethyl)benzene. MS(m/e): 464.4 (MH+).
Example 34 In y to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3S)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 3-chloro (chloromethyl)pyridine. ): 431.3 (MH+). e 35 (3S)Methyl[3-[(3-methyl-1,2,4-oxadiazolyl)methyl]morpholin yltriazolo[4,5-d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3S)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 5-(chloromethyl) methyl-1,2,4-oxadiazole. MS(m/e): 402.3 (MH+).
Example 36 (3R)[3-[(2-Chlorophenyl)methyl]morpholinyltriazolo[4,5-d]pyrimidinyl]- 3-methylpyrrolidinol a) (3R)[3-[(4-Methoxyphenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol In analogy to the procedure described for the synthesis of chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was prepared from (3R)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol and morpholine. MS(m/e): 426.4 (MH+). b) (3R)Methyl(5-morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol (3R)[3-[(4-Methoxyphenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol (0.45 g, 1 mmol) in TFA (3.87 mL) was heated to 80 °C for 4h and evaporated. The crude product was used in the consecutive step without r purification. MS(m/e): 306.2 (MH+). c) (3R)[3-[(2-Chlorophenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] -pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and momethyl) chlorobenzene. MS(m/e): 430.3 (MH+).
Example 37 (3R)Methyl[5-morpholinyl[[2- (trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) (trifluoromethyl)benzene. MS(m/e): 464.3 (MH+).
Example 38 (3R)Methyl[3-[(2-methylsulfonylphenyl)methyl]morpholinyltriazolo[4,5- d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of -butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine le 22) the title compound was prepared from (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) (methylsulfonyl)benzene. MS(m/e): 474.3 (MH+).
Example 39 (3R)Methyl[3-[(3-methyl-1,2,4-oxadiazolyl)methyl]morpholin yltriazolo[4,5-d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine le 22) the title compound was prepared from (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 5-(chloromethyl) methyl-1,2,4-oxadiazole. MS(m/e): 402.3 (MH+).
Example 40 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy) triazolo[4,5-d]pyrimidine A e of 5-chloro[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine (example 8, step a) (38.5 mg, 0.1 mmol), 2,2,2-Trifluoro- ethanol (99 mg, 1 mmol) and NaH (suspension in oil, 20 mg, 5 mmol) in DMF (1 mL) was stirred at 110 °C for 6 h. After g to room temperature formic acid was added and the mixture was subjected to purification by preparative HPLC on ed phase eluting with a gradient formed from acetonitrile, water and formic acid. After evaporation of the product containing fractions 29.3 mg (65 %) of the title compound was isolated. MS(m/e): 449.2 (MH+).
Example 41 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1,1,1-trifluoropropan- 2-yloxy)triazolo[4,5-d]pyrimidine In analogy to the procedure bed for the synthesis of chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 1,1,1-trifluoropropanol. MS(m/e): 463.2 (MH+). 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the ure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and (S)-1,1,1-trifluoropropanol.
MS(m/e): 463.3 (MH+).
Example 43 3-[(2-Chlorophenyl)methyl](2,2-difluoroethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In y to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2,2-difluoroethanol. MS(m/e): 431.3 (MH+).
Example 44 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)ethoxytriazolo[4,5- d]pyrimidine In y to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and ethanol with the use of Cs2CO3 instead of NaH. MS(m/e): 395.3 (MH+).
Example 45 -Butoxy[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and butanol with the use of Cs2CO3 instead of NaH. MS(m/e): 423.3 (MH+).
Example 46 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2-fluoroethoxy) triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and roethanol with the use of Cs2CO3 instead of NaH. MS(m/e): 413.2 (MH+).
Example 47 Chlorophenyl)methyl](cyclopropylmethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and cyclopropylmethanol with the use of Cs2CO3 instead of NaH. MS(m/e): 421.3 (MH+).
Example 48 3-[(2-Chlorophenyl)methyl]cyclobutyloxy(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and cyclobutanol with the use of Cs2CO3 instead of NaH. MS(m/e): 421.3 (MH+).
Example 49 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(oxetanyloxy)triazolo [4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and oxetanol with the use of Cs2CO3 instead of NaH. MS(m/e): 423.3 (MH+).
Example 50 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(3-methyloxetan yl)methoxy]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and hyloxetanyl)methanol with the use of Cs2CO3 instead of NaH. MS(m/e): 451.3 (MH+).
Example 51 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2R)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and (R)-1,1,1-trifluoropropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 463.3 (MH+).
Example 52 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy) triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and methylpropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 437.3 (MH+). e 53 3-[(2-Chlorophenyl)methyl](2,2-difluoropropoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In y to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2,2-difluoropropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 445.3 (MH+).
Example 54 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2-methylpropoxy) triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2-methylpropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 423.3 (MH+).
Example 55 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propanyloxytriazolo ]pyrimidine In analogy to the procedure described for the synthesis of chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and propanol with the use of Cs2CO3 instead of NaH. ): 409.3 (MH+).
Example 56 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propynoxytriazolo [4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and propynol with the use of Cs2CO3 instead of NaH. MS(m/e): 405.2 (MH+).
Example 57 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1-methoxypropan yloxy)triazolo[4,5-d]pyrimidine In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 1-methoxypropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 439.3 (MH+).
Example 58 1-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]oxymethylpropanol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2-methylpropane-1,2-diol with the use of Cs2CO3 instead of NaH. MS(m/e): 439.3 (MH+).
Example 59 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propoxytriazolo[4,5- d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and ol with the use of Cs2CO3 instead of NaH. MS(m/e): 409.3 (MH+).
Example 60 (3S)[3-[(2-Chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinol a) (3S)[3-[(4-Methoxyphenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) and 1,1,1-trifluoropropanol. MS(m/e): 425.4 (MH+). b) (3S)[5-(2,2,2-Trifluoroethoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol (3R)[3-[(4-Methoxyphenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-pyrrolidinol (0.45 g, 1 mmol) in TFA (3.87 mL) was heated to 80 °C for overnight and concentrated. The intermediately built ester was cleaved by NaOH (1M) and extracted with ethyl acetate. The combined organic layers were evaporated. The crude product was used in the utive step t further purification. MS(m/e): 306.2 (MH+). c) (3S)[3-[(2-Chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from (3S)[5-(2,2,2- trifluoroethoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 1-(bromomethyl) chlorobenzene. MS(m/e): 429.4 (MH+). e 61 (3S)[5-(2,2,2-Trifluoroethoxy)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from (3S)[5-(2,2,2- trifluoroethoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 1-(bromomethyl) (trifluoromethyl)benzene. ): 463.4 (MH+).
Example 62 (3S)[3-[(2-Chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]pyrrolidinol a) (3S)[5-Isopropoxy[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title nd was prepared from (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) and propanol. MS(m/e): 385.4 (MH+). b) [(3S)(5-Isopropoxy-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinyl] 2,2,2- trifluoroacetate (3S)[5-Isopropoxy[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol in TFA was heated to 70 °C for overnight and evaporated. The crude product was used in the consecutive step without further purification. c) (3S)[3-[(2-Chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from [(3S)(5-isopropoxy-3H- triazolo[4,5-d]pyrimidinyl)pyrrolidinyl] 2,2,2-trifluoroacetate and momethyl)- 2-chlorobenzene. ): 389.3 (MH+).
Example 63 (3S)[3-[(2-Methylsulfonylphenyl)methyl]propanyloxytriazolo[4,5- d]pyrimidinyl]pyrrolidinol In analogy to the procedure described for the sis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from [(3S)(5-isopropoxy-3H- triazolo[4,5-d]pyrimidinyl)pyrrolidinyl] 2,2,2-trifluoroacetate and 1-(bromomethyl)- 2-(methylsulfonyl)benzene. MS(m/e): 433.3 (MH+).
Example 64 (3S)[3-[(1-Methyltetrazolyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinol In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from [(3S)(5-isopropoxy-3H- triazolo[4,5-d]pyrimidinyl)pyrrolidinyl] 2,2,2-trifluoroacetate and oromethyl)- 1-methyl-1H-tetrazole. MS(m/e): 361.3 (MH+).
Example 65 -Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]triazolo[4,5-d]pyrimidine a) 7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(4-methoxyphenyl)methyl] triazolo[4,5-d]pyrimidine In analogy to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine (example 20, step a) and 2,2- dimethylpropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 433.2 (MH+). b) 7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidine 7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(4-methoxyphenyl)methyl] lo[4,5-d]pyrimidine in TFA was heated to 80 °C for 3 h and evaporated. The crude product was used in the consecutive step without further purification. MS(m/e): 313.3 (MH+). c) 7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]triazolo[4,5-d]pyrimidine In y to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was ed from 7-(3,3-difluoropyrrolidinyl)- -(2,2-dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidine and 5-(chloromethyl)methyl- 1H-tetrazole. MS(m/e): 409.4 (MH+).
Example 66 7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2-methylsulfonylphenyl) methyl]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- -(2,2-dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidine and 1-(bromomethyl) (methylsulfonyl)benzene. MS(m/e): 481.4 (MH+).
Example 67 3-[[7-(3,3-Difluoropyrrolidinyl)(2,2-dimethylpropoxy)triazolo[4,5-d]pyrimidin- 3-yl]methyl]methyl-1,2,5-oxadiazole In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidine and 3-(chloromethyl)methyl- 1,2,5-oxadiazole. ): 409.4 (MH+).
Example 68 -Difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine a) 7-(3,3-Difluoropyrrolidinyl)[(4-methoxyphenyl)methyl][(1S)-2,2,2-trifluoro -ethoxy]triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from 5-chloro(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine (example 20, step a) and (S)-1,1,1- trifluoropropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 459.4 (MH+). b) 7-(3,3-Difluoropyrrolidinyl)[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H- triazolo[4,5-d]pyrimidine 7-(3,3-Difluoropyrrolidinyl)[(4-methoxyphenyl)methyl][(1S)-2,2,2-trifluoro methyl-ethoxy]triazolo[4,5-d]pyrimidine in TFA was heated to 80 °C for 2 h and evaporated. The mixture was poured into NaHCO3 aq. (1M) and extracted with ethyl acetate. The combined organic layers were filtered and evaporated. The crude t was used in the consecutive step without further purification. c) 7-(3,3-Difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- )-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 1- (bromomethyl)(trifluoromethyl)benzene. MS(m/e): 497.4 (MH+).
Example 69 7-(3,3-Difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In y to the procedure described for the synthesis of -butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 1- (bromomethyl)(methylsulfonyl)benzene. MS(m/e): 507.4 (MH+).
Example 70 3-[(3-Chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the procedure bed for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 3-chloro (chloromethyl)pyridine. MS(m/e): 464.3 (MH+).
Example 71 (3,3-Difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxytriazolo[4,5- d]pyrimidinyl]methyl]methyl-1,3,4-oxadiazole In analogy to the procedure described for the sis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from -difluoropyrrolidinyl)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 2- (chloromethyl)methyl-1,3,4-oxadiazole. MS(m/e): 435.4 (MH+).
Example 72 -[[7-(3,3-Difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxytriazolo[4,5- d]pyrimidinyl]methyl]methyl-1,2,4-oxadiazole In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- ropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 5- (chloromethyl)methyl-1,2,4-oxadiazole. MS(m/e): 435.4 (MH+).
Example 73 7-(3,3-Difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine le 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 5- omethyl)methyl-1H-tetrazole. MS(m/e): 435.4 (MH+).
Example 74 3-[[7-(3,3-Difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxytriazolo[4,5- d]pyrimidinyl]methyl]methyl-1,2,5-oxadiazole In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from -difluoropyrrolidinyl)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 3- (bromomethyl)methyl-1,2,5-oxadiazole. MS(m/e): 435.4 (MH+).
Example 75 7-(3,3-Difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxy(3,3,3- trifluoropropyl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from -difluoropyrrolidinyl)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 3-bromo-1,1,1- trifluoropropane. MS(m/e): 435.4 (MH+).
Example 76 3-[(1-Cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- oropropanyl]oxytriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from 7-(3,3-difluoropyrrolidinyl)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 5- (chloromethyl)cyclopropyl-1H-tetrazole. MS(m/e): 461.4 (MH+).
Example 77 )[3-[(2-Chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide a) N-[(3S)[5-(2,2-Dimethylpropoxy)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was ed from N-[(3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide (example 21, step a) and 2,2-dimethylpropanol. MS(m/e): 254.4 (MH+). b) N-[(3S)[5-(2,2-Dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidin yl]acetamide N-[(3S)[5-(2,2-Dimethylpropoxy)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide was hydrogenated over Pd/C in methanol to yield the title compound which was used in the consecutive step without further purification. c) )[3-[(2-Chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- midinyl]pyrrolidinyl]acetamide In analogy to the ure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-[(3S)[5-(2,2- dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 1- (bromomethyl)chlorobenzene. MS(m/e): 458.4 (MH+).
Example 78 N-[(3S)[3-[(3-Chloropyridinyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from N-[(3S)[5-(2,2- dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 3- chloro(chloromethyl)pyridine. MS(m/e): 459.4 (MH+).
Example 79 N-[(3S)[5-(2,2-Dimethylpropoxy)[(4-methyl-1,2,5-oxadiazolyl)methyl]triazolo [4,5-d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine le 22) the title compound was prepared from N-[(3S)[5-(2,2- dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 3- (bromomethyl)methyl-1,2,5-oxadiazole. MS(m/e): 430.4 (MH+).
Example 80 N-[(3S)[3-[(2-Chlorophenyl)methyl][(2S)-1,1,1-trifluoropropanyl]oxytriazolo [4,5-d]pyrimidinyl]pyrrolidinyl]acetamide a) N-[(3S)[3-[(4-Methoxyphenyl)methyl][(1S)-2,2,2-trifluoromethyl-ethoxy] triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title compound was prepared from N-[(3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide (example 21, step a) and (S)-1,1,1-trifluoropropanol. MS(m/e): 480.5 (MH+). b) N-[(3S)[5-[(1S)-2,2,2-Trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidin yl]pyrrolidinyl]acetamide N-[(3S)[3-[(4-Methoxyphenyl)methyl][(1S)-2,2,2-trifluoromethylethoxy ]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide was hydrogenated over Pd/C in methanol to yield the title compound which was used in the consecutive step without further purification. c) N-[(3S)[3-[(2-Chlorophenyl)methyl][(2S)-1,1,1-trifluoropropanyl]oxytriazolo [4,5-d]pyrimidinyl]pyrrolidinyl]acetamide In y to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was ed from N-[(3S)[5-[(1S)-2,2,2- trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and momethyl)chlorobenzene. MS(m/e): 484.4 (MH+).
Example 81 N-[(3S)[3-[[2-(Trifluoromethyl)phenyl]methyl][(2S)-1,1,1-trifluoropropanyl] oxytriazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title compound was prepared from N-[(3S)[5-[(1S)-2,2,2- oromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 1-(bromomethyl)(trifluoromethyl)benzene. MS(m/e): 528.5 (MH+).
Example 82 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo [4,5-d]pyrimidine A mixture of 5-chloro[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin azolo[4,5-d]pyrimidine (example 8, step a) (77 mg, 0.2 mmol), DIPEA (90.5 mg, 0.7 mmol) and ethanethiol (62.5 mg, 1 mmol) in DMF (3 mL) was stirred at 110 °C overnight. The e was concentrated and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 62.3 mg (50 %) of the title compound. MS(m/e): 411.2 (MH+).
Example 83 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2- trifluoroethylsulfanyl)triazolo[4,5-d]pyrimidine In analogy to the ure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 2,2,2- trifluoroethanethiol. MS(m/e): 465.2 (MH+).
Example 84 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfanyltriazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and ethiol.
MS(m/e): 425.3 (MH+).
Example 85 -tert-Butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 2- propanethiol. MS(m/e): 439.3 (MH+).
Example 86 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo [4,5-d]pyrimidine A mixture of 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) (79.4 mg, 0.2 mmol) and 3- chlorobenzoperoxoic acid (80 mg, 0.46 mmol) in DCM (2 mL) was stirred at room temperature for 4 h. The mixture was evaporated and the residue was subjected to purification by preparative HPLC on reversed phase eluting with a nt formed from itrile, water and formic acid. The product containing fractions were evaporated to yield 26 mg (29 %) of the title compound. MS(m/e): 443.2 (MH+).
Example 87 -Benzylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo [4,5-d]pyrimidine a) 5-Benzylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and phenylmethanethiol. MS(m/e): 473.2 (MH+). b) 5-Benzylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was prepared from 5-benzylsulfanyl[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine through oxidation with MCPBA.
MS(m/e): 505.2 (MH+).
Example 88 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfonyltriazolo[4,5-d]pyrimidine In analogy to the ure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was prepared from 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin- 1-yl)propanylsulfanyltriazolo[4,5-d]pyrimidine through oxidation with MCPBA. ): 457.3 (MH+). e 89 2-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5-d] pyrimidinyl]sulfanylethanol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine le 8, step a) and 2- toethanol. MS(m/e): 427.2 (MH+).
Example 90 1-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfanylpropanol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 1- mercaptopropanol. MS(m/e): 441.2 (MH+).
Example 91 -Butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo [4,5-d]pyrimidine In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and butanethiol at elevated temperature in DMF. MS(m/e): 439.2 (MH+).
Example 92 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfanyl)triazolo[4,5-d]pyrimidine In analogy to the ure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title nd was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 2- methylpropanethiol at elevated temperature in DMF. MS(m/e): 439.2 (MH+).
Example 93 -Butylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo [4,5-d]pyrimidine In analogy to the procedure bed for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was prepared from 5-butylsulfanyl[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine through oxidation with MCPBA.
MS(m/e): 471.3 (MH+).
Example 94 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfonyl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title nd was prepared from 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin- 1-yl)(2-methylpropylsulfanyl)triazolo[4,5-d]pyrimidine h oxidation with MCPBA. MS(m/e): 471.3 (MH+).
Example 95 1-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfonylpropanol In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] ifluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was prepared from 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin- 1-yl)(2-methylpropylsulfanyl)triazolo[4,5-d]pyrimidine through oxidation with MCPBA. MS(m/e): 473.2 (MH+). e 96 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfonyl)triazolo[4,5-d]pyrimidine a) 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfanyl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfanyltriazolo[4,5-d]pyrimidine (example 82) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 2- methoxyethanethiol at elevated temperature in DMF. MS(m/e): 441.2 (MH+). b) 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfonyl)triazolo[4,5-d]pyrimidine In analogy to the procedure described for the sis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was prepared from 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin- 1-yl)(2-methoxyethylsulfanyl)triazolo[4,5-d]pyrimidine through oxidation with MCPBA. MS(m/e): 473.2 (MH+).
Example 97 N-[(3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinyl]acetamide In analogy to the procedure described for the synthesis of N-tert-butyl(3,3- ropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was prepared from N-[(3S)[5-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 1-(bromomethyl) chlorobenzene. MS(m/e): 443.4 (MH+).
Example 98 Pharmacological tests The following tests were carried out in order to ine the activity of the compounds of formula I: Radioligand binding assay The ty of the compounds of the invention 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 [3H]-CP-55,940 n 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 on was terminated by rapid filtration through iltration plates coated with 0.5% polyethylenimine lter 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 [3H]CP55,940 determined from saturation experiments. The compounds of formula (I) show an excellent affinity for the CB2 receptor with affinities below 10 µM, more particularly of 1 nM to 3 µM and most particularly of 1 nM to 100 nM. cAMP Assay CHO cells expressing human CB1 or CB2 receptors are seeded 17-24 hours prior to the experiment 50.000 cells per well in a black 96 well plate with flat clear bottom (Corning Costar #3904) in DMEM (Invitrogen No. 31331), 1x HT 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 Bicarbonate 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 reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN3) and 50 µl detection solutions (20 µM mAb Alexa700- cAMP 1:1, and 48 µM RutheniumAHA-cAMP) and shaken for 2h at room temperature.
The time-resolved energy transfer is measured by a TRF reader (Evotec logies GmbH), equipped with a ND:YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the on with a delay of 100 ns and a gate of 100 ns, total exposure time 10s at 730 (bandwidth30 nm) or 645 nm (bandwidth 75 nm), tively. 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 rd curve ng from 10 µM to 0.13 nM cAMP.
EC50 values were determined using Activity Base analysis (ID Business Solution, Limited). The EC50 values for a wide range of cannabinoid agonists generated from this assay were in ent with the values published in the scientific literature.
The compounds of the invention are CB2 receptor agonists with EC50 below 1 μM and ivity versus CB1 in the corresponding assay of at least 10 fold. Particular compound of the invention are CB2 receptor agonists with EC50 below 0.05 μM and selectivity versus CB1 in the ponding assay of at least 500 fold.
For example, the following compounds showed the following human EC50 values in the functional cAMP assay described above: CB2 h CB1 CB2 h CB1 Example cAMP hcAMP Example cAMP hcAMP EC50 uM EC50 uM EC50 uM EC50 uM 1 0.001 >10 49 0.0219 >10 2 0.0064 >10 50 0.0028 >10 3 0.0005 0.77 51 0.0021 >10 4 0.001 0.75 52 0.0008 >10 0.001 >10 53 0.0055 >10 6 0.0036 >10 54 0.0012 >10 7 0.0092 >10 55 0.0012 >10 8 0.0045 >10 56 0.011 >10 9 0.0016 0.363 57 0.0088 >10 0.0029 0.217 58 0.0157 >10 11 0.0026 >10 59 0.0009 >10 12 0.0009 0.365 60 0.0008 >10 13 0.0125 >10 61 0.0075 >10 14 0.0035 >10 62 0.0148 >10 0.0022 0.336 63 0.1898 >10 16 0.0031 >10 64 0.1735 >10 17 0.0266 >10 65 0.0119 >10 18 0.0081 0.967 66 0.0039 >10 19 0.0274 >10 67 0.0017 >10 0.0203 >10 68 0.0004 >10 21 0.1411 >10 69 0.0032 >10 22 0.0021 >10 70 0.0051 >10 23 0.0011 0.487 71 0.2135 >10 24 0.0034 >10 72 0.0674 >10 0.0075 >10 73 0.0423 >10 26 0.001 >10 74 0.0018 >10 27 0.2674 >10 75 0.0043 >10 28 0.0023 >10 76 0.0177 >10 29 0.0486 >10 77 0.0582 >10 0.0899 >10 78 0.1676 >10 31 0.056 >10 79 0.0727 >10 32 0.0096 >10 80 0.1594 >10 33 0.0072 >10 81 0.0789 >10 34 0.0453 >10 82 0.0007 0.183 0.0108 >10 83 0.0019 >10 36 0.2204 >10 84 0.0023 0.08 37 0.0236 >10 85 0.0009 0.108 38 0.3118 >10 86 0.0866 >10 39 0.3014 >10 87 0.083 >10 40 0.0061 >10 88 0.0017 >10 41 0.0085 >10 89 0.0074 >10 42 0.0033 >10 90 0.0156 >10 43 0.0264 >10 91 0.0069 >10 44 0.004 >10 92 0.0025 >10 45 0.0012 >10 93 0.0088 >10 46 0.0053 >10 94 0.0028 >10 47 0.0036 >10 95 0.0644 >10 48 0.0017 >10 96 0.0051 >10 97 0.038 >10 Example A Film coated tablets containing the following ients can be manufactured in a conventional manner: 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 Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg hylene 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 e 0.8 mg 1.6 mg The active ient is sieved and mixed with microcrystalline cellulose 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 s are lacquered with an aq. solution / suspension of the above mentioned film coat.
Example B Capsules containing the following ingredients can be manufactured in a conventional 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 a (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml The active ingredient is dissolved in a mixture of Polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by 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 (19)

Claims
1. A compound of formula (I) wherein 5 R1 is haloalkyl, enyl, alkoxyphenyl, alkyl-1,2,5-oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl; R2 is alkylamino, cycloalkylamino, alkyloxetanylamino, alkyl)(alkyl)amino, haloalkyloxy, , cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, 10 alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl; R3 and R4 are independently selected from hydrogen, halogen, hydroxyl, alkylcarbonylamino and alkyl, provided that R3 and R4 are not both hydrogen at the same time; and 15 n is 1 or 2; or a pharmaceutically acceptable salt or ester thereof; provided that [3-(4-Methoxy-benzyl)(2,2,2-trifluoro-ethoxy)-3H- [1,2,3]triazolo[4,5-d]pyrimidinyl]-pyrrolidinol is excluded.
2. A compound according to claim 1, wherein R1 is halophenyl, haloalkylphenyl or 20 alkylsulfonylphenyl.
3. A compound according to claim 1 or 2, n R1 is chlorophenyl, trifluoromethylphenyl or methylsulfonylphenyl.
4. A compound according to any one of claims 1 to 3, wherein R2 is alkylamino, alkoxy, haloalkyloxy or alkylsulfanyl.
5. A compound according to any one of claims 1 to 4, wherein R2 is tert.-butylamino, pentyloxy, isopropyloxy, trifluoroethyloxy, trifluoropropyloxy, ethylsulfanyl or tert.- 5 butylsulfanyl.
6. A compound according to any one of claims 1 to 5, n R3 and R4 are ndently selected from en, halogen and hydroxyl.
7. A compound according to any one of claims 1 to 6, wherein one of R3 and R4 is hydrogen and the other one is hydroxyl, or wherein R3 and R4 are both halogen at the 10 same time.
8. A compound according to any one of claims 1 to 7, wherein one of R3 and R4 is hydrogen and the other one is hydroxyl, or n R3 and R4 are both fluorine at the same time.
9. A compound according to any one of claims 1 to 8 selected from 15 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5- d]pyrimidinamine; 3-[(2-chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine; N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- 20 d]pyrimidinamine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(3-methyloxetan azolo[4,5-d]pyrimidinamine; N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine; 25 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(2,2- dimethylpropyl)triazolo[4,5-d]pyrimidinamine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(oxetan yl)triazolo[4,5-d]pyrimidinamine; 3-[(2-chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine; (3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol; 5 N-tert-butyl(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinamine; N-[(3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; N-tert-butyl(3,3-difluoropyrrolidinyl)[[2- 10 (trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidin azolo[4,5-d]pyrimidinamine; 15 -butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazol yl)methyl]triazolo[4,5-d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(4-methyl-1,2,5-oxadiazol yl)methyl]triazolo[4,5-d]pyrimidinamine; N-[(3S)[5-(tert-butylamino)[(3-chloropyridinyl)methyl]triazolo[4,5- 20 d]pyrimidinyl]pyrrolidinyl]acetamide; (3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinol; (3S)[5-(tert-butylamino)[(1-methyltetrazolyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol; 25 (3S)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin yl]methylpyrrolidinol; (3R)[5-(tert-butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin- 7-yl]methylpyrrolidinol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2- trifluoroethoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1,1,1-trifluoropropan- 2-yloxy)triazolo[4,5-d]pyrimidine; 5 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- oropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](2,2-difluoroethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)ethoxytriazolo[4,5- 10 d]pyrimidine; 5-butoxy[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- fluoroethoxy)triazolo[4,5-d]pyrimidine; 15 3-[(2-chlorophenyl)methyl](cyclopropylmethoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl]cyclobutyloxy(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(oxetan 20 triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(3-methyloxetan yl)methoxy]triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2R)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 25 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](2,2-difluoropropoxy)(3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan yloxytriazolo[4,5-d]pyrimidine; 5 chlorophenyl)methyl](3,3-difluoropyrrolidinyl)prop ynoxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1-methoxypropan yloxy)triazolo[4,5-d]pyrimidine; 1-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- 10 d]pyrimidinyl]oxymethylpropanol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propoxytriazolo[4,5- d]pyrimidine; (3S)[3-[(2-chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinol; 15 (3S)[5-(2,2,2-trifluoroethoxy)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol; (3S)[3-[(2-chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]pyrrolidinol; -[3-[(2-methylsulfonylphenyl)methyl]propanyloxytriazolo[4,5- 20 d]pyrimidinyl]pyrrolidinol; (3S)[3-[(1-methyltetrazolyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinol; 7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)methyl]triazolo[4,5-d]pyrimidine; 25 7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(2- methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidine; 3-[[7-(3,3-difluoropyrrolidinyl)(2,2-dimethylpropoxy)triazolo[4,5-d]pyrimidin- 3-yl]methyl]methyl-1,2,5-oxadiazole; -difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 7-(3,3-difluoropyrrolidinyl)[(2-methylsulfonylphenyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 5 3-[(3-chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 2-[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]methyl]methyl-1,3,4-oxadiazole; 5-[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan 10 yl]oxytriazolo[4,5-d]pyrimidinyl]methyl]methyl-1,2,4-oxadiazole; 7-(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[[7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]methyl]methyl-1,2,5-oxadiazole; 15 7-(3,3-difluoropyrrolidinyl)[(2S)-1,1,1-trifluoropropanyl]oxy(3,3,3- trifluoropropyl)triazolo[4,5-d]pyrimidine; 3-[(1-cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidinyl)[(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; N-[(3S)[3-[(2-chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- 20 d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[5-(2,2-dimethylpropoxy)[(4-methyl-1,2,5-oxadiazol yl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; 25 )[3-[(2-chlorophenyl)methyl][(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1-trifluoropropan yl]oxytriazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfanyltriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2,2- trifluoroethylsulfanyl)triazolo[4,5-d]pyrimidine; 5 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfanyltriazolo[4,5-d]pyrimidine; 5-tert-butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) 10 ethylsulfonyltriazolo[4,5-d]pyrimidine; 5-benzylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan ylsulfonyltriazolo[4,5-d]pyrimidine; 15 2-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfanylethanol; 1-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfanylpropanol; 5-butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin 20 yl)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfanyl)triazolo[4,5-d]pyrimidine; 5-butylsulfonyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 25 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfonyl)triazolo[4,5-d]pyrimidine; (2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]sulfonylpropanol; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfonyl)triazolo[4,5-d]pyrimidine; and N-[(3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin- 7-yl]pyrrolidinyl]acetamide. 5 10. A compound according to any one of claims 1 to 9 selected from N-tert-butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinamine; N-tert-butyl(3,3-difluoropyrrolidinyl)[(2- methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidinamine;
10.3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- dimethylpropoxy)triazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropoxy)triazolo[4,5-d]pyrimidine; (3S)[3-[(2-chlorophenyl)methyl](2,2,2-trifluoroethoxy)triazolo[4,5- 15 d]pyrimidinyl]pyrrolidinol; 7-(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl) ethylsulfanyltriazolo[4,5-d]pyrimidine; and 20 -butylsulfanyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine.
11. A process for the ation of a compound according to any one of claims 1 to 10, comprising one of the ing steps: (a) the reaction of a compound of formula (A1) N N R (A1) in the presence of a nd of formula (A2) (CH2)n R R (A2) wherein R2 is isopropyl, cycloalkyl or alkenyl and R1, R3, R4 and n are as defined in 5 any one of claims 1 to 8; (b) the reaction of a compound of formula (B1) H 2 N N R (CH2)n R R (B1) in the presence of R1CH2X wherein X is a halogen, a hydroxyl or a sulfonate group, wherein R2 is isopropyl, cycloalkyl or alkenyl and wherein R3 to R4 and n are as 10 defined in any one of claims 1 to 8; (c) the reaction of a nd of formula (C1) N N Cl (CH2)n R R in the ce of R2-H wherein R2 is piperidinyl, alkylamino, azetidinyl, pyrrolidinyl, cycloalkylamino, alkyloxetanylamino, morpholinyl, (cycloalkyl)(alkyl)amino, kyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, 5 oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl and n R1, R3, R4 and n are as defined in any one of claims 1 to 8.
12. A compound according to any one of claims 1 to 10 for use as therapeutically active 10 substance.
13. A pharmaceutical composition comprising a nd in accordance with any one of claims 1 to 10 and a eutically inert carrier.
14. The use of a compound according to any one of claims 1 to 10 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related 15 macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic is, acute aft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, 20 myocardial infarction, systemic sclerosis, thermal , burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
15. A nd according to any one of claims 1 to 10 for use in the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic 25 retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver is, lung fibrosis, kidney fibrosis, systemic is, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, l injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, 5 regulation of bone mass, neurodegeneration, stroke, transient ic attack or uveitis.
16. The compound according to any one of claims 1 to 10, 12 and 15, substantially as herein described with reference to any e f.
17. The process according to claim 11, substantially as herein described with reference 10 to any e thereof.
18. The pharmaceutical composition according to claim 13, substantially as herein described with reference to any example thereof.
19. The use according to claim 14, substantially as herein described with reference to any example thereof. 15 ***
NZ715085A 2013-09-06 2014-09-03 Novel triazolo[4,5-d]pyrimidine derivatives NZ715085B2 (en)

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