NZ756513B2 - Novel triazolo[4,5-d]pyrimidine derivatives - Google Patents

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

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NZ756513B2
NZ756513B2 NZ756513A NZ75651314A NZ756513B2 NZ 756513 B2 NZ756513 B2 NZ 756513B2 NZ 756513 A NZ756513 A NZ 756513A NZ 75651314 A NZ75651314 A NZ 75651314A NZ 756513 B2 NZ756513 B2 NZ 756513B2
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New Zealand
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methyl
triazolo
chlorophenyl
difluoropyrrolidinyl
pyrimidine
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NZ756513A
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NZ756513A (en
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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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    • 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 particular to compounds that are preferential agonists of the Cannabinoid Receptor 2.
The invention provides a compound of formula (I) wherein R1 is haloalkyl, enyl, alkoxyphenyl, alkyl-1,2,5-oxadiazolyl, haloalkylphenyl, alkylsulfonylphenyl, halopyridinyl or alkyltetrazolyl; R2 is dinyl, azetidinyl, pyrrolidinyl, or morpholinyl; 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 thereof.
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, piperidinyl, alkylamino, inyl, pyrrolidinyl, cycloalkylamino, xetanylamino, linyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, kylsulfanyl, 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 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.
The nd of formula (I) is particularly useful in the treatment or prophylaxis of e.g. pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, ma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemiareperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ia, myocardial tion, systemic sis, thermal injury, burning, hypertrophic scars, keloids, itis pyrexia, liver sis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
The inoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, termed Cannabinoid Receptor 1 (CB1) and Cannabinoid Receptor 2 (CB2). The CB1 or is mainly expressed in the central nervous (i.e. amygdala cerebellum, hippocampus) system and to a lesser amount in the periphery. CB2, which is encoded by the CNR2 gene, is mostly expressed peripherally, on cells of the immune system, such as macrophages and T-cells n, J. C. et al. Curr Neuropharmacol 2007, 5(2), 73-80; Miller, A. M. et al. Br J Pharmacol 2008, 153(2), 299-308; Centonze, D., et al. Curr Pharm Des 2008, 14(23), 2370-42), and in the gastrointestinal system (Wright, K. L. et al. Br J Pharmacol 2008, 153(2), 263-70). The CB2 receptor is also widely buted in the brain where it is found primarily on microglia and not neurons (Cabral, G. A. et al. Br J Pharmacol 2008, : 240-51).
The interest in CB2 receptor agonists has been steadily on the rise during the last decade ntly 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 c pain (Beltramo, 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), ia/reperfusion injury (Pacher, P. et al. Br J col 2008, 153(2), 252-62), systemic is (Akhmetshina, A. et al. Arthritis Rheum 2009, 60(4), 1129-36; Garcia- Gonzalez, E. et al. Rheumatology (Oxford) 2009, 48(9), 1050-6), liver fibrosis (Julien, B. et al. Gastroenterology 2005, 128(3), ; Munoz-Luque, J. et al. J Pharmacol Exp Ther 2008, 324(2), 475-83).
Ischemia/reperfusion (I/R) injury is the principal cause of tissue damage occurring in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular surgeries, and organ 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., usion 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 ation 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 reintroduces oxygen within cells that damages cellular proteins, DNA, and the plasma membrane.
Remote ischemic preconditioning (RIPC) represents a gy for harnessing the body’s endogenous protective capabilities against the injury incurred by ia and reperfusion. It describes the uing phenomenon in which transient 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, endocannabinoids, Angiotensin I or some other as yet unidentified humoral factor) generated in the remote organ or tissue enters the blood stream and activates its respective receptor in the target tissue and thereby recruiting the various intracellular pathways of cardioprotection implicated in ischemic preconditioning.
Recent data indicates that endocannabinnoids 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 , N. et al. Faseb J 2009, 23(7), 2120-30), the brain (Zhang, M. et al. J Cereb Blood Flow Metab 2007, 27(7), 1387-96), the liver (Batkai, S. et al. Faseb J 2007, 21(8), 00) and the kidney (Feizi, A. et al. Exp l Pathol 2008, ), 405-10).
Moreover, over the last few years, a growing body of ture indicates that CB2 can also be of interest in sub-chronic and chronic setting. Specific lation 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 is ssion. tion of CB2 receptor by selective CB2 agonist has in fact been shown to exert ibrotic effect in e systemic 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 hysiology, including fibrogenesis associated with chronic liver es (Lotersztajn, S. et al. Gastroenterol Clin Biol 2007, 31(3), 255-8; , A. et al.
Expert Opin Ther s 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 ation, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, particularly a straight or branched-chain alkyl group with 1 to 6 carbon atoms and more particularly a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straightchain and branched-chain C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls 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 cycloalkyl ring with 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, utyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclobutyl.
The term "alkenyl", alone or in combination, signifies a straight-chain or branched hydrocarbon residue comprising an ic bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1- yl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.
The term "alkynyl", alone or in ation, signifies a straight-chain or ed 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 alkyl-O- in which the term "alkyl" has the previously given significance, such as methoxy, ethoxy, n-propoxy, poxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy. ular "alkoxy" are methoxy, ethoxy, n-propyloxy, isopropyloxy, isobutyloxy, tert.- butyloxy and neopentyloxy.
The terms "halogen" or "halo", alone or in combination, signifies fluorine, chlorine, bromine or iodine and particularly fluorine, ne or bromine, more ularly fluorine and chlorine. The term "halo", in combination with another group, denotes the substitution of said group with at least one halogen, particularly tuted with one to five halogens, 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. ular "haloalkyl" are trifluoromethyl, trifluoroethyl and oropropyl.
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 ns, particularly one to three halogens. Particular "haloalkyloxy" are trifluoroethyloxy, trifluoropropyloxy, fluoroethyloxy, difluoroethyloxy 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 ation, signifies the - group.
The term "sulfanyl", alone or in combination, signifies the -S- group.
The term aceutically 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 nic acids such as hydrochloric acid, hydrobromic acid, ic acid, nitric acid, phosphoric acid, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, ic acid, fumaric acid, ic 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 inorganic 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 tuted , cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine . The nd of formula (I) can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
"Pharmaceutically able esters" means that the compound of general formula (I) may be derivatised at functional groups to provide tives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds e logically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
Additionally, any physiologically acceptable equivalents of the nd of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compound of l formula (I) in vivo, are within the scope of this invention.
If one of the starting materials or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more on steps, appropriate protecting groups (as described e.g. in "Protective Groups in Organic Chemistry" by T. W. Greene and P. G. M. Wuts, 3rd Ed., 1999, Wiley, New York) can be uced 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 formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for e, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention an asymmetric carbon atom can be of the "R" or "S" configuration.
The invention relates in particular to: A compound of formula (I) wherein R1 is halophenyl, alkoxyphenyl, alkyl-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 chlorophenyl, trifluoromethylphenyl or methylsulfonylphenyl; A compound of formula (I) wherein R3 and R4 are independently selected from hydrogen, n 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 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 fluorine at the same time.
Also described are: A compound of formula (I) n R2 is cycloalkyl, isopropyl, alkylamino, alkoxy, haloalkyloxy or alkylsulfanyl; A compound of formula (I) wherein R2 is utyl, isopropyl, tert.-butylamino, pentyloxy, isopropyloxy, trifluoroethyloxy, trifluoropropyloxy, ethylsulfanyl or tert.- butylsulfanyl.
The invention further relates in particular to a compound of formula (I) ed from: 3-[(2-chlorophenyl)methyl]-5,7-di(piperidinyl)triazolo[4,5-d]pyrimidine; -(azetidinyl)[(2-chlorophenyl)methyl](3,3-difluoropyrrolidin yl)triazolo[4,5-d]pyrimidine; 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; -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.
Also described in particular is a compound of formula (I) selected from: chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine; 5-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 azolo[4,5-d]pyrimidine; 3-[[5-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](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- 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; 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; )[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- methylsulfonylphenyl)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 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- 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; -[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; 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- d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- fluoroethoxy)triazolo[4,5-d]pyrimidine; 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 yloxy)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; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2,2- ylpropoxy)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; -[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- 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; 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; (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 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- midinyl]pyrrolidinyl]acetamide; N-[(3S)[3-[(3-chloropyridinyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- midinyl]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; -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; -benzylsulfonyl[(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-[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; lsulfanyl[(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; lsulfonyl[(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) selected from: 3-[(2-chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine; 3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)propan zolo[4,5-d]pyrimidine; 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; 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- d]pyrimidinyl]pyrrolidinol; -difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[4,5-d]pyrimidine; 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.
In the definition of R2, haloalkyloxy is in particular trifluoroethyloxy, trifluoropropyloxy, difluoroethyloxy, ethyloxy or ropropyloxy, and in particular trifluoropropyloxy, difluoroethyloxy, fluoroethyloxy or difluoropropyloxy.
Abbreviations: In the present description the following 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 = dimethyl-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 = oroacetic acid ; THF = tetrahydrofuran; tlc = thin layer chromatography; CAN = CAS ry Number.
The preparation of compounds of formula (I) of the present invention may be d out in sequential or convergent synthetic routes. Syntheses of the compounds of the invention are shown in the ing schemes. The skills required for carrying out the reactions and purifications of the resulting products are known to those skilled in the art.
The tuents 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 t. There is no ular restriction on the nature of the t to be employed, ed that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some . The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the ion. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the 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 limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity the sequence of reaction steps can be freely altered. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods bed 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 meaning 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 s II are conveniently d with sodium azide in a suitable t such as acetonitrile, ethanol or DMF to afford azide tives III. Alternative preferred conditions involve the use of solvents 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 acetonitrile, 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 e 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 example 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 tives IV can be prepared by a [3+2] cycloaddition of azide derivatives III with oacetamide in the presence of an appropriate base such as sodium ide or sodium ethoxide in a suitable solvent such as methanol, ethanol or DMF.
Alternative red conditions involve reacting the azide with 2-cyanoacetamide in solvents like NMP or DMSO, in the presence of sodium hydroxide. The batch process is usually med at room temperature to 50°C, preferably between room temperature and 40°C on, process safety has always to be carefully assessed). The cycloaddition process is also ble to continuous mode (for a relevant literature example, see Org.
Process Res. Dev., 2009, 13 (6), pp 1401–1406) and in this case the reaction ature can be increased above 50°C, for example (but not limited to) between 50°C and 90°C, preferably between 60°C and 70°C. c) Triazole IV can conveniently be reacted with an appropriate acid chloride (commercially available or known in the art) in the presence of a base (pyridine, DIPEA, NEt3 and the like) in the ce 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 triazolopyrimidine derivatives VI. e) Chlorides VII can be obtained by reaction of VI with a chlorination t such as POCl3, SOCl2 or (COCl)2 in the presence of an riate base such as N,N-diethyl aniline, lutidine, or pyridine. Alternative preferred conditions e the use of the Vislmeier reagent as chlorinating agent. It can also be generated in situ by reacting oxalyl chloride with DMF. The chlorination can be med 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 acetonitrile, methanol, toluene or DMF to yield triazolo-pyrimidine derivatives I.
These derivatives can be the final compounds, r preferably when R1-A is a substituted benzyl group such as p-methoxy benzyl, these groups can be cleaved with TFA, CAN, hydrogenation 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 presence of acids.
The triazole derivatives wherein R1-A has been replaced with H is conveniently reacted either with a halide (or sulfonate) in the ce 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 phosphine such as PBu3 or PPh3 in an appropriate t such as THF, DCM, toluene to afford final triazolopyrimidine derivatives 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 d with diethyl carbonate (or any other le gment, 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 ed by reaction of VIII 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 reagent as chlorinating agent. It can also be generated in situ by reacting oxalyl chloride with DMF. The chlorination can be performed for example in in acetonitrile, DCM or AcOEt, preferably in DCM. The crude product can be introduced 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 lopyrimidine X. d) Nucleophilic substitution of lopyrimidine X with an appropriate amine, sulfide or alcohol can be performed in the ce or absence of a base (DBU, DIPEA, NaH, Cs2CO3 and the like) and a t (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 cleaved 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 rd hydrogenolysis conditions also for example in the presence 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 l under Mitsunobu reaction conditions using suitable icarboxylate (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 wherein R2 is a sulfur containing group as defined above (e.g. a sulfanyl) can be be conveniently ed with m-CPBA to afford a sulfone of formula I.
The invention also relates to a s for the preparation of a compound of formula (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) wherein 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 hydroxyl or a sulfonate group, n R2 is isopropyl, cycloalkyl or alkenyl and wherein R3 to R4 and n are as defined above; or (c) the reaction 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, morpholinyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, alkoxy, cycloalkylalkoxy, cycloalkyloxy, oxetanyloxy, xetanylalkyloxy, alkynyloxy, alkoxy, hydroxyalkyloxy, ulfanyl, kylsulfanyl, 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 d 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 carried out in a t such as DMF, dioxane or toluene.
When X is a hydroxyl group, step (b) can be carried out under Mitsunobu reaction conditions using suitable diazodicarboxylate (e.g. DEAD, DIAD) and ine such as PBu3 or PPh3. The reaction can be done in an appropriate solvent such as THF, DCM or Step (c) can be carried out in the presence or e 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 ment of the invention es a pharmaceutical composition or medicament containing a compound of the invention and a therapeutically inert carrier, diluent or ent, as well as a method of using the compounds of the invention to prepare such composition and medicament. In one example, the compound of formula (I) may be ated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are nontoxic to recipients at the dosages and 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 stered in a fashion consistent with good medical practice. Factors for eration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the dual 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, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local ent, intralesional administration.
Parenteral ons include uscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The compounds of the present invention may be administered in any ient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking , and further active agents.
A l formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery s. elphia: 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 ents. 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, sing aids, colorants, sweeteners, perfuming , flavoring agents, ts 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 ular to: The use of a compound according of formula (I) for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes us, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, s, gingivitis pyrexia, liver cirrhosis or , regulation of bone mass, neurodegeneration, stroke, transient ic attack or uveitis; A nd of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related r degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, s, gingivitis pyrexia, liver sis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; and A method for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver e, liver fibrosis, lung is, kidney fibrosis, systemic fibrosis, acute aft rejection, chronic allograft pathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, rophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, , transient ischemic attack or uveitis, which method comprises administering an effective amount of a nd of formula (I) to a patient in need f.
Also described are: The use of a compound of formula (I) for the ent or prophylaxis of pain, atherosclerosis, lated macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel e, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, myopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis a, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; and A method for the treatment or prophylaxis of pain, atherosclerosis, age-related r degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver e, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, dial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis, which method comprises administering an effective amount of a nd 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 ia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion .
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 "consisting at least in part of". When interpreting statements in this specification and claims which include the term "comprising", other features besides the features ed by this term in each statement can also be present. Related terms such as ise" and "comprises" are to be interpreted in r manner.
In the description in this ication reference may be made to subject matter which is not within the scope of the ed claims. That subject matter should be readily identifiable by a person d in the art and may assist in putting into practice the invention as defined in the appended claims.
In this specification where reference has been made to patent specifications, other external 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 documents, or such sources of ation, 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 ing examples which have no limiting character.
Examples Example 1 3-[(2-Chlorophenyl)methyl]cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidine a) 5-Amino(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 mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude domethyl)chlorobenzene. The e 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 concentrated in vacuo, diluted with 4M AcOH aq. and ed. 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 cyclobutanecarbonyl 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 c layers were dried with MgSO4, ed and ated to dryness. The residue was used in the utive 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 evaporated 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 containing 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 mixture 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 3,3-difluoropyrrolidine 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 ature. After evaporation of the mixture the residue was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from itrile, water and NEt3. After ation 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 opropyl(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 atmosphere.
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 domethyl)methoxybenzene. The residue was used for the next reaction without further purification.
A mixture of the above crude e, 2-cyanoacetamide (10.8 g, 128 mmol) and sodium ethanolate (8.71 g, 128 mmol) in ethanol (250 mL) was refluxed for 21 h under N2 atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to afford 5-amino(4- methoxybenzyl)-1H-1,2,3-triazolecarboxamide as range 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 cyclopropanecarbonyl 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 lopropanecarbonylamino)[(4-methoxyphenyl)methyl]triazole carboxamide (1g, crude) and KHCO3 aq. (2.36 g, 23.6 mmol) in 46 mL water was heated to reflux overnight. After cooling to room ature the e was filtered and the light yellow solid dried. The te was extracted with DCM (3 x 125 mL) and the combined organic 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 organic layers were dried with MgSO4 and evaporated. The residue was taken up in acetonitrile (15 mL) and 3,3-difluoropyrrolidine hloride (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 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 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 e 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 as light yellow solid which was used in the consecutive step without further cation. 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 overnight. After cooling to room temperature with mixture was filtered 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 mixture of 3-[(2-chlorophenyl)methyl]isopropyl-6H-triazolo[4,5-d]pyrimidinone (0.74 g, crude), POCl3 (8.97 g, 58.5 mmol) and N,N-diethylaniline (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 ated. 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 ative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 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 e 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 combined 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 opropyl(3,3-difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidine (55 mg, crude), momethyl)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 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 8.1 mg (10 %, 2 steps) of the title nd 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 ed from 5-cyclopropyl(3,3-difluoropyrrolidinyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidine and momethyl)methyl-1,2,5-oxadiazole as light brown solid. MS(m/e): 363.2 (MH+).
Example 6 (3S)[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 e 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 evaporated and poured into HCl aq. (50 mL, 1M) and ted with ethyl acetate (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 g to room temperature the mixture was extracted with DCM (2 x 200 mL). The ed 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 evaporated and poured into ice / water (100 mL) and extracted with DCM (2 x 200 mL). The ed organic layers were dried with MgSO4, filtered and evaporated to yield 2.5 g of the crude chlorinated intermediate. 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 ature 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 containing 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) 3-[(2-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 de (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 e was ed and the precipitate was filtered, washed with l 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 mixture was poured into ice / water (25 mL) and extracted 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 further 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 stirred at room temperature for 1 h. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a nt formed from acetonitrile, water and NEt3. After evaporation of the product containing fractions 27 mg (0.065 mmol) of the title compound was isolated as white solid. MS(m/e): 412.2 (MH+).
Example 8 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5- d]pyrimidinamine 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 g with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 421 mg (1.09 mmol, 20 %) of the title nd as yellow oil. ): 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 preparative HPLC on reversed phase g with a gradient formed from acetonitrile, water and formic acid.
After evaporation of the product ning fractions 13.8 mg (50 %) of the title compound was isolated. MS(m/e): 394.2 (MH+).
Example 9 tidinyl)[(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- difluoropyrrolidinyl)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] (3,3-difluoropyrrolidinyl)-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 pyrrolidine. MS(m/e): 420.3 (MH+). e 11 3-[(2-Chlorophenyl)methyl]-N-cyclobutyl(3,3-difluoropyrrolidinyl)triazolo[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- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and cyclobutylamine. MS(m/e): 420.3 (MH+).
Example 12 N-tert-Butyl[(2-chlorophenyl)methyl](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 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 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 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 ure 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 morpholine. MS(m/e): 436.3 (MH+).
Example 15 N-tert-Butyl[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N- methyltriazolo[4,5-d]pyrimidinamine In y 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 tert-butyl-methyl-amine. MS(m/e): 436.3 (MH+).
Example 16 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(2,2-dimethylpropyl) triazolo[4,5-d]pyrimidinamine In y 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 2,2-dimethylpropanamine.
MS(m/e): 436.3 (MH+).
Example 17 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)-N-(oxetanyl)triazolo ]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 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- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and N-methylcyclobutanamine hydrochloride. MS(m/e): 434.3 (MH+). e 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 de (3.76 g, 55.3 mmol) and diethyl ate (4.72 g, 39.9 mmol) in ethanol (97.1 mL) was heated to reflux overnight. After cooling to room temperature the mixture was filtered and the precipitate was washed with ethanol to yield after drying 8.54 g (51 %) of the title compound 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 organic 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 rrolidinol (1.82 g, 20.9 mmol) in DCM (150 mL) was stirred at room temperature for 30 min. The e was poured into water (150 mL) and extracted with DCM (2 x 125 mL). The ed organic layers were dried with MgSO4, filtered and evaporated to yield the crude title compound as dark brown foam which was used in the consecutive step without further purification.
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 described for the synthesis of 3-[(2-chlorophenyl)methyl] (3,3-difluoropyrrolidinyl)-N-ethyltriazolo[4,5-d]pyrimidinamine (example 8) the title compound was ed from (3S)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol and 2-methylpropanamine. MS(m/e): 398.5 (MH+). e 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 y 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 compounds was prepared from the crude 5,7-dichloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine and fluoropyrrolidine 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 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(3,3-difluoropyrrolidinyl)[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidine and tert-butylamine as light yellow foam. ): 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 described for the synthesis of (3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) the title compounds was prepared from the crude 5,7-dichloro[(4- yphenyl)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 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+). e 22 N-tert-Butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] triazolo[4,5-d]pyrimidinamine a) N-tert-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 consecutive step without further purification. b) -Butyl(3,3-difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl] lo[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 g with a gradient formed from acetonitrile, water and NEt3. After evaporation of the product containing 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- difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and momethyl) (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 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-chloro (chloromethyl)pyridine. MS(m/e): 423.3 (MH+).
Example 25 N-tert-Butyl(3,3-difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl]triazolo [4,5-d]pyrimidinamine 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 N-tert-butyl(3,3- difluoropyrrolidinyl)-3H-triazolo[4,5-d]pyrimidinamine and 5-(chloromethyl) 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 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 3-(bromomethyl) -1,2,5-oxadiazole. ): 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 nd which was used in the utive 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- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine le 22) the title compound was prepared from N-[(3S)[5-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 3-chloro (chloromethyl)pyridine. MS(m/e): 444.4 (MH+).
Example 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 utive step without r 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- 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 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 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-(tert-butylamino)- 3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 5-(chloromethyl)methyl-1H- tetrazole. MS(m/e): 374.3 (MH+).
Example 30 (3S)[5-(tert-Butylamino)[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidin methylpyrrolidinol a) (3S)[5-Chloro[(4-methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]methylpyrrolidinol In analogy to the procedure described for the synthesis of -[5-chloro[(4- yphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinol (example 19, step b) the title compounds was prepared from the crude 5,7-dichloro[(4-methoxyphenyl) methyl]triazolo[4,5-d]pyrimidine and 3-methylpyrrolidinol. 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 sis 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 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 (3R)[5-chloro[(4-methoxyphenyl)methyl]triazolo[4,5- d]pyrimidinyl]methyl-pyrrolidinol (isolated as described in example 30) and tertbutylamine. ): 412.3 (MH+).
Example 32 (3S)[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 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- midinyl]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. ): 430.3 (MH+).
Example 33 (3S)Methyl[5-morpholinyl[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5- d]pyrimidinyl]pyrrolidinol 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 (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 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 -methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 3-chloro (chloromethyl)pyridine. MS(m/e): 431.3 (MH+).
Example 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+). e 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 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 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 further cation. MS(m/e): 306.2 (MH+). c) (3R)[3-[(2-Chlorophenyl)methyl]morpholino-triazolo[4,5-d]pyrimidinyl] methyl-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 (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) 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 bed 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 (3R)methyl(5- morpholino-3H-triazolo[4,5-d]pyrimidinyl)pyrrolidinol and 1-(bromomethyl) (methylsulfonyl)benzene. ): 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 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 -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 mixture 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 cooling to room temperature formic acid was added and the mixture was ted to purification by preparative HPLC on reversed 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+). e 41 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1,1,1-trifluoropropan- 2-yloxy)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 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 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 ed 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+). e 43 3-[(2-Chlorophenyl)methyl](2,2-difluoroethoxy)(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 nd was ed 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 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 ethanol with the use of Cs2CO3 d 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 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 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 prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and 2-fluoroethanol with the use of Cs2CO3 instead of NaH. MS(m/e): 413.2 (MH+).
Example 47 3-[(2-Chlorophenyl)methyl](cyclopropylmethoxy)(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- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and cyclopropylmethanol with the use of Cs2CO3 instead of NaH. ): 421.3 (MH+).
Example 48 3-[(2-Chlorophenyl)methyl]cyclobutyloxy(3,3-difluoropyrrolidin yl)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 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. ): 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 prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and oxetanol with the use of Cs2CO3 instead of NaH. ): 423.3 (MH+).
Example 50 3-[(2-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 le 40) the title compound was prepared from 5-chloro[(2-chlorophenyl)methyl](3,3- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and (3-methyloxetanyl)methanol with the use of Cs2CO3 instead of NaH. MS(m/e): 451.3 (MH+).
Example 51 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)[(2R)-1,1,1- trifluoropropanyl]oxytriazolo[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 (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 2,2-dimethylpropanol with the use of Cs2CO3 instead of NaH. MS(m/e): 437.3 (MH+).
Example 53 3-[(2-Chlorophenyl)methyl](2,2-difluoropropoxy)(3,3-difluoropyrrolidin yl)triazolo[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- ropyrrolidinyl)triazolo[4,5-d]pyrimidine and fluoropropanol 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 ure 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 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 [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 propanol with the use of Cs2CO3 instead of NaH. MS(m/e): 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 nd 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+). e 57 3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(1-methoxypropan yloxy)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 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 prepared 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] (3,3-difluoropyrrolidinyl)(2,2,2-trifluoroethoxy)triazolo[4,5-d]pyrimidine (example 40) the title nd was prepared from ro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine and propanol with the use of Cs2CO3 d 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 3-[(2-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 e. The combined organic layers were evaporated. The crude product was used in the consecutive step t further purification. MS(m/e): 306.2 (MH+). c) -[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 compound was prepared from (3S)[5-(2,2,2- trifluoroethoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 1-(bromomethyl) benzene. MS(m/e): 429.4 (MH+).
Example 61 (3S)[5-(2,2,2-Trifluoroethoxy)[[2-(trifluoromethyl)phenyl]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-(2,2,2- trifluoroethoxy)-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinol and 1-(bromomethyl) (trifluoromethyl)benzene. MS(m/e): 463.4 (MH+).
Example 62 (3S)[3-[(2-Chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]pyrrolidinol a) -[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 compound 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 r cation. c) (3S)[3-[(2-Chlorophenyl)methyl]propanyloxytriazolo[4,5-d]pyrimidin yl]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 (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-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 synthesis of N-tert-butyl(3,3- difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl]triazolo[4,5-d]pyrimidin amine (example 22) the title nd was ed 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 5-(chloromethyl)- 1-methyl-1H-tetrazole. ): 361.3 (MH+).
Example 65 7-(3,3-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 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 2,2- dimethylpropanol with the use of Cs2CO3 instead of NaH. ): 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] triazolo[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 r purification. MS(m/e): 313.3 (MH+). c) -Difluoropyrrolidinyl)(2,2-dimethylpropoxy)[(1-methyltetrazol yl)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 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. ): 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 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 nd was prepared from 7-(3,3-difluoropyrrolidinyl)- 5-(2,2-dimethylpropoxy)-3H-triazolo[4,5-d]pyrimidine and 3-(chloromethyl)methyl- 1,2,5-oxadiazole. MS(m/e): 409.4 (MH+).
Example 68 7-(3,3-Difluoropyrrolidinyl)[[2-(trifluoromethyl)phenyl]methyl][(2S)-1,1,1- oropropanyl]oxytriazolo[4,5-d]pyrimidine a) 7-(3,3-Difluoropyrrolidinyl)[(4-methoxyphenyl)methyl][(1S)-2,2,2-trifluoro methyl-ethoxy]triazolo[4,5-d]pyrimidine In analogy to the ure 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(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 product 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)- -[(1S)-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 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 le 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+). e 70 3-[(3-Chloropyridinyl)methyl](3,3-difluoropyrrolidinyl)[(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)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 3-chloro omethyl)pyridine. MS(m/e): 464.3 (MH+).
Example 71 2-[[7-(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 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 7-(3,3-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 (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- 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)methyl-1,2,4-oxadiazole. ): 435.4 (MH+).
Example 73 -Difluoropyrrolidinyl)[(1-methyltetrazolyl)methyl][(2S)-1,1,1- trifluoropropanyl]oxytriazolo[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 prepared from 7-(3,3-difluoropyrrolidinyl)- -[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 5- (chloromethyl)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 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- (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 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)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and o-1,1,1- trifluoropropane. MS(m/e): 435.4 (MH+).
Example 76 3-[(1-Cyclopropyltetrazolyl)methyl](3,3-difluoropyrrolidinyl)[(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)- 5-[(1S)-2,2,2-trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidine and 5- (chloromethyl)cyclopropyl-1H-tetrazole. ): 461.4 (MH+).
Example 77 N-[(3S)[3-[(2-Chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide a) )[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 prepared 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) N-[(3S)[3-[(2-Chlorophenyl)methyl](2,2-dimethylpropoxy)triazolo[4,5- d]pyrimidinyl]pyrrolidinyl]acetamide In analogy to the ure 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 N-[(3S)[5-(2,2- ylpropoxy)-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 compound 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+). e 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 (example 22) the title nd 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 ed from N-[(3S)[5-chloro[(4- methoxyphenyl)methyl]triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide le 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 analogy to the ure 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 N-[(3S)[5-[(1S)-2,2,2- trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 1-(bromomethyl)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 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 N-[(3S)[5-[(1S)-2,2,2- trifluoromethyl-ethoxy]-3H-triazolo[4,5-d]pyrimidinyl]pyrrolidinyl]acetamide and 1-(bromomethyl)(trifluoromethyl)benzene. ): 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 yl)triazolo[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 mixture was concentrated and the residue was subjected to purification by preparative HPLC on reversed phase g 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 procedure 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 2,2,2- trifluoroethanethiol. MS(m/e): 465.2 (MH+).
Example 84 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 ed from 5-chloro[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and propanethiol.
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 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- ropyrrolidinyl)triazolo[4,5-d]pyrimidine (example 8, step a) and 2- methylpropanethiol. MS(m/e): 439.3 (MH+).
Example 86 3-[(2-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 e was evaporated and the e 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 26 mg (29 %) of the title compound. ): 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] (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 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] ifluoropyrrolidinyl)ethylsulfonyltriazolo[4,5-d]pyrimidine (example 86) the title compound was ed from 5-benzylsulfanyl[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)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 procedure described for the synthesis of 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)propanylsulfanyltriazolo[4,5-d]pyrimidine h oxidation with MCPBA.
MS(m/e): 457.3 (MH+).
Example 89 2-[3-[(2-Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5-d] pyrimidinyl]sulfanylethanol 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 2- mercaptoethanol. MS(m/e): 427.2 (MH+). e 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 nd 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 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 butanethiol at elevated temperature in DMF. ): 439.2 (MH+).
Example 92 Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methylpropylsulfanyl)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 ed 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 y 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-butylsulfanyl[(2-chlorophenyl)methyl](3,3- difluoropyrrolidinyl)triazolo[4,5-d]pyrimidine through oxidation with MCPBA. ): 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 compound was prepared from chlorophenyl)methyl](3,3-difluoropyrrolidin- 1-yl)(2-methylpropylsulfanyl)triazolo[4,5-d]pyrimidine through 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] (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 through ion with MCPBA. MS(m/e): 473.2 (MH+).
Example 96 3-[(2-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 nd 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) Chlorophenyl)methyl](3,3-difluoropyrrolidinyl)(2- methoxyethylsulfonyl)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 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+). e 97 N-[(3S)[5-(tert-butylamino)[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin yl]pyrrolidinyl]acetamide 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 N-[(3S)[5-(tert-butylamino)- azolo[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 determine the activity of the compounds of a I: Radioligand binding assay The affinity 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 (Perkin Elmer) as radioligand, respectively. Binding was performed in binding buffer (50 mM Tris, 5 mM MgCl2, 2.5 mM EDTA, and 0.5% l) 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 g. The reaction was terminated by rapid filtration through microfiltration plates coated with 0.5% polyethylenimine (UniFilter GF/B filter plate; d). Bound radioactivity was analyzed for Ki using nonlinear sion 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 ty 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 ion solutions (20 µM mAb Alexa700- cAMP 1:1, and 48 µM RutheniumAHA-cAMP) and shaken for 2h at room ature.
The time-resolved energy transfer is measured by a TRF reader (Evotec Technologies GmbH), equipped with a ND:YAG laser as excitation source. The plate is measured twice with the excitation at 355 nm and at the emission with a delay of 100 ns and a gate of 100 ns, total exposure time 10s at 730 (bandwidth30 nm) or 645 nm (bandwidth 75 nm), respectively. The FRET signal is calculated as follows: FRET = T730-Alexa730-P(T645- B645) with P = Ru730-B730/Ru645-B645, where T730 is the test well measured at 730 nM, T645 is the test well measured at 645 nm, B730 and B645 are the buffer controls at 730 nm and 645 nm, respectively. cAMP t is determined from the function of a standard curve spanning from 10 µM to 0.13 nM cAMP.
EC50 values were determined using Activity Base analysis (ID Business Solution, Limited). The EC50 values for a wide range of cannabinoid ts ted from this assay were in agreement with the values published in the scientific literature.
The compounds of the invention are CB2 receptor agonists with EC50 below 1 μM and selectivity versus CB1 in the corresponding assay of at least 10 fold. Particular compound of the invention are CB2 or agonists with EC50 below 0.05 μM and selectivity versus CB1 in the corresponding assay of at least 500 fold.
For example, the following compounds showed the following human EC50 values in the functional cAMP assay bed 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 ning the following ingredients 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 te 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 Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8 mg 1.6 mg The active ingredient is sieved and mixed with rystalline 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 kernels are lacquered with an aq. solution / suspension of the above mentioned film coat.
Example B es ning 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 ons can have the following composition: Compound of formula (I) 3.0 mg Polyethylene glycol 400 150.0 mg Acetic acid q.s. ad pH 5.0 Water for 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 adjusted to 1.0 ml by addition of the al amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Claims (16)

Claims
1. A compound of formula (I) wherein 5 R1 is haloalkyl, enyl, alkoxyphenyl, 1,2,5-oxadiazolyl, haloalkylphenyl, ulfonylphenyl, halopyridinyl or alkyltetrazolyl; R2 is piperidinyl, azetidinyl, pyrrolidinyl, or morpholinyl; R3 and R4 are independently selected from hydrogen, halogen, hydroxyl, alkylcarbonylamino and alkyl, provided that R3 and R4 are not both hydrogen 10 at the same time; and n is 1 or 2; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein R1 is halophenyl, haloalkylphenyl or alkylsulfonylphenyl. 15
3. A compound ing to claim 1 or 2, wherein R1 is chlorophenyl, trifluoromethylphenyl or methylsulfonylphenyl.
4. A compound according to any one of claims 1 to 3, wherein R3 and R4 are independently selected from en, halogen and hydroxyl.
5. A compound according to any one of claims 1 to 4, wherein one of R3 and R4 is 20 hydrogen and the other one is hydroxyl, or wherein R3 and R4 are both halogen at the same time.
6. A compound according to any one of claims 1 to 5, 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.
7. A nd according to any one of claims 1 to 6 selected from 5 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; chlorophenyl)methyl](3,3-difluoropyrrolidinyl)pyrrolidin yltriazolo[4,5-d]pyrimidine; 10 4-[3-[(2-chlorophenyl)methyl](3,3-difluoropyrrolidinyl)triazolo[4,5- d]pyrimidinyl]morpholine; (3S)[3-[(2-chlorophenyl)methyl]morpholinyltriazolo[4,5-d]pyrimidin yl]methylpyrrolidinol; (3S)methyl[5-morpholinyl[[2- 15 (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; 20 (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- 25 d]pyrimidinyl]pyrrolidinol; (3R)methyl[3-[(3-methyl-1,2,4-oxadiazolyl)methyl]morpholin yltriazolo[4,5-d]pyrimidinyl]pyrrolidinol
8. A process for the preparation of a compound according to any one of claims 1 to 7, comprising one of the ing steps: (a) the reaction of a compound of formula (A1) N N R (A1) 5 in the presence of a compound of formula (A2) (CH2)n R R (A2) wherein R2 is pyl, cycloalkyl or alkenyl and R1, R3, R4 and n are as defined in any one of claims 1 to 7; (b) the on of a compound of formula (B1) H 2 N N R (CH2)n 10 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 defined in any one of claims 1 to 7; (c) the reaction of a compound of formula (C1) N N Cl (CH2)n R R in the presence of R2-H wherein R2 is piperidinyl, alkylamino, azetidinyl, idinyl, cycloalkylamino, alkyloxetanylamino, linyl, (cycloalkyl)(alkyl)amino, haloalkyloxy, , cycloalkylalkoxy, cycloalkyloxy, 5 oxetanyloxy, alkyloxetanylalkyloxy, alkynyloxy, alkoxyalkoxy, hydroxyalkyloxy, alkylsulfanyl, haloalkylsulfanyl, alkylsulfonyl, hydroxyalkylsulfanyl, hydroxyalkylsulfonyl or alkoxyalkylsulfonyl and wherein R1, R3, R4 and n are as defined in any one of claims 1 to 7.
9. A compound according to any one of claims 1 to 7 for use as eutically active 10 substance.
10. A pharmaceutical composition sing a compound in accordance with any one of claims 1 to 7 and a therapeutically inert carrier.
11. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related 15 macular degeneration, diabetic pathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel e, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, 20 myocardial infarction, systemic sclerosis, l injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or , regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
12. A compound according to any one of claims 1 to 7 for use in the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic 25 pathy, glaucoma, diabetes mellitus, inflammation, matory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic pathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, 5 regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
13. The compound ing to any one of claims 1 to 7, 9 and 12, substantially as herein bed with reference to any e thereof.
14. The process ing to claim 8, substantially as herein described with reference to 10 any example thereof.
15. The pharmaceutical composition according to claim 10, ntially as herein described with reference to any example thereof.
16. The use according to claim 11, substantially as herein described with reference to any example thereof. 15 ***
NZ756513A 2013-09-06 2014-09-03 Novel triazolo[4,5-d]pyrimidine derivatives NZ756513B2 (en)

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EP13183385.7 2013-09-06
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