HK1196361B - [1, 2, 3]triazolo[4,5-d] pyrimidine derivatives as agonists of the cannabinoid receptor 2 agonists - Google Patents
[1, 2, 3]triazolo[4,5-d] pyrimidine derivatives as agonists of the cannabinoid receptor 2 agonists Download PDFInfo
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Description
The present invention relates to organic compounds useful for therapy and/or prophylaxis in a mammal, and in particular to compounds which are preferred agonists of cannabinoid receptor 2. The compounds of formula (I) are particularly useful for the treatment or prophylaxis of, for example, pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
The invention relates in particular to compounds of the formula (I),
wherein the content of the first and second substances,
a is alkylene, hydroxyalkylene, -CH2C(O)-、-C(O)-、-SO2-or is absent;
R1is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, (halo) (haloalkyl) phenyl, (halo) (alkoxy) phenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl, haloheteroaryl, alkylheteroaryl, (alkyl) (alkylsulfonyl) heteroaryl, (halo) (alkylamino) heteroaryl, haloalkylheteroaryl, cycloalkylheteroaryl or nitro-benzo [1,2, 5 ] or]Oxadiazolyl aminoheteroaryl, wherein heterocyclyl is a three-to eight-membered carbocyclic ring containing at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridyl, pyrazolyl,Oxadiazolyl, furazanyl, tetrazolyl, triazolyl or oxypyridinyl;
R2is alkyl, alkyl halideA group, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, cycloalkylalkoxy, haloalkoxy, alkoxy or alkylamino;
R3is halogen or-NR4R5；
R4And R3One is hydrogen or alkyl and the other is alkyl or cycloalkyl;
or R4And R5Together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic group, wherein the heterocyclic group is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-6-azaspiro [3.3]]Heptyl, azetidinyl, thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa-6-azaspiro [3.4 ]]Octyl, 6-oxa-1-azaspiro [3.3]Heptyl, 2-oxa-5-aza-spiro [3.4 ]]Octyl radical, iso radicalOxazolidinyl, aziridinyl or dioxoisothiazolidinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, carboxy, alkoxyalkyl, cyano, and alkylcarbonylamino;
or a pharmaceutically acceptable salt or ester thereof.
Cannabinoid receptors are a class of cell membrane receptors belonging to the G protein-coupled receptor superfamily. There are currently two known subtypes, known as cannabinoid receptor 1(CB1) and cannabinoid receptor 2(CB 2). The CB1 receptor is expressed predominantly in the central nervous (i.e. amygdala cerebellum, hippocampus) system and in lesser amounts in the periphery. CB2 encoded by the CNR2 gene is expressed predominantly on cells of the immune system, such as macrophages and T-cells (Ashton, J.C. et al, Curr Neuropharmacol2007, 5(2), 73-80; Miller, A.M. et al, Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al, Curr PharmDes2008, 14(23), 2370-42), and peripherally in the gastrointestinal system (Wright, K.L. et al, Br J Pharmacol2008, 153(2), 263-70). The CB2 receptor is also widely distributed in the brain, where it is found primarily on microglia rather than neurons (Cabral, g.a. et al Br JPharmacol2008, 153 (2): 240-51).
Interest in agonists of the CB2 receptor has steadily increased over the past decade (there are currently 30-40 patent applications/years) due to the fact that several of the early compounds have shown beneficial effects in preclinical models of many human diseases, including chronic pain (Beltramo, m.mini Rev Med Chem2009, 9(1), 11-25), atherosclerosis (Mach, f. et al JNeuroendocrinol2008, 20Suppl1, 53-7), regulation of bone mass (Bab, i. et al Br jrmacol 2008 (153), (2), 182-8), neuroinflammation (Cabral, g.a. et al J leukooc 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, p. et al Br J rmacol2008, 153-62), system (akhmethyshi, a. et al, arherthia 2009, 60-36, rgzaz et al; rghyz et al), 48(9), 1050-6), liver fibrosis (gaulien, b. et al Gastroenterology2005, 128(3), 742-55; Munoz-Luque, J. et al J Pharmacol Exp Ther2008, 324(2), 475-83).
Ischemia/reperfusion (I/R) injury is the leading cause of tissue damage that occurs in conditions such as stroke, myocardial infarction, cardiopulmonary bypass and other vascular procedures, and organ transplantation, and is the major mechanism of end organ damage that complicates the circulatory shock process of various etiologies. All of these disorders are characterized by an interruption of normal blood supply, resulting in inadequate tissue oxygenation. Reoxygenation, e.g. reperfusion, is the final treatment to restore normal tissue oxygenation. But the lack of oxygen and nutrients from the blood produces a condition in which the restoration of circulation leads to further tissue damage. Reperfusion injury is caused in part by the inflammatory response of the damaged tissue. Leukocytes transported to the area by the newly regurgitated blood release large amounts of inflammatory factors such as interleukins and free radicals in response to tissue damage. The restored blood flow reintroduces intracellular oxygen, which damages cellular proteins, DNA, and plasma membranes.
Remote Ischemic Preconditioning (RIPC) represents a strategy to exploit the body's endogenous protective capacity against damage caused by ischemia and reperfusion. It describes the interesting phenomenon where transient non-lethal ischemia and reperfusion of one organ or tissue confers resistance to subsequent events of "lethal" ischemia reperfusion injury in distant organs or tissues. Despite several hypotheses, the actual mechanism by which transient ischemia and reperfusion of an organ or tissue confers protection is currently unknown.
The humoral hypothesis suggests various intracellular pathways for endogenous substances produced in distant organs or tissues (such as adenosine, bradykinin, opioids, CGRP, endocannabinoids, angiotensin I or some other not yet identified humoral factors) to enter the bloodstream and activate their respective receptors in the target tissues and thereby restore cardioprotection involved in ischemic preconditioning.
Recent data indicate that endocannabinoids and their receptors, in particular CB2, may be involved in pretreatment and contribute to the prevention of reperfusion injury through down-regulation of the inflammatory response (pocher, p. et al Br J Pharmacol2008, 153(2), 252-62). In particular, recent studies using CB2 tool agonists have shown the efficacy of this concept for reducing I/R damage in the heart (Defer, n. et al faeb J2009, 23(7), 2120-30), brain (Zhang, m. et al J Cereb Blood Flow Metab2007, 27(7), 1387-96), liver (Batkai, s. et al faeb J2007, 21(8), 1788-.
Furthermore, over the past years, increasing literature has shown that CB2 may also be of interest in subchronic and chronic situations. Specific up-regulation of CB1 and CB2 has been shown to be associated with CB 2-related expression in myofibroblasts, i.e. cells that are responsible for the progress of fibrosis, in animal models of chronic diseases associated with fibrosis (Garcia-Gonzalez, e. et al rheumatology (oxford)2009, 48(9), 1050-6; Yang, y. et al Liver Int2009, 29(5), 678-85).
Activation of the CB2 receptor by selective CB2 agonists has in fact been shown to produce an anti-fibrotic effect in diffuse systemic sclerosis (Garcia-Gonzalez, e. et al rheumatogy (oxford)2009, 48(9), 1050-6) and CB2 receptor has been shown to be a key target in experimental dermal fibrosis (akhmmetshina, a. et al Arthritis Rheum2009, 60(4), 1129-36) and in liver pathophysiology, including fibrosis associated with chronic liver disease (Lotersztajn, s. et al gastroentreol Clin Biol2007, 31(3), 255-8; Mallat, a. et al Expert op targets2007, 11(3), 403-9; Lotersztajn, s. et 2008 et Br J (Pharmacol), 286), 153-9).
The compounds of the present invention bind to and modulate the CB2 receptor and have reduced CB1 receptor activity.
In the present specification, the term "alkyl", alone or in combination, denotes a straight or branched alkyl group having 1 to 8 carbon atoms, in particular a straight or branched alkyl group having 1 to 6 carbon atoms, more in particular a straight or branched alkyl group having 1 to 4 carbon atoms. Straight and branched C1-C8Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyl groups, the isomeric hexyl groups, the isomeric heptyl groups and the isomeric octyl groups, in particular methyl, ethyl, propyl, butyl and pentyl groups, more particularly methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl and isopentyl groups. Particular examples of alkyl groups are methyl, ethyl and tert-butyl.
In the present specification, the term "alkylene", alone or in combination, denotes a straight-chain or branched alkylene group having 1 to 8 carbon atoms, in particular a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Straight and branched C1-C8Examples of alkylene are methylene or ethylene, more particularly-CH2-、-CH2CH2-or-CH (CH)3)-。
The term "cycloalkyl", alone or in combination, denotes a cycloalkyl ring having 3 to 8 carbon atoms, and in particular a cycloalkyl ring having 3 to 6 carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular examples of cycloalkyl groups are cyclohexyl or cyclopropyl.
The term "alkoxy", alone or in combination, denotes a group of formula alkyl-O-, wherein the term "alkyl" has the meaning given before, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, especially methoxy.
The term "oxy", alone or in combination, denotes an-O-group.
The term "halogen" or "halo", alone or in combination, denotes fluorine, chlorine, bromine or iodine and especially fluorine, chlorine or bromine, more especially fluorine and chlorine. The term "halo", in combination with another group, means that the group is substituted with at least one halogen, in particular with one to five halogens, in particular one to four halogens, i.e. one, two, three or four halogens. Particular halogens are fluorine, bromine and chlorine, more particularly fluorine and chlorine.
The term "haloalkyl", alone or in combination, denotes an alkyl substituted by at least one halogen, in particular by one to five halogens, in particular one to three halogens. A particular "haloalkyl" is trifluoromethyl.
The term "haloalkoxy", alone or in combination, denotes an alkoxy group substituted by at least one halogen, in particular by one to five halogens, in particular one to three halogens. A particular "haloalkoxy" group is trifluoromethoxy.
The term "halophenyl", alone or in combination, denotes phenyl substituted by at least one halogen, in particular by one to three halogens. Particular "halophenyl" groups are chlorophenyl, dichlorophenyl, bromophenyl and chlorodifluorophenyl groups.
The terms "hydroxy" and "hydroxyl", alone or in combination, denote an-OH group.
The term "carbonyl", alone or in combination, denotes a-c (o) -group.
The term "carboxyl (carboxyl)" or "carboxyl (carboxyl)", alone or in combination, denotes a-COOH group.
The term "amino", alone or in combination, denotes a primary amino group (-NH)2) A secondary amino group (-NH-), or a tertiary amino group (-N-).
The term "sulfonyl", alone or in combination, denotes-SO2-a group.
R1Specific heterocyclic radicals in the definition of (1) are oxetanyl, tetrahydrofuranyl, 1-dioxo-1. lamda.6Thietanyl and 1, 1-dioxo-tetrahydro-1. lamda. (Thietanyl)6-thiophene.
Particular halopyrrolidinyl groups in the definition of R3 and R4 are difluoropyrrolidinyl and tetrafluoropyrrolidinyl.
The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, and which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. In addition, these salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyamine resins. The compounds of formula (I) may also be present in zwitterionic form. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are salts of hydrochloric, hydrobromic, sulfuric, phosphoric and methanesulfonic acids.
By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) that is similar to the metabolically labile ester and is capable of producing the parent compound of formula (I) in vivo is within the scope of the invention.
If one of the starting materials or the compound of formula (I) contains one or more functional Groups which are unstable or reactive under the reaction conditions of one or more reaction steps, suitable protecting Groups can be introduced before the critical step using methods known in the art (as described, for example, in T.W.Greene and P.G.M.Wuts in "Protective Groups in organic chemistry", 3 rd edition, 1999, Wiley, New York). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are t-butyloxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz) and p-methoxybenzyloxycarbonyl (Moz).
The compounds of formula (I) may contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to Cahn-Ingold-Prelog Convention, the asymmetric carbon atoms may be in either the "R" or "S" configuration.
The invention relates in particular to compounds of the formula (I)
Wherein
A is alkylene, hydroxyalkylene, -CH2C(O)-、-C(O)-、-SO2-or is absent;
R1is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl or haloheteroaryl, wherein heterocyclyl is a 3-to 8-membered carbocyclic ring containing at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridyl, pyrazolyl,oxadiazolyl or furazanyl;
R2is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl or cycloalkylalkoxy;
R3is halogen or-NR4R5；
R4And R5One is hydrogen or alkyl and the other is alkyl or cycloalkyl;
or R4And R5Together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic group, wherein the heterocyclic group is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-6-azaspiro [3.3]]Heptyl, azetidinyl, thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa-6-azaspiro [3.4 ]]Octyl, 6-oxa-1-azaspiro [3.3]Heptyl, 2-oxa-5-aza-spiro [3.4 ]]Octyl radical, isoOxazolidinyl, aziridinyl or dioxoisothiazolidinylAnd wherein substituted heterocyclyl is heterocyclyl substituted with 1 to 4 substituents independently selected from: alkyl, halogen, hydroxy, alkoxy, hydroxyalkyl, carboxy, alkoxyalkyl and cyano;
or a pharmaceutically acceptable salt or ester thereof.
The invention also relates in particular to the following:
a compound of formula (I) wherein A is alkylene, -CH2C (O) -or is absent;
a compound of formula (I) wherein a is alkylene;
a compound of formula (I) wherein A is methylene, ethylene or-CH (CH)3)-；
A compound of formula (I) wherein R1Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, hydroxyalkoxyphenyl, alkylsulfonylphenyl, alkylsulfonylaminophenyl, cyano, cycloalkyl, cycloalkylalkoxy, amino, heterocyclyl, alkylheterocyclyl, hydroxyheterocyclyl, alkylheterocyclyl, heteroaryl or haloheteroaryl, wherein heterocyclyl is a three-to eight-membered carbocyclic ring containing at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridyl, pyrazolyl, C,Oxadiazolyl or furazanyl;
a compound of formula (I) wherein R1Is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, cycloalkyl, oxetanyl or pyridyl;
a compound of formula (I) wherein R1Is trifluoromethyl, phenyl, chlorophenyl, bromophenyl, cyanophenyl, cyclohexyl or pyridyl;
formula (A), (B) andI) wherein R is1Is alkyl, haloalkyl, hydroxy, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, cycloalkyl, heterocyclyl, haloheteroaryl, or alkylheteroaryl, wherein heterocyclyl is oxetanyl, and wherein heteroaryl is pyridyl or furazanyl;
a compound of formula (I) wherein R1Is alkyl, haloalkyl, hydroxy, alkoxy, phenyl, halophenyl, alkoxyphenyl, haloalkylphenyl, haloalkoxyphenyl, cyanophenyl, cycloalkyl, oxetanyl, pyridyl, halopyridyl or alkylfurazanyl;
a compound of formula (I) wherein R1Is trifluoromethyl, phenyl, chlorophenyl, bromophenyl, cyanophenyl, cyclohexyl, pyridyl, chloropyridyl, methylfurazanyl or trifluoromethylphenyl;
a compound of formula (I) wherein R2Is an alkyl group;
a compound of formula (I) wherein R2Is a tert-butyl group;
a compound of formula (I) wherein R3is-NR4R5；
A compound of formula (I) wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl or halopyrrolidinyl;
a compound of formula (I) wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl or difluoropyrrolidinyl;
a compound of formula (I) wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl, halopyrrolidinyl or hydroxypyrrolidinyl; and
a compound of formula (I) wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl, difluoropyrrolidinyl or hydroxypyrrolidinyl.
The invention also relates in particular to compounds of formula (I) selected from
5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -ethanol;
5-tert-butyl-2-cyclohexylmethyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 3-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 4-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 5-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 6-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-2-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-3-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-4-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,2, 2-trifluoro-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4, 5-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3, 6-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (2-bromo-benzyl) -5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -benzonitrile;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-phenethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-phenyl-ethanone;
5-tert-butyl-2- [ (R) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [ (S) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-5-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine; and
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-oxetan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine.
The invention also relates in particular to compounds of formula (I) selected from
5-tert-butyl-2- (2, 6-dichloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 5-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2,4]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- [2- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [2- (3-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [2- (4-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 4-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (R) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (S) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (2-chloro-phenyl) -ethanone;
5-tert-butyl-2- (2, 3-dichloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-2-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-oxetan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (3-chloro-phenyl) -ethanone;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (4-chloro-phenyl) -ethanone;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-3-yl-ethanone;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,3, 6-trichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-6-fluoro-3-methoxy-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-3-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-4-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 3-dichloro-6-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-1 λ 6-thietane-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-2-yl-ethanone;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3,4]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-4-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,2,4]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methanesulfonyl-4-methyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
{3- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -5-chloro-pyridin-4-yl } -dimethyl-amine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 3-dichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-1-oxy-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,2, 4)]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- { 5-tert-butyl-2- [2- (7-nitro-benzo [1,2, 5 ] benzo]Oxadiazol-4-ylamino) -pyridin-3-ylmethyl]-2H-[1，2，3]Triazolo [4,5-d]Pyrimidin-7-yl } -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(2S,3S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol;
(2S,3S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol;
5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-methyl- [1,2,4]]Oxadiazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-methanesulfonyl-benzyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [2- (2-chloro-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [5- (2,2, 2-trifluoro-ethoxy) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [2- (2-chloro-benzyl) -5-isopropoxy-2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
- Λ/- { (S) -1- [2- (2-chloro-benzyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (3-chloro-pyridin-2-ylmethyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
- Λ/- { (S) -1- [2- (2-chloro-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [ 5-tert-butylamino-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide; and
(S) -1- [ 5-tert-butylamino-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol.
The invention also relates in particular to compounds of formula (I) selected from
5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2-cyclohexylmethyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-4-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,2, 2-trifluoro-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (2-bromo-benzyl) -5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -benzonitrile;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-phenethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine; and
5-tert-butyl-2- [ (R) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine.
The invention also relates in particular to compounds of formula (I) selected from
5-tert-butyl-2- (4-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-4-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine; and
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol.
The preparation of the compounds of formula (I) according to the invention can be carried out in a sequential or convergent synthetic route. The synthesis of the compounds of the present invention is shown in the following scheme. The skills required to carry out the reaction and to purify the resulting product are known to those skilled in the art. The substituents and symbols used in the following description of the process have the meanings given above, unless indicated to the contrary. More specifically, the compounds of formula (I) may be prepared by the methods given below, by the methods given in the examples, or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to the person skilled in the art. Furthermore, for the reaction conditions described in the literature which influence the reaction see, for example: comprehensive organic transformations: AGuide to Functional Group precursors, 2 nd edition, RichardC.Larock. John Wiley & Sons, New York, NY, 1999). The inventors have found it convenient to carry out the reaction in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent employed, provided that it does not adversely affect the reaction or the reagents involved and that it can dissolve the reagents at least to some extent. The reaction can take place over a wide temperature range, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reaction at a temperature in the range of from-78 ℃ to reflux. The time required for the reaction may also vary widely, depending on a number of factors, in particular the reaction temperature and the nature of the reagents. However, a time of 0.5 hours to several days will generally be sufficient to obtain the intermediates and compounds. The reaction sequence is not limited to the one shown in the scheme, but the order of the reaction steps may be freely changed depending on the starting materials and their respective reactivities. Starting materials are commercially available or can be prepared by methods analogous to those given below, by methods described in the literature cited in the specification or in the examples, or by methods known in the art.
a) Halide II is commercially available or can be synthesized according to methods known in the art. These halides II are conveniently reacted with sodium azide in a suitable solvent such as acetonitrile, ethanol or DMF to provide azide derivatives III.
b) Triazole derivatives IV can be prepared by the [2+3] cycloaddition of azide derivative III with 2-cyanoacetamide in the presence of a suitable base such as sodium methoxide or sodium ethoxide in a suitable solvent such as methanol, ethanol or DMF.
c) Triazole derivative V can be obtained by acylation of IV with an acid halide in the presence of a base such as DIEA, DMAP, pyridine or the like.
d) Triazolopyrimidine derivatives VI can be prepared by reaction of triazole derivatives V in bases such as KHCO3，Na2CO3And water in the presence or absence of solvents such as methanol, ethanol, bisIntramolecular cyclization in the case of alkanes and toluene.
e) Chloride VII may be reacted with a chlorinating agent such as POCl via VI3，SOCl2Or (COCl)2In the presence of a suitable base such as N, N-diethylaniline, lutidine, or pyridine.
f) VII is conveniently reacted with various nucleophiles, especially amines, in the presence of a suitable base such as triethylamine, DIEA or DBU in a suitable solvent such as acetonitrile, methanol, toluene or DMF to obtain the triazolo-pyrimidine derivative VIII.
g) Deprotection of VIII is carried out under suitable conditions, in the case of PG ═ MPM under acidic conditions (TFA, etc.), using Pd catalysts for hydrogenation or oxidative cleavage (DDQ or CAN, etc.) to give IX.
h) Triazole derivatives IX are conveniently reacted with halides (or sulfonates) in a suitable base such as DIEA, DBU, K2CO3Or Cs2CO3In particular Ag2SO4In the presence of a solvent such as DMF, bisIn an alkane or toluene, or alternatively with an alcohol under Mitsunobu reaction conditions using a suitable diazodicarboxylate (DEAD, DIAD, etc.) and a phosphine such as PBu3Or PPh3In a suitable solvent such as THF, DCM, toluene to provide the final triazolo-pyrimidine derivative I.
The present invention therefore also relates to a process for the preparation of a compound of formula (I), which process comprises reacting a compound of formula (A)
At R1In the presence of A-X and a base, or in the presence of R1-A-OH in the presence of a catalyst under three different conditions, wherein A and R1To R3Is the same as defined above and wherein X is halogen or SO2。
The reaction conditions of step h) above can thus be used in the process of the invention.
The invention also relates to compounds of formula (I) prepared according to the process of the invention.
The invention also relates to compounds of formula (I) for use as therapeutically active substances.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
The invention relates in particular to:
the compounds of formula (I) are useful for the treatment or prophylaxis of pain, atherosclerosis (atherosclerosis), age-related macular degeneration (age-related macular degeneration), diabetic retinopathy (diabetic retinopathy), glaucoma (glaucoma), diabetes mellitus (diabetes mellitus), inflammation (inflammation), inflammatory bowel disease (inflammatory bowel disease), ischemia-reperfusion injury (ischemin), acute liver failure (acute liver failure), liver fibrosis (liver fibrosis), lung fibrosis (lung fibrosis), kidney fibrosis (kidney fibrosis), systemic fibrosis (systemic fibrosis), acute allograft rejection (heart transplant rejection), chronic allograft nephropathy (chronic allograft failure), myocardial ischemia (myocardial infarction), myocardial infarction (myocardial infarction), use of systemic sclerosis (systemic sclerosis), thermal injury (thermal injury), burn (burning), hypertrophic scars (hypertonicscars), keloids (keloids), gingivitis pyrexia (gingivitis pyrexia), liver cirrhosis (liver cirrhosis) or tumors, regulation of bone mass, neurodegeneration (neuro-degeneration), stroke (stroke), transient ischemic attack (transient ischemic attack) or uveitis (uveitis);
use of a compound according to formula (I) in the manufacture of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis;
a compound of formula (I) for use in the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney fibrosis, systemic fibrosis, acute allograft rejection, chronic allograft nephropathy, diabetic nephropathy, glomerulonephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis; and
a 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 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, 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 compound of formula (I) to a patient in need thereof.
The use of a compound of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors is a further object of the present invention.
The use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of chronic pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors is a further object of the present invention.
The invention also relates to compounds of formula (I) for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors.
The invention relates in particular to compounds of formula (I) for use in the treatment or prevention of ischemia, reperfusion injury, liver fibrosis or kidney fibrosis, in particular ischemia or reperfusion injury.
The invention further relates to compounds of formula (I) prepared by the process according to the invention.
A method for the treatment or prophylaxis of pain, in particular chronic pain, atherosclerosis, regulation of bone mass, inflammation, ischemia, reperfusion injury, systemic fibrosis, liver fibrosis, lung fibrosis, kidney fibrosis, chronic allograft nephropathy, congestive heart failure, myocardial infarction, systemic sclerosis, glomerulonephropathy, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia, liver cirrhosis or tumors, which method comprises administering an effective amount of a compound of formula (I), is also an object of the present invention.
Another embodiment of the present invention provides pharmaceutical compositions or medicaments comprising a compound of the present invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the present invention for preparing such compositions and medicaments. In one example, the compound of formula (I) may be formulated as follows: the galenical administration form is prepared by mixing at ambient temperature, at a suitable pH, and at the desired degree of purity, with a physiologically acceptable carrier, i.e. a carrier which is non-toxic to the recipient at the dosages and concentrations employed. The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably anywhere in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH5. In another embodiment, the compounds of formula (I) are sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.
The compositions are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to be considered herein include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the timing of administration, and other factors known to the practitioner.
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 topical treatment is desired, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
The compounds of the present invention may be administered in any convenient form of administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain conventional ingredients of pharmaceutical preparations such as diluents, carriers, pH adjusting agents, sweeteners, fillers, and other active agents.
Typical formulations are prepared by mixing a compound of the invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard c, et al, Ansel's pharmaceutical dosage Forms and Drug Delivery systems. Lippincott, Williams & Wilkins, 2004; gennaro, Alfonso r., et al Remington: the Science and Practice of pharmacy, Philadelphia: lippincott, Williams & Wilkins, 2000; and Rowe, Raymond. handbook of Pharmaceutical excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents (glidants), glidants, processing aids, colorants, sweeteners, flavoring agents, diluents, and other known additives to provide a superior presentation of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the preparation of the pharmaceutical product (i.e., a pharmaceutical product).
The invention will now be illustrated by the following examples which are not to be construed as limiting in nature.
Examples
Abbreviations
MS ═ mass spectrum; CAN ═ ceric ammonium nitrate; ac ═ acetyl; DIEA ═ N, N-diisopropylethylamine; DBU ═ 1, 8-diazabicyclo [5.4.0] undec-7-ene; DMF ═ dimethylformamide; HPLC ═ LC ═ high performance liquid chromatography; THF ═ tetrahydrofuran; TFA ═ trifluoroacetic acid; ph ═ phenyl; DCM ═ dichloromethane; MPM ═ p-methoxyphenylmethyl; DDQ ═ 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone; PMB ═ p-methoxy-benzyl; DIPEA ═ diisopropylethylamine.
Chiral separation of 1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3-methyl-pyrrolidin-3-ol (example 124, step a) gave the respective enantiomerically pure R and S derivatives. However, explicit stereochemical assignments are pending. Therefore, no stereochemical assignment was made to enantiomerically pure example 124-133.
Example 1
5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4, 5d ] pyrimidine
a) 5-amino-1- (4-methoxybenzyl) -1H-1,2, 3-triazole-4-carboxamide
A mixture of 1- (chloromethyl) -4-methoxybenzene (20.0g, 128mmol) and sodium azide (12.5g, 192mmol) in acetonitrile (255mL) was stirred in N2Refluxing for 5h under the atmosphere. The mixture was filtered and concentrated in vacuo. The residue was diluted in DCM and washed with H2O and brine, over Na2SO4Dried and concentrated in vacuo to give crude 1- (azidomethyl) -4-methoxybenzene. The residue was used for the next reaction without further purification.
A mixture of the crude residue, 2-cyanoacetamide (10.8g, 128mmol) and sodium ethoxide (8.71g, 128mmol) in ethanol (256mL) was placed in N2Refluxing for 21h under atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aqueous solution and filtered. The residue is taken up in H2The O wash and vacuum dried afforded 5-amino-1- (4-methoxybenzyl) -1H-1,2, 3-triazole-4-carboxamide as a light orange solid (26.5g, 84% over 2 steps). MS (m/e): 248.1 (MH)+)。
b) 5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7 (4H) -one
A mixture of 5-amino-1- (4-methoxybenzyl) -1H-1,2, 3-triazole-4-carboxamide (10.0g, 40.4mmol) and pivaloyl chloride (7.47mL, 60.7mmol) in pyridine (20.2mL) was reacted at 80 deg.C in N2Stirred under atmosphere for 2 h. Then, 8M aqueous sodium hydroxide (15.2mL, 121mmol) and methanol (20.2mL) were added to the reaction mixture. After stirring at 80 ℃ for 1h, the reaction mixture was poured into 1M aqueous HCl, extracted with diethyl ether, washed with 2M aqueous HCl, water and brine, and washed with Na2SO4Dried and concentrated in vacuo to provide a mixture of crude 1- (4-methoxybenzyl) -5-pivaloylamido-1H-1, 2, 3-triazole-4-carboxamide and N- (4-cyano-1- (4-methoxybenzyl) -1H-1,2, 3-triazol-5-yl) pivaloylamide. The residue was used in the next reaction without further purification.
Will be at H2Crude residue above and KHCO in O (242mL)3The mixture (12.1g, 121mmol) was refluxed for 18 h. The reaction mixture was poured into 1M aqueous HCl, extracted with EtOAc, washed with brine, and washed with Na2SO4Dried and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 10% to 70% EtOAc in heptane) to afford 5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7 (4H) -one (4.44g, 35% in 2 steps). MS (m)/e)：314.2(MH+)。
c)4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7 yl) morpholine
Reacting 5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7 (4H) -one (50.0mg, 160. mu. mol) and N, N-diethylaniline (50.8. mu.L, 319. mu. mol) in POCl3Mixture in (1000. mu.L, 10.9mmol) in N2Reflux under atmosphere for 4 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc and cooled H2O and brine, Na2SO4Dried and concentrated in vacuo to provide crude 5-tert-butyl-7-chloro-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]A pyrimidine. The residue was used in the next reaction without further purification.
A mixture of the crude residue, morpholine (28.0. mu.L, 320. mu. mol) and DIEA (55.9. mu.L, 320. mu. mol) in acetonitrile (250. mu.L) was stirred at room temperature overnight. The reaction mixture was passed through preparative HPLC (column: Gemini5umC18110A75x30mm. mobile phase: water (0.05% Et)3N): acetonitrile 45: 55% to 5: 95%. WL: flow rate at 280 nm: 30mL/min.) afforded the title compound as a white solid (47.7mg, 78% over 2 steps). MS (m/e): 383.4 (MH)+)。
d) 5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
A mixture of 4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) morpholine (49.0mg, 128. mu. mol) and TFA (1000. mu.L) was refluxed under an atmosphere of N2 for 8H. The reaction mixture was concentrated in vacuo to give crude 5-tert-butyl-7-morpholin-4-yl-3H- [1,2,3] triazolo [4,5-d ] pyrimidine. The residue was used for the next reaction without further purification.
The residue (85.3 μ)mol), a mixture of 1- (bromomethyl) -2-chlorobenzene (22.1 μ L, 171 μmol) and DBU (25.7 μ L, 171 μmol) in DMF (500 μ L) was stirred at rt overnight. The reaction mixture was passed through preparative HPLC (column: Gemini5um C18110A75x30mm. mobile phase: water (0.05% Et)3N): acetonitrile 65: 35% to 5: 95%. WL: 300 nm. Flow rate: 30 mL/min) to give the title compound as a white solid (8.0mg, 24%). MS (m/e): 387.4 (MH)+)。
Example 2
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 1, step d) the procedure described is analogous to that described for 5-tert-butyl-7-morpholin-4-yl-3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2-chloro-4-fluorobenzene the title compound was prepared and isolated as a white solid (5.1mg, 30%). MS (m/e): 405.4 (MH)+)。
Example 3
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a) 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) morpholine (example 1, step c) the procedure described was analogous to that described for 5-tert-butyl-7-chloro-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3, 3-difluoropyrrolidine hydrochloride the title compound was prepared and isolated as a white solid (5.1mg, 30%). MS (m/e): 405.4 (MH)+)。
b) 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
Reacting 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3]Triazolo [4,5-d]A mixture of pyrimidine (264mg, 656. mu. mol) and TFA (5.00mL) in N2Refluxing under atmosphere for 8 h. The reaction mixture was concentrated in vacuo to provide crude 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]A pyrimidine. The residue was used in the next reaction without further purification.
A mixture of the above residue fraction (41.0. mu. mol), iodoethane (6.63. mu.L, 82.0. mu. mol) and DBU (12.4. mu.L, 82.0. mu. mol) in DMF (250. mu.L) was stirred at room temperature overnight. The reaction mixture was passed through preparative HPLC (column: Gemini5um C18110A75x30mm. mobile phase: water (0.05% Et)3N): acetonitrile 60: 40% to 5: 95%. WL: flow rate at 300 nm: 30mL/min.) provided the title compound as a white solid (4.2mg, 33%). MS (m/e): 311.3 (MH)+)。
Example 4
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1-bromo-2-methoxyethane the title compound was prepared and isolated as a pale yellow gum (4.5mg, 32%). MS (m/e): 341.3 (MH)+)。
Example 5
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -ethanol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromoethanol the title compound was prepared and isolated as a white solid (1.9mg, 14%). MS (m/e): 327.3 (MH)+)。
Example 6
5-tert-butyl-2-cyclohexylmethyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Pyrimidines (fruit)Example 3, Synthesis of step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and (bromomethyl) cyclohexane the title compound was prepared and isolated as a white solid (6.1mg, 39%). MS (m/e): 379.4 (MH)+)。
Example 7
5-tert-butyl-2- (3-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -3-chlorobenzene the title compound was prepared and isolated as a white solid (4.8mg, 29%). MS (m/e): 407.4 (MH)+)。
Example 8
5-tert-butyl-2- (4-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -4-chlorobenzene the title compound was prepared and isolated as a white solid(5.1mg，31％)。MS(m/e)：407.4(MH+)。
Example 9
5-tert-butyl-2- (2, 3-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2, 3-dichlorobenzene prepared the title compound and isolated as a white solid (5.5mg, 30%). MS (m/e): 441.4 (MH)+)。
Example 10
5-tert-butyl-2- (2, 4-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2, 4-dichlorobenzene prepared the title compound and isolated as a white solid (5.3mg, 29%). MS (m/e): 441.4 (MH)+)。
Example 11
5-tert-butyl-2- (2, 5-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -1, 4-dichlorobenzene prepared the title compound and isolated as a white solid (4.6mg, 25%). MS (m/e): 441.4 (MH)+)。
Example 12
5-tert-butyl-2- (2, 6-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -1, 3-dichlorobenzene prepared the title compound and isolated as a white solid (5.8mg, 32%). MS (m/e): 441.4 (MH)+)。
Example 13
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2-chloro-4-fluorobenzene the title compound was prepared and isolated as a colourless gum (5.5mg, 32%). MS (m/e): 425.4 (MH)+)。
Example 14
5-tert-butyl-2- (2-chloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1-chloro-2- (chloromethyl) -3-fluorobenzene the title compound was prepared and isolated as a white solid (5.4mg, 31%). MS (m/e): 425.4 (MH)+)。
Example 15
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-2-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) pyridine hydrobromic acid the title compound was prepared and isolated as a white gum (5.0mg, 33%). MS (m/e): 374.4 (MH)+)。
Example 16
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-3-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) pyridine hydrochloride the title compound was prepared and isolated as a colorless gum (2.2mg, 14%). MS (m/e): 374.4 (MH)+)。
Example 17
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-4-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b)The procedure described is analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 4- (bromomethyl) pyridine hydrobromic acid the title compound was prepared and isolated as an orange solid (4.1mg, 27%). MS (m/e): 374.4 (MH)+)。
Example 18
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,2, 2-trifluoro-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2,2, 2-trifluoroethyl triflate the title compound was prepared and isolated as a pale yellow solid (3.0mg, 20%). MS (m/e): 365.3 (MH)+)。
Example 19
5-tert-butyl-2- (2-chloro-4, 5-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2-chloro-4, 5-difluorobenzene to prepare the title compoundAnd isolated as a colorless gum (6.2mg, 34%). MS (m/e): 443.4 (MH)+)。
Example 20
5-tert-butyl-2- (2-chloro-3, 6-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -3-chloro-1, 4-difluorobenzene prepared the title compound and was isolated as a white solid (7.0mg, 38%). MS (m/e): 443.4 (MH)+)。
Example 21
2- (2-bromo-benzyl) -5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1-bromo-2- (bromomethyl) benzene the title compound was prepared and isolated as a colorless gum (6.9mg, 37%). MS (m/e): 451.3 (MH)+)。
Example 22
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2- (trifluoromethyl) benzene the title compound was prepared and isolated as a colorless gum (8.5mg, 47%). MS (m/e): 441.4 (MN)+)。
Example 23
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (chloromethyl) -2-methoxybenzene the title compound was prepared and isolated as a colourless gum (6.6mg, 40%). MS (m/e): 403.4 (MH)+)。
Example 24
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2- (trifluoromethoxy) benzene the title compound was prepared and isolated as a pale yellow gum (7.3mg, 39%). MS (m/e): 457.4 (MH)+)。
Example 25
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -benzonitrile
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) benzonitrile the title compound was prepared and isolated as a white solid (6.1mg, 37%). MS (m/e): 398.3 (MH)+)。
Example 26
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-phenethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and (2-bromoethyl) benzene the title compound was prepared and isolated as a pale yellow gum (7.3mg, 46%). MS (m/e): 387.4 (MH)+)。
Example 27
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-phenyl-ethanone
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H-di- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromo-1-phenylethanone the title compound was prepared and the brown gum was isolated (0.8mg, 5%). MS (m/e): 401.4 (MH)+)。
Example 28
5-tert-butyl-2- [ (R) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3 at 0 deg.C]Triazolo [4,5-d]Pyrimidine (41.3. mu. mol), (S) -1- (2-chlorophenyl) ethanol (C.), (12.9mg, 82.6. mu. mol) and PPh3(21.7mg, 82.6. mu. mol) to a solution in THF (250. mu.L) was added DEAD (13.1. mu.L, 82.6. mu. mol). After stirring at room temperature for 2h, the reaction mixture was passed through preparative HPLC (column: Gemini5um C18110A75x30mm. mobile phase: water (0.05% Et)3N): acetonitrile 50: 50% to 5: 95%. WL: flow rate at 300 nm: 30mL/min.) provided the title compound as a white solid (3.5mg, 20%). MS (m/e): 421.4 (MH)+)。
Example 29
5-tert-butyl-2- [ (S) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
With 2- [ (R) -1- (2-chloro-phenyl) -ethyl-5-tert-butyl]-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 28) the procedure described is analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and (R) -1- (2-chlorophenyl) ethanol the title compound was prepared and isolated as a white solid (3.7mg, 21%). MS (m/e): 421.4 (MH)+)。
Example 30
5-tert-butyl-2- (2-chloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Pyrimidines (example 3, procedure)b) Analogously to the procedure described for the synthesis of (5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2-chloro-3-fluorobenzene the title compound was prepared and isolated as a pale yellow gum (4.9mg, 28%). MS (m/e): 425.3 (MH)+)。
Example 31
5-tert-butyl-2- (2-chloro-5-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -1-chloro-4-fluorobenzene the title compound was prepared and isolated as a pale yellow gum (4.0mg, 23%). MS (m/e): 425.3 (MH)+)。
Example 32
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-oxetan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-bromooxetane the title compound was prepared and isolated as a lightBrown solid (2.8mg, 20%). MS (m/e): 339.3 (MH)+)。
Example 33
5-tert-butyl-2- (2, 6-dichloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -1, 3-dichloro-4-fluorobenzene the title compound was prepared and isolated as a white solid. MS (m/e): 459.2 (MH)+)。
Example 34
5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -2-chloropyridine hydrobromide the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 408.3 (MH)+)。
Example 35
5-tert-butyl-2- (4-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 4-chloro-3- (chloromethyl) pyridine the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 408.3 (MH)+)。
Example 36
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-chloro-2- (chloromethyl) pyridine the title compound was prepared and isolated as a light brown gum. MS (m/e): 408.3 (MH)+)。
Example 37
5-tert-butyl-2- (2, 5-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2, 5-dichloro-3- (chloromethyl) pyridine the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 442.3 (MH)+)。
Example 38
5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3, 6-dichloro-2- (chloromethyl) pyridine the title compound was prepared and isolated as a light brown gum. MS (m/e): 442.3 (MH)+)。
Example 39
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 379.3 (MH)+)。
Example 40
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2,4]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -3-methyl-1, 2,4-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 379.3 (MH)+)。
EXAMPLE 41
5-tert-butyl-2- [2- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (2-bromoethyl) -2-chlorobenzene the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 421.3 (MH)+)。
Example 42
5-tert-butyl-2- [2- (3-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (2-bromoethyl) -3-chlorobenzene the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 421.3 (MH)+)。
Example 43
5-tert-butyl-2- [2- (4-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (2-bromoethyl) -4-chlorobenzene the title compound was prepared and isolated as a white solid. MS (m/e): 421.3 (MH)+)。
Example 44
5-tert-butyl-2- (2, 4-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -2, 4-dichloropyridine hydrobromide the title compound was prepared and isolated as a pale green solid. MS (m/e): 442.3 (MH)+)。
Example 45
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (R) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
Mixing 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine (11.6mg, 41.1. mu. mol), (S)) A mixture of-tetrahydrofuran-3-ol (7.24mg, 6.6. mu.l, 82.2. mu. mol) and triphenylphosphine (21.6mg, 82.2. mu. mol) was combined with THF (250. mu.l) to give a pale yellow solution. DEAD (14.3mg, 13.0. mu.l, 82.2. mu. mol) was added to the solution at 0 ℃. The reaction mixture was stirred at rt for 4 h. The crude material was eluted by preparative HPLC on reversed phase with a gradient formed from acetonitrile, water and NEt 3. The product containing fractions were evaporated to yield 3.1mg (21%) of the title compound as a colorless gum. MS (m/e): 353.3 (MH)+)。
Example 46
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (S) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (R) -tetrahydro-furan-3-yl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 45) the procedure described is analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and (R) -tetrahydrofuran-3-ol the title compound was prepared as a colorless gum. MS (m/e): 353.3 (MH)+)。
Example 47
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (2-chloro-phenyl) -ethanone
Mixing 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine (11.6mg, 41.1. mu. mol), 2-bromo-1- (2-chlorobenzeneYl) A mixture of ethanone (11.5mg, 7.19. mu.l, 49.3. mu. mol) and DIPEA (10.6mg, 14.4. mu.l, 82.2. mu. mol) was combined with DCM (250. mu.l) to give a pale yellow solution. The reaction mixture was stirred at room temperature for 4h and on reverse phase by preparative HPLC using a mixture of acetonitrile, water and NEt3The gradient formed elutes. The product containing fractions were evaporated to yield 1.9mg (11%) of the title compound as a yellow gum. MS (m/e): 435.3 (MH)+)。
Example 48
5-tert-butyl-2- (2, 3-dichloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -3, 4-dichloro-1-fluorobenzene the title compound was prepared and isolated as a white solid. MS (m/e): 459.3 (MH)+)。
Example 49
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidines (example 3, step b) the procedure described is analogous to that described by 5-Tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2- (methylsulfonyl) benzene the title compound was prepared and isolated as a white solid. MS (m/e): 451.3 (MH)+)。
Example 50
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-2-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (2-bromoethyl) pyridine hydrobromide the title compound was prepared and isolated as a colorless gum. MS (m/e): 388.3 (MH)+)。
Example 51
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-oxetan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (iodomethyl) -3-methyloxetane the title compound was prepared and isolated as a white solid. MS (m/e): 367.3 (MH)+)。
Example 52
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (3-chloro-phenyl) -ethanone
To react with p-2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3]Triazolo [4,5-d]Pyrimidin-2-yl]Synthesis of (E) -1- (2-chloro-phenyl) -ethanone (example 47) analogously to the procedure described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromo-1- (3-chlorophenyl) ethanone the title compound was prepared and isolated as a yellow solid. MS (m/e): 435.3 (MH)+)。
Example 53
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (4-chloro-phenyl) -ethanone
To react with p-2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3]Triazolo [4,5-d]Pyrimidin-2-yl]Synthesis of (E) -1- (2-chloro-phenyl) -ethanone (example 47) analogously to the procedure described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromo-1- (4-chlorophenyl) ethanone the title compound was prepared and isolated as a light yellow solid. MS (m/e): 435.3 (MH)+)。
Example 54
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-3-yl-ethanone
To react with p-2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3]Triazolo [4,5-d]Pyrimidin-2-yl]Synthesis of (E) -1- (2-chloro-phenyl) -ethanone (example 47) analogously to the procedure described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromo-1- (pyridin-3-yl) ethanone hydrobromide the title compound was prepared and isolated as a light yellow solid. MS (m/e): 402.3 (MH)+)。
Example 55
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,3, 6-trichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -1, 3, 4-trichlorobenzene the title compound was prepared and isolated as a light red solid. MS (m/e): 475.2 (MH)+)。
Example 56
5-tert-butyl-2- (2-chloro-3-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2-chloro-3- (trifluoromethyl) benzene the title compound was prepared and isolated as a white solid. MS (m/e): 475.3 (MH)+)。
Example 57
5-tert-butyl-2- (2-chloro-6-fluoro-3-methoxy-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -3-chloro-1-fluoro-4-methoxybenzene the title compound was prepared and isolated as a white solid. MS (m/e): 455.3 (MH)+)。
Example 58
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-3-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (2-bromoethyl) pyridine hydrobromide the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 388-3 (MH)+)。
Example 59
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-4-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 4- (2-bromoethyl) pyridine hydrobromide the title compound was prepared and isolated as a white solid. MS (m/e): 388.3 (MH)+)。
Example 60
5-tert-butyl-2- (2, 3-dichloro-6-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Pyrimidine (example 3, step b) SynthesisAnalogously to the procedure described, starting from 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -3, 4-dichloro-1- (trifluoromethyl) benzene the title compound was prepared and isolated as a white solid. MS (m/e): 509.3 (MH)+)。
Example 61
5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (bromomethyl) -3, 4-dichloropyridine hydrobromide the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 442.3 (MH)+)。
Example 62
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-1. lamda.6-thietane-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidines and 3-bromo-thietane 11-dioxide the title compound was prepared and isolated as a white solid. MS (m/e): 387.3 (MH)+)。
Example 63
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-tetrahydro-1. lamda.6-thiophen-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-bromo-tetrahydro-thiophene 1, 1-dioxide the title compound was prepared and isolated as a white solid. MS (m/e): 401.3 (MH)+)。
Example 64
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-2-yl-ethanone
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2-bromo-1- (pyridin-2-yl) ethanone hydrobromide the title compound was prepared and isolated as a brown solid. MS (m/e): 402.3 (MH)+)。
Example 65
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3,4]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (chloromethyl) -5-methyl-1, 3, 4-Diazole the title compound was prepared and isolated as a colorless gum. MS (m/e): 379.3 (MH)+)。
Example 66
5-tert-butyl-2- (3-chloro-pyridin-4-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 4- (bromomethyl) -3-chloropyridine hydrobromide the title compound was prepared and isolated as a yellow gum. MS (m/e): 408.3 (MH)+)。
Example 67
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,2,4]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) -5-methyl-1, 2,4-Diazole the title compound is prepared and isolated as a yellow gum. MS (m/e): 379.3 (MH)+)。
Example 68
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-tetrazole the title compound was prepared and isolated as a white solid. MS (m/e): 379.3 (MH)+)。
Example 69
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride the title compound was prepared and isolated as a colorless gum. MS (m/e): 378.3 (MH)+)。
Example 70
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methanesulfonyl-4-methyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (iodomethyl) -4-methyl-5- (methylsulfonyl) -4H-1,2, 4-triazole the title compound was prepared and isolated as a white solid. MS (m/e): 456.3 (MH)+)。
Example 71
{3- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -5-chloro-pyridin-4-yl } -dimethyl-amine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -5-chloro-N, N-dimethylpyridin-4-amine hydrobromide the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 451.4 (MH)+)。
Example 72
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a) 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and 4- (bromomethyl) -3- (trifluoromethyl) -1-trityl-1H-pyrazole and used in the subsequent steps without further purification.
b) 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
Crude 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidine and triethylsilane were stirred in TFA at room temperature for 3 h. The reaction mixture was concentrated in vacuo and eluted by preparative HPLC on reversed phase with a gradient formed from acetonitrile, water and NEt 3. The product containing fractions were evaporated to yield the title compound as a white solid. MS (m/e): 431.3 (MH)+)。
Example 73
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a) (S) -1- [ 5-tert-butyl-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7 yl) morpholine (example 1, step c) the procedure described was analogous to that described for 5-tert-butyl-3- (4-methoxybenzyl)Radical) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7 (4H) -one in POCl3After chlorination and nucleophilic substitution with (S) -pyrrolidin-3-ol, the title compound was prepared as a pale green viscous oil, which was used in subsequent steps without further purification.
b) Trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-yl-ester
A mixture of (S) -1- [ 5-tert-butyl-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol and triethylsilane in TFA was heated to 70 ℃ for 22H and evaporated to dryness. The residue was used in the subsequent step without further purification.
c) (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-esters and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole preparation of the title compound. After completion of the substitution reaction, methanol was added and the mixture was stirred at room temperature for 1h and then purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt 3. After evaporation of the product containing fractions, the title compound was isolated as a pale yellow gum. MS (m/e): 359.3 (MH)+)。
Example 74
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -3-methyl-1, 2,4-Diazole the title compound is prepared and isolated as a brown gum. MS (m/e): 359.3 (MH)+)。
Example 75
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 3-chloro-2- (chloromethyl) pyridine the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 388.3 (MH)+)。
Example 76
(S) -1- [ 5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 3, 6-dichloro-2- (chloromethyl) pyridine the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 422.3 (MH)+)。
Example 77
(S) -1- [ 5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 3- (bromomethyl) -2-chloropyridine hydrobromic acid the title compound was prepared and isolated as a light brown gum. MS (m/e): 388.3 (MH)+)。
Example 78
(S) -1- [ 5-tert-butyl-2- (2, 3-dichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 1- (bromomethyl) -2, 3-dichlorobenzene were prepared and isolated as light brown gum. MS (m/e): 421.3 (MH)+)。
Example 79
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 1- (bromomethyl) -2- (trifluoromethyl) benzene the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 421.3 (MH)+)。
Example 80
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 1- (bromomethyl) -2- (methylsulfonyl) benzene the title compound was prepared and isolated as a white solid. MS (m/e): 431.3 (MH)+)。
Example 81
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1, 3-dimethyl-1H-pyrazole the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 391.3 (MH)+)。
Example 82
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-1, 2, 3-triazole hydrochloride the title compound was prepared and isolated as a light yellow solid. MS (m/e): 378.3 (MH)+)。
Example 83
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) -4, 5-dimethyl-4H-1, 2, 4-triazole the title compound was prepared and isolated as a light yellow solid. MS (m/e): 392.3 (MH)+)。
Example 84
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-1-oxy-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) -2-methylpyridine 1-oxide the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 404.3 (MH)+)。
Example 85
(S) -1- [ 5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 2- (bromomethyl) -3, 4-dichloropyridine hydrobromide the title compound was prepared and isolated as a white solid. MS (m/e): 422.2 (MH)+)。
Example 86
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,2, 4)]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol
With para (S) -1- [ 5-tert-butyl-2-, (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 3- (chloromethyl) -5-methyl-1, 2,4-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 359.5(MH +).
Example 87
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 2- (chloromethyl) -5-methyl-1, 3, 4-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 359.5 (MH)+)。
Example 88
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1-methyl-1H-tetrazole the title compound was prepared and isolated as a yellow gum. MS (m/e): 359.3 (MH)+)。
Example 89
(S) -1- [ 5-tert-butyl-2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 358.2 (MH)+)。
Example 90
(S) -1- [ 5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1-methyl-1H-1, 2, 3-triazole hydrochloride the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 358.3 (MH)+)。
Example 91
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1, 3-dimethyl-1H-oxadiazole the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 371.3 (MH)+)。
Example 92
5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole the title compound was prepared and isolated as a red gum. MS (m/e): 405.3 (MH)+)。
Example 93
(S) -1- { 5-tert-butyl-2- [2- (7-nitro-benzo [1,2, 5 ] benzo]Oxadiazol-4-ylamino) -pyridin-3-ylmethyl]-2H-[1，2,3]Triazolo [4,5-d]Pyrimidin-7-yl } -pyrrolidin-3-ol
Reacting (S) -1- (5-tert-butyl-2- ((2-chloropyridin-3-yl) methyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl) pyrrolidin-3-ol (5.70mg, 14.7. mu. mol) (example 75), 7-nitrobenzo [ c][1，2，5]Diazol-4-amine (3.18mg, 17.6. mu. mol), Pd2(dba)3(1.35mg, 1.47. mu. mol), xanthphos (2.55mg, 4.41. mu. mol) and Cs2CO3(9.58mg, 29.4. mu. mol) in twoThe mixture in the alkane (500. mu.l) was heated to 120 ℃ (microwave) and stirred for 20 minutes. The crude material was filtered, concentrated and purified by preparative HPLC on reversed phase using a mixture of acetonitrile, water and NEt3The gradient formed elutes. After evaporation of the product-containing fractions, 3.1mg (40%) of the title compound were isolated as a red solid. MS (m/e): 532.4 (MH)+)。
Example 94
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 385.3 (MH)+)。
Example 95
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To (S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -pyrrolidin-3-ol (example 73) the procedure described is analogous to that described for trifluoro-acetic acid (S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl-ester and 5- (chloromethyl) -1, 3-dimethyl-1H-1, 2, 4-triazole the title compound was prepared and isolated as a colorless gum. MS (m/e): 372.3 (MH)+)。
Example 96
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (3, 3-difluoropyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1, 3-dimethyl-1H-1, 2, 4-triazole the title compound was prepared and isolated as a pale yellow gum. MS (m/e): 392.3 (MH)+)。
Example 97
(2S,3S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol
a) (2S,3S) -1- [ 5-tert-butyl-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7 yl) morpholine (example 1, step c) the procedure described was analogous to that described for 5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidines-7(4H) -one in POCl3After chlorination and nucleophilic substitution with (2S,3S) -2-hydroxymethyl-1-methyl-pyrrolidin-3-ol, the title compound was prepared as a pale yellow gum. MS (m/e): 413.4 (MH)+)。
b) Trifluoro-acetic acid (2S,3S) -1- (5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -2- (2,2, 2-trifluoro-acetyloxymethyl) -pyrrolidin-3-yl ester
A mixture of (2S,3S) -1- [ 5-tert-butyl-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol and triethylsilane in TFA was heated to 70 ℃ for 22H and evaporated to dryness. The residue was used in the subsequent step without further purification.
c) (2S,3S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for trifluoro-acetic acid (2S,3S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -2- (2,2, 2-trifluoro-acetyloxymethyl) -pyrrolidin-3-yl ester and 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole. After completion of the substitution reaction, methanol was added and the mixture was stirred at room temperature for 1h and then purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt 3. After evaporation of the product-containing fractions, the title compound was isolated as a pale yellow solid. MS (m/e): 415.4 (MH)+)。
Example 98
(2S,3S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol
To (2S,3S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Synthesis of (E) -2-hydroxymethyl-pyrrolidin-3-ol (example 97) the procedure described is analogous to that described for trifluoro-acetic acid (2S,3S) -1- (5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -2- (2,2, 2-trifluoro-acetoxymethyl) -pyrrolidin-3-yl ester and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole the title compound is prepared and isolated as a white solid. MS (m/e): 389.3 (MH)+)。
Example 99
5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a) 5-tert-butyl-3- (4-methoxy-benzyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Procedure described for the Synthesis of pyrimidin-7 yl) morpholine (example 1, step c)Similarly, from 5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Preparation of the title Compound from pyrimidin-7 (4H) -one in POCl3After chlorination and nucleophilic substitution with 3,3, 4, 4-tetrafluoro-pyrrolidine, it is a purple oil and is used in subsequent steps without further purification.
b) 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
A mixture of 5-tert-butyl-3- (4-methoxy-benzyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and triethylsilane in TFA was heated to 70 ℃ for 22H and evaporated to dryness. The residue was used in the subsequent step without further purification.
c) 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 415.3 (MH)+)。
Example 100
5-tert-butyl-2- (3-methyl- [1,2,4]]Oxadiazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -3-methyl-1, 2,4-Diazole the title compound is prepared and isolated as a pale yellow gum. MS (m/e): 415.3 (MH)+)。
Example 101
5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (chloromethyl) -5-methyl-1, 3, 4-Preparation of the title CompoundAnd isolated as a white solid. MS (m/e): 415.3 (MH)+)。
Example 102
5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-tetrazole the title compound was prepared and isolated as a light yellow solid. MS (m/e): 415.3 (MH)+)。
Example 103
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) -4, 5-dimethyl-4H-1, 2, 4-triazole hydrochloride the title compound was prepared and isolated as a white solid. MS (m/e): 428.3 (MH)+)。
Example 104
5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 5-tert-butyl-7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-1, 2, 3-triazole hydrochloride the title compound was prepared and isolated as a yellow gum. MS (m/e): 414.3 (MH)+)。
Example 105
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a) 5-tert-butyl-3- (4-methoxy-benzyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7 yl) morpholine (example 1, step c) the procedure described was analogous to that described for5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7 (4H) -one in POCl3By chlorination with 2-oxa-6-aza-spiro [3.3]]After nucleophilic substitution with heptane, the title compound was prepared and used in subsequent steps without further purification.
b) [1- (5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3-chloromethyl-azetidin-3-yl ] -methanol
Reacting 6- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl) -2-oxa-6-azaspiro [3.3]A mixture of heptane (361mg, 915. mu. mol) and palladium (II) chloride (81.1mg, 458. mu. mol) in MeOH (3.00mL) at room temperature in H2Stirring was carried out for 9h under an atmosphere of (1 atm, bubbling). At H2With N2After displacement, the reaction mixture was filtered with cotton, concentrated in vacuo and used in the subsequent step without further purification.
c) 5-tert-butyl-7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
A mixture of (1- (5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3- (chloromethyl) azetidin-3-yl) methanol (284mg, 915. mu. mol) and potassium tert-butoxide (205mg, 1.83mmol) in THF (3.00mL) was stirred at 0 ℃ to room temperature and at room temperature for 20H. The reaction mixture was filtered and concentrated in vacuo and used without further purification.
d) 5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (2-oxa-6-aza-spiro [3.3]]Hept-6-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole the title compound was prepared and isolated as a white solid. MS (m/e): 397.3 (MH)+)。
Example 106
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (2-oxa-6-aza-spiro [3.3]]Hept-6-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (chloromethyl) -4, 5-dimethyl-4H-1, 2, 4-triazole hydrochloride the title compound was prepared and isolated as a white solid. MS (m/e): 384.3 (MH)+)。
Example 107
5-tert-butyl-2- (2-methanesulfonyl-benzyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To form a crystalline form of the compound with respect to 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2，3]triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (2-oxa-6-aza-spiro [3.3]]Hept-6-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 1- (bromomethyl) -2- (methylsulfonyl) benzene the title compound was prepared and isolated as a white solid. MS (m/e): 443.3 (MH)+)。
Example 108
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 5-tert-butyl-7- (2-oxa-6-aza-spiro [3.3]]Hept-6-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-chloro-2- (chloromethyl) pyridine the title compound was prepared and isolated as a light brown gum. MS (m/e): 400.3 (MH)+)。
Example 109
(S) -1- [2- (2-chloro-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a)3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine-5, 7-diol
A mixture of 5-amino-1- (4-methoxybenzyl) -1H-1,2, 3-triazole-4-carboxamide (example 1, step a) (7.59g, 30.7mmol), diethyl carbonate (4.72g, 39.9mmol) and sodium ethoxide (3.76g, 55.3mmol) in ethanol (97.1mL) was heated to reflux overnight. The solid was filtered, washed with EtOH and dried to give 3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine-5, 7(4H,6H) -dione (8.542g, 15.6mmol, 50.9% yield), which was used in subsequent steps without further purification. MS (m/e): 272.0 (MH)+)。
b)5, 7-dichloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
Reacting 3- (4-methoxy-benzyl) -3H- [1,2,3]Triazolo [4,5-d]A mixture of pyrimidine-5, 7-diol (example 109, a) and N, N-diethylaniline (2.73mL) at 0 ℃ was treated with POCl3(44.4mL) and heated to 120 ℃ for 4 h. Adding excess POCl3The residue was removed by distillation and poured into 100mL of water/ice and extracted with DCM. The combined organic layers were washed with MgSO4Dried, filtered and evaporated. The title compound was used in the subsequent step without further purification.
c) (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
Mixing 5, 7-dichloro-3- (4-methoxy-benzyl) -3H- [1,2,3]Triazolo [4,5-d]A mixture of pyrimidine (example 109, b) (2.95g), (S) -pyrrolidinol (1.82g, 20.9mmol) and DIPEA (9.83g, 76.1mmol) in DCM was stirred at room temperature for 30 min. The mixture was poured into water and extracted with DCMCollecting and mixing the combined organic layers with MgSO4Dried, filtered and evaporated to give the crude title compound, which was used in the next step without further purification. MS (m/e): 361.3 (MH)+)。
d) (S) -1- [3- (4-methoxy-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
A mixture of 2,2, 2-trifluoroethanol (936mg, 9.35mmol) in THF was treated with NaH at room temperature for 1 h. Adding (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Pyrrolidin-3-ol (example 109, c) and the mixture was stirred at 100 ℃ for 2 h. The reaction mixture was poured into 1M HCl and extracted with EtOAc. The combined organic layers were washed with MgSO 24Dried above and concentrated in vacuo to give the crude title compound, which was used in the subsequent step without further purification. MS (m/e): 425.4 (MH)+)。
e) (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
Mixing (S) -1- [3- (4-methoxy-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Pyrrolidin-3-ol (example 109, d) was heated to 80 ℃ overnight in 4.57mL TFA and evaporated. The residue was treated with 1M NaOH and washed with EtOAc. The combined organic layers were evaporated to give the crude title compound, which was used in the subsequent step without further purification. MS (m/e): 305.2 (MH)+)。
f) (S) -1- [2- (2-chloro-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol and 1- (bromomethyl) -2-chlorobenzene the title compound was prepared. MS (m/e): 429.4 (MH)+)。
Example 110
(S) -1- [5- (2,2, 2-trifluoro-ethoxy) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol and 1- (bromomethyl) -2- (trifluoromethyl) benzene the title compound was prepared. MS (m/e): 463.4 (MH)+)。
Example 111
(S) -1- [2- (2-chloro-benzyl) -5-isopropoxy-2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a) Trifluoro-acetic acid (S) -1- (5-isopropoxy-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e), the title compound was prepared from (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, c) by nucleophilic substitution with isopropanol followed by cleavage of the 4-methoxybenzyl group with TFA and the crude product was used in the subsequent step.
b) (S) -1- [2- (2-chloro-benzyl) -5-isopropoxy-2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for trifluoro-acetic acid (S) -1- (5-isopropoxy-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl ester and 1- (bromomethyl) -2-chlorobenzene. MS (m/e): 389.3 (MH)+)。
Example 112
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a) 5-chloro-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, c) the title compound was prepared from 5, 7-dichloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and 3, 3-difluoro-pyrrolidine and was used in the subsequent step without further purification.
b)7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e), the title compound was prepared from 5-chloro-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 112, a) by nucleophilic substitution with 2, 2-dimethylpropan-1-ol and subsequent cleavage of the 4-methoxybenzyl group with TFA and the crude product was used in the subsequent step.
c)7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 409.4 (MH)+)。
Example 113
(R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a) (R) -1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol
To react with p-4- (5-tert-butyl-3- (4-methoxybenzyl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7 yl) morpholine/procedure described for the synthesis of example 1c) analogously to 3-benzyl-5-tert-butyl-7-chloro-triazolo [4,5-d]Pyrimidine and (R) -pyrrolidin-3-ol the title compound was prepared and isolated as a white foam. MS (m/e): 352.4 (MH)+)。
b) (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) pyrrolidin-3-ol
Mixing (R) -1- (3-benzyl-5-tert-butyl-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-ol hydrogenation on Pd/C and (R) -1- (5-tert-butyl-3H- [1,2, 3) obtained]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-ol with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogously reacted with 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 359.3 (MH)+)。
Example 114
1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a)1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of (R) -1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol (example 113, a) the title compound was prepared from 3-benzyl-5-tert-butyl-7-chloro-triazolo [4,5-d ] pyrimidine and pyrrolidin-3-ol and isolated as light yellow oil.
b)1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b)1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol was hydrogenated and subsequently reacted with 5- (chloromethyl) -1-methyl-1H-tetrazole and isolated as light yellow oil. MS (m/e): 359.3(MH +).
Example 115
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
a)7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 112, b) from 5-chloro-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 112, a) the title compound was prepared by nucleophilic substitution with (S) -1, 1, 1-trifluoro-propan-2-ol followed by cleavage of the 4-methoxybenzyl group with TFA, and the crude product is used in a subsequent step.
b)7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 3, step b) the title compound was prepared from 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and 1- (bromomethyl) -2- (trifluoromethyl) benzene. MS (m/e): 497.4(MH +).
Example 116
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
In analogy to the procedure described for the synthesis of 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 3, step b) the title compound was prepared from 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and 1- (bromomethyl) -2- (methylsulfonyl) benzene. MS (m/e): 507.4(MH +).
Example 117
2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-chloro-2- (chloromethyl) pyridine. MS (m/e): 464.4 (MH)+)。
Example 118
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for 7- (3, 3-bis)Fluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 2- (chloromethyl) -5-methyl-1, 3, 4-Diazole preparation of the title compound. MS (m/e): 435.4 (MH)+)。
Example 119
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidines
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -3-methyl-1, 2,4-Diazole preparation of the title compound. MS (m/e): 435.4 (MH)+)。
Example 120
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 435.3 (MH)+)。
Example 121
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole preparation of the title compound. MS (m/e): 435.3 (MH)+)。
Example 122
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 3-bromo-1, 1, 1-trifluoropropane the title compound was prepared. MS (m/e): 435.3 (MH)+)。
Example 123
2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for 7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidine and 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole. MS (m/e): 461.4 (MH)+)。
Example 124-a and example 124-b
(S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
a)1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3-methyl-pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of (R) -1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol (example 113, a) the title compound was prepared from 3-benzyl-5-tert-butyl-7-chloro-triazolo [4,5-d ] pyrimidine and 3-methyl-pyrrolidin-3-ol and separated by chiral HPLC to give (S) -1- (3-benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3-methylpyrrolidin-3-ol and (R) -1- (3- benzyl-5-tert-butyl-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -3-methylpyrrolidin-3-ol. The isolated enantiomerically pure intermediate had 39% and 36% yields.
b) (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 1- (bromomethyl) -2-chlorobenzene. MS (m/e): 401.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol hydrogenation and subsequent reaction with1- (bromomethyl) -2-chlorobenzene reaction. MS (m/e): 401.4 (MH)+)。
Example 125-a and example 125-b
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 1- (bromomethyl) -2- (trifluoromethyl) benzene. MS (m/e): 435.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 1- (bromomethyl) -2- (trifluoromethyl) benzene. MS (m/e): 435.4 (MH)+)。
Example 126-a and example 126-b
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 1- (bromomethyl) -2- (methylsulfonyl) benzene. MS (m/e): 445.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 1- (bromomethyl) -2- (methylsulfonyl) benzene. MS (m/e): 445.4 (MH)+)。
Example 127-a and example 127-b
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 3-chloro-2- (chloromethyl) pyridine. MS (m/e): 402.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 3-chloro-2- (chloromethyl) pyridine. MS (m/e): 402.4 (MH)+)。
Example 128-a and example 128-b
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 2- (chloromethyl) -5-methyl-1, 3, 4-And (4) carrying out oxadiazole reaction. MS (m/e):373.4(MH+)。
to (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 2- (chloromethyl) -5-methyl-1, 3, 4-And (4) carrying out oxadiazole reaction. MS (m/e): 373.4 (MH)+)。
Example 129-a and example 129-b
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 5- (chloromethyl) -3-methyl-1, 2,4-And (4) carrying out oxadiazole reaction. MS (m/e): 373.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 5- (chloromethyl) -3-methyl-1, 2,4-And (4) carrying out oxadiazole reaction. MS (m/e): 373.4 (MH)+)。
Example 130-a and example 130-b
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol hydrogenation and subsequent reaction with 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 373.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol hydrogenation and subsequent reaction with 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 373.4 (MH)+)。
Example 131-a and example 131-b
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 3- (bromomethyl) -4-methyl-1, 2,5-And (4) carrying out oxadiazole reaction. MS (m/e): 373.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]Hydrogenation of 3-methyl-pyrrolidin-3-ol and subsequent reaction with 3- (bromomethyl) -4-methyl-1, 2,5-And (4) carrying out oxadiazole reaction. MS (m/e): 373.4 (MH)+)。
Example 132-a and example 132-b
(S) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 3-bromo-1, 1, 1-trifluoropropane. MS (m/e): 373.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol is hydrogenated and subsequently reacted with 3-bromo-1, 1, 1-trifluoropropane. MS (m/e): 373.4 (MH)+)。
Example 133-a and example 133-b
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol and (R) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol hydrogenation and subsequent reaction with 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole. MS (m/e): 399.4 (MH)+)。
To (R) -1- (5-tert-butyl-3- ((1-methyl-1H-tetrazol-5-yl) methyl) -3H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidin-7-yl) pyrrolidin-3-ol (example 113, b) analogously to the procedure described for (R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol hydrogenation and subsequent reaction with 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole. MS (m/e): 399.4 (MH)+)。
Example 134
N- { (S) -1- [2- (2-chloro-benzyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
a) N- { (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
In analogy to the procedure described for the synthesis of (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, c) the title compound was prepared from 5, 7-dichloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine and (S) -N- [ pyrrolidin-3-yl-acetamide and used in the subsequent steps without further purification.
b) N- { (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e) the title compound was prepared from N- { (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide (example 134, a) by nucleophilic substitution with 2,2, 2-trifluoro-ethanol and subsequent cleavage of the 4-methoxybenzyl group with TFA, and the crude product is used in a subsequent step.
c) N- { (S) -1- [2- (2-chloro-benzyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for N- { (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-yl } -acetamide and 1- (bromomethyl) -2-chlorobenzene the title compound was prepared. MS (m/e): 458.4 (MH)+)。
Example 135
N- { (S) -1- [2- (3-chloro-pyridin-2-ylmethyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for N- { (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-yl } -acetamide and 3-chloro-2- (chloromethyl) pyridine. MS (m/e): 459.4 (MH)+)。
Example 136
Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
a) Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e) the title compound was prepared from 5-chloro-7- (3, 3-difluoro-pyrrolidin-1-yl) -3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidine (example 112, a) by nucleophilic substitution with tert-butylamine and subsequent cleavage of 4-methoxybenzyl group with TFA and the crude product was used in the subsequent step.
b) Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-5-yl]-amine and 1- (bromomethyl) -2- (trifluoromethyl) benzene the title compound was prepared. MS (m/e): 456.4 (MH)+)。
Example 137
Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-5-yl]-amine and 1- (bromomethyl) -2- (methylsulfonyl) benzene the title compound was prepared. MS (m/e): 466.4 (MH)+)。
Example 138
Tert-butyl- [2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
To 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-5-yl]-amine and 3-chloro-2- (chloromethyl) pyridine. MS (m/e): 423.3 (MH)+)。
Example 139
Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-5-yl]The title compound was prepared from amine and 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 394.4 (MH)+)。
Example 140
Tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described was analogous to that described for tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-5-yl]Amine and 3- (bromomethyl) -4-methyl-1, 2,5-Diazole preparation of the title compound. MS (m/e): 394.4 (MH)+)。
Example 141
N- { (S) -1- [2- (2-chloro-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
a) N- { (S) -1- [5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e) the title compound was prepared from N- { (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide (example 134, a) by nucleophilic substitution with (S) -1, 1, 1-trifluoro-propan-2-ol followed by cleavage by hydrogenation, and the crude product is used in a subsequent step.
b) N- { (S) -1- [2- (2-chloro-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Pyrimidine (example 3, step b) SynthesisAnalogously to the procedure described, a compound of formula N- { (S) -1- [5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-yl } -acetamide and 1- (bromomethyl) -2-chlorobenzene the title compound was prepared. MS (m/e): 484.4 (MH)+)。
Example 142
N- { (S) -1- [2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for N- { (S) -1- [5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -3H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-yl } -acetamide and 1- (bromomethyl) -2- (trifluoromethyl) benzene the title compound was prepared. MS (m/e): 518.5 (MH)+)。
Example 143
N- { (S) -1- [2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidines (example 3, step b) the procedure described is analogous to that described for N- { (S) -1- [5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -3H- [1,2,3]triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-yl } -acetamide and 1- (bromomethyl) -2- (methylsulfonyl) benzene the title compound was prepared. MS (m/e): 528.5 (MH)+)。
Example 144
N- { (S) -1- [ 5-tert-butylamino-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
a) N- [ (S) -1- (5-tert-butylamino-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-yl ] -acetamide
In analogy to the procedure described for the synthesis of (S) -1- [5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 108, e) the title compound was prepared from N- { (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide (example 134, a) by nucleophilic substitution with tert-butylamine followed by cleavage by hydrogenation, and the crude product is used in a subsequent step.
b) N- { (S) -1- [ 5-tert-butylamino-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for N- [ (S) -1- (5-tert-butylamino-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-yl]Preparation of-acetamide and 1- (bromomethyl) -2-chlorobenzeneThe title compound. MS (m/e): 443.4 (MH)+)。
Example 145
(S) -1- [ 5-tert-butylamino-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
a) (S) -1- (5-tert-butylamino-3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl) -pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of d) (S) -1- [3- (4-methoxy-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 109, d), the title compound was prepared from (S) -1- [ 5-chloro-3- (4-methoxy-benzyl) -3H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol (example 109, c) and tert-butylamine followed by cleavage of the PMB protecting group and used in subsequent steps without further purification.
b) (S) -1- [ 5-tert-butylamino-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol
To react with p-5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3]Triazolo [4,5-d]Synthesis of pyrimidine (example 3, step b) the procedure described is analogous to that described for (S) -1- (5-tert-butylamino-3H- [1,2, 3)]Triazolo [4,5-d]Pyrimidin-7-yl) -pyrrolidin-3-ol and 5- (chloromethyl) -1-methyl-1H-tetrazole. MS (m/e): 374.3 (MH)+)。
Example 146
Pharmacological testing
The following assays were performed to determine the activity of the compounds of formula I:
radioligand binding assays
Affinity of the compounds of the invention for cannabinoid CB1 receptor use suggested amounts of membrane preparations (PerkinElmer) of Human Embryonic Kidney (HEK) cells expressing the human CNR1 or CNR2 receptor each bound 1.5 or 2.6nM [ 3H) respectively]-CP-55,940(Perkin Elmer) was determined as radioligand. Binding to a binding buffer (50 mM Tris, 5mM MgCl2, 2.5mM EDTA for CB1 receptor, and 0.5% (wt/vol) fatty acid free BSA, pH7.4, and 50mM Tris, 5mM MgCl for CB2 receptor, in a total volume of 0.2ml22.5mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH7.4), shaking at 30 ℃ for 1 h. The reaction was terminated by rapid filtration through a 0.5% polyethyleneimine coated micro filter plate (UniFilter GF/B filter plate; Packard). Bound radioactivity was analyzed using non-linear regression analysis (Activity Base, ID Business Solution, Limited) for Ki for [3H]The Kd value of CP55,940 was determined from saturation experiments. The compounds of formula (I) show excellent affinity for the CB2 receptor, below 10 μ M, more particularly 1nM to 3 μ M and most particularly 1nM to 100 nM.
The activity (Ki) of the compounds according to formula I in the above assay is in particular 0.5nM to 10. mu.M, more in particular 0.5nM to 3. mu.M and most in particular 0.5nM to 100 nM.
cAMP assay
CHO cells expressing human CB1 or CB2 receptors were seeded 17-24 hours prior to the experiment at 50.000 cells/well in black 96-well plates with clear flat bottom (Corning Costar #3904), in DMEM (Invitrogen No.31331), supplemented with 1 HT, with 10% fetal bovine serum, and in a humidified incubator at 5% CO2And incubated at 37 ℃. The medium was exchanged with Krebs Ringer Bicarbonate buffer with 1mM IBMX and incubated at 30 ℃ for 30 minutes. The compound was added to a final assay volume of 100. mu.l and incubated at 30 ℃ for 30 minutes. Using the cAMP-Nano-TRF detection kit (Roche Diagnostics), by adding 50. mu.l lysis reagent (Tris, NaCl, 1.5% Triton X100, 2.5% NP40, 10% NaN)3) And 50. mu.l of detection solution (20. mu.M mAb Alexa700-cAMP 1: 1, and 48. mu.M Ruthenium-2-AHA-cAMP) were stopped and shaken at room temperature for 2 h. The time-resolved energy transfer was measured by a TRF reader (Evotec Technologies GmbH) equipped with an ND: YAG laser as excitation source. The plate was measured twice, excited at 355nm and emitted at 730 (bandwidth 30nm) or 645nm (bandwidth 75nm) respectively with a 100ns delay and a 100ns gate (gate), for a total exposure time of 10 s. The FRET signal is calculated as follows: FRET-T730-Alexa 730-P (T645-B645), P-Ru 730-B730/Ru645-B645, where T730 is the test well measured at 730nM, T645 is the test well measured at 645nM, and B730 and B645 are buffer controls at 730nM and 645nM, respectively. cAMP content is determined from a function spanning a standard curve from 10. mu.M to 0.1nM cAMP.
EC is determined using Activity Base analysis (ID Business Solution, Limited)50The value is obtained. EC for a broad range of cannabinoid agonists generated from this assay50The values are in agreement with the values disclosed in the scientific literature.
All compounds are CB2 agonists, the EC thereof50Less than 3uM, in particular less than 1uM, more in particular less than 0.5uM, and at least a 10-fold selectivity in the corresponding assay relative to CB 1.
For example, the following compounds show the following human EC in the above-described functional cAMP assay50The value:
β -arrestin translocation assay-PathHunter
TM
(DiscoveRx)
PathHunterTMβ -arrestin CHO-K1CNR1 cell line (catalog #93-0200C2) and β -arrestin CHO-K1CNR2 cell line (catalog #93-0706C2) were purchased from DiscoveRxC corporation, cell lines engineered to express a β -galactosidase EA fragment fused to a β -arrestin and a ProLink complement peptide fused to a receptor of interestTMProtein complementation assay (Discovex Corporation #93-0001) was performed according to the manufacturer's protocol. Assay plates were seeded to contain 7500(CNR1) and 10000(CNR2) cells in 20. mu.L cell plate reagent 2(discover #93-0563R2A) in 384 well plates (Corning Costar #3707, white, clear bottom). At 37 deg.C (5% CO)295% relative humidity) was incubated overnight, 5 μ l of test compound (1% final DMSO concentration) was added and incubation continued at 30 ℃ for 90 min. Detection reagents (12. mu.l) were then added and incubation continued at room temperature for 60 min. Then using Victor3A V reader (Perkin Elmer) analyzes the chemiluminescent signal of the plate.
Example A
Film-coated tablets containing the following ingredients can be prepared in a conventional manner:
| composition (I) | Each sheet is | |
| And (3) nucleus: | ||
| a compound of formula (I) | 10.0mg | 200.0mg |
| Microcrystalline cellulose | 23.5mg | 43.5mg |
| Hydrous lactose | 60.0mg | 70.0mg |
| Polyvinylpyrrolidone (Povidone) K30 | 12.5mg | 15.0mg |
| Sodium starch glycolate | 12.5mg | 17.0mg |
| Magnesium stearate | 1.5mg | 4.5mg |
| (nuclear weight) | 120.0mg | 350.0mg |
| Film coating: | ||
| hydroxypropyl methylcellulose | 3.5mg | 7.0mg |
| Polyethylene glycol 6000 | 0.8mg | 1.6mg |
| Talc | 1.3mg | 2.6mg |
| Iron oxide (yellow) | 0.8mg | 1.6mg |
| Titanium dioxide | 0.8mg | 1.6mg |
The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with an aqueous solution of polyvinylpyrrolidone. The granules were then mixed with sodium starch glycolate and magnesium stearate and compressed to obtain 120 or 350mg of cores, respectively. The core is coated with the aqueous solution/suspension of the film coating described above.
Example B
Capsules containing the following ingredients can be prepared in a conventional manner:
| composition (I) | Each capsule |
| A compound of formula (I) | 25.0mg |
| Lactose | 150.0mg |
| Corn starch | 20.0mg |
| Talc | 5.0mg |
The ingredients were sieved and mixed and filled into size 2 capsules.
Example C
The injection solution may have the following composition:
| a compound of formula (I) | 3.0mg |
| Polyethylene glycol 400 | 150.0mg |
| Acetic acid | In a proper amount to obtain pH5.0 |
| Water for injection | Adding to 1.0ml |
The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (a portion). The pH was adjusted to 5.0 by adding acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.
Claims (18)
1. A compound of formula (I)
Wherein
A is C1-8Alkylene, hydroxy C1-8Alkylene radical, -CH2C(O)-、-C(O)-、-SO2-or is absent;
R1is hydrogen, C1-8Alkyl, halo C1-8Alkyl, hydroxy, C1-8Alkoxy, halo C1-8Alkoxy, phenyl, halophenyl, C1-8Alkoxyphenyl, halo C1-8Alkylphenyl, halogeno C1-8Alkoxyphenyl, cyanophenyl, hydroxy C1-8Alkoxyphenyl radical, C1-8Alkylsulfonylphenyl radical, C1-8Alkylsulfonylaminophenyl, (halo) (halo C)1-8Alkyl) phenyl, (halo) (C)1-8Alkoxy) phenyl, cyano, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-8Alkoxy, amino, heterocyclic radical, C1-8Alkylheterocyclic group, hydroxyheterocyclic group, heteroaryl group, halogenated heteroaryl group, C1-8Alkyl heteroaryl, (C)1-8Alkyl) (C1-8Alkylsulfonyl) heteroaryl, (halo) (C)1-8Alkylamino) heteroaryl, halo C1-8Alkyl heteroaryl, C3-8Cycloalkyl heteroaryl or nitro-benzo [1,2, 5 ]]Oxadiazolyl aminoheteroaryl, wherein heterocyclyl is a three-to eight-membered carbocyclic ring containing at least one nitrogen or oxygen atom, and wherein heteroaryl is pyridyl, pyrazolyl,Oxadiazolyl, furazanyl, tetrazolyl, triazolyl or oxypyridinyl;
R2is C1-8Alkyl, halo C1-8Alkyl, hydroxy C1-8Alkyl radical, C1-8Alkoxy radical C1-8Alkyl, halo C1-8Alkoxy radical, C1-8Alkoxy or C1-8alkyl-NH-;
R3is halogen or-NR4R5；
R4And R5Together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic group, wherein the heterocyclic group is morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-oxa-6-azaspiro [3.3]]Heptyl, azetidinyl, thiazolidinyl, thiomorpholinyl, dioxothiomorpholinyl, oxazepanyl, 2-oxa-6-azaspiro [3.4]Octyl, 6-oxa-1-azaspiro [3.3]Heptyl, 2-oxa-5-aza-spiro [3.4 ]]Octyl radical, iso radicalOxazolidinyl, aziridinyl or dioxoisothiazolidinyl, and wherein substituted heterocyclyl is heterocyclyl substituted with one to four substituents independently selected from: c1-8Alkyl, halogen, hydroxy, C1-8Alkoxy, hydroxy C1-8Alkyl, carboxyl, C1-8Alkoxy radical C1-8Alkyl, cyano and C1-8An alkylcarbonylamino group;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein a is C1-8Alkylene radical, -CH2C (O) -or is absent.
3. The compound of claim 1 or 2, wherein a is C1-8An alkylene group.
4. The compound of claim 1 or 2, wherein A is methylene, ethylene, or-CH (CH)3)-。
5. The compound of claim 1 or 2, wherein R1Is C1-8Alkyl, halo C1-8Alkyl, hydroxy, C1-8Alkoxy, phenyl, halophenyl, C1-8Alkoxyphenyl, halo C1-8Alkylphenyl, halogeno C1-8Alkoxyphenyl, cyanophenyl, C3-8Cycloalkyl, heterocyclyl, haloheteroaryl or C1-8Alkylheteroaryl, wherein heterocyclyl is oxetanyl, and wherein heteroaryl is pyridyl or furazanyl.
6. The compound of claim 1 or 2, wherein R1Is C1-8Alkyl, halo C1-8Alkyl, hydroxy, C1-8Alkoxy, phenyl, halophenyl, C1-8Alkoxyphenyl, halo C1-8Alkylphenyl, halogeno C1-8Alkoxyphenyl, cyanophenyl, C3-8Cycloalkyl, oxetanyl, pyridyl, halopyridyl or C1-8Alkyl furazanyl.
7. The compound of claim 1 or 2, wherein R1Is trifluoromethyl, phenyl, chlorophenyl, bromophenyl, cyanophenyl, cyclohexyl, pyridyl, chloropyridyl, methylfurazanyl or trifluoromethylphenyl.
8. The compound of claim 1 or 2, wherein R2Is C1-8An alkyl group.
9. The compound of claim 1 or 2, wherein R2Is a tert-butyl group.
10. The compound of claim 1 or 2, wherein R3is-NR4R5。
11. The compound of claim 1 or 2, wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl, halopyrrolidinyl or hydroxypyrrolidinyl.
12. The compound of claim 1 or 2, wherein R4And R5Together with the nitrogen atom to which they are attached form morpholinyl, difluoropyrrolidinyl or hydroxypyrrolidinyl.
13. A compound according to claim 1 or 2, selected from
5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-ethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -ethanol;
5-tert-butyl-2-cyclohexylmethyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4-chloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 3-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 4-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 5-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 6-dichloro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-2-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-3-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-4-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,2, 2-trifluoro-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-4, 5-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3, 6-difluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (2-bromo-benzyl) -5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethoxy-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -benzonitrile;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-phenethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-phenyl-ethanone;
5-tert-butyl-2- [ (R) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [ (S) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-5-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-oxetan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 6-dichloro-3-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 5-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2,4]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- [2- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [2- (3-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [2- (4-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 4-dichloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (R) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (S) -tetrahydro-furan-3-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (2-chloro-phenyl) -ethanone;
5-tert-butyl-2- (2, 3-dichloro-6-fluoro-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-2-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-oxetan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (3-chloro-phenyl) -ethanone;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1- (4-chloro-phenyl) -ethanone;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-3-yl-ethanone;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,3, 6-trichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-3-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-chloro-6-fluoro-3-methoxy-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-3-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-pyridin-4-yl-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2, 3-dichloro-6-trifluoromethyl-benzyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-1 λ 6-thietane-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1, 1-dioxo-tetrahydro-1 λ 6-thiophen-3-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-yl ] -1-pyridin-2-yl-ethanone;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3,4]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-4-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,2,4]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methanesulfonyl-4-methyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
{3- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -5-chloro-pyridin-4-yl } -dimethyl-amine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-trifluoromethyl-1H-pyrazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3, 6-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-chloro-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 3-dichloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methyl-1-oxy-pyridin-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (3, 4-dichloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,2, 4)]Oxadiazol-3-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H-pyrazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- { 5-tert-butyl-2- [2- (7-nitro-benzo [1,2, 5 ] benzo]Oxadiazol-4-ylamino) -pyridin-3-ylmethyl]-2H-[1，2，3]Triazolo [4,5-d]Pyrimidin-7-yl } -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 5-dimethyl-2H- [1,2,4] triazol-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(2S,3S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol;
(2S,3S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -2-hydroxymethyl-pyrrolidin-3-ol;
5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-methyl- [1,2,4]]Oxadiazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3]A triazolo [ 4] group,5-d]a pyrimidine;
5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-methyl-3H- [1,2,3] triazol-4-ylmethyl) -7- (3,3, 4, 4-tetrafluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4, 5-dimethyl-4H- [1,2,4] triazol-3-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (2-methanesulfonyl-benzyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [2- (2-chloro-benzyl) -5- (2,2, 2-trifluoro-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [5- (2,2, 2-trifluoro-ethoxy) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
(S) -1- [2- (2-chloro-benzyl) -5-isopropoxy-2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- (2, 2-dimethyl-propoxy) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3]Triazolo [4,5-d]A pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
(S) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (5-methyl- [1,3, 4)]Oxadiazol-2-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3-methyl- [1,2, 4)]Oxadiazol-5-ylmethyl) -2H- [1,2,3]Triazolo [4,5-d]Pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (3,3, 3-trifluoro-propyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(S) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
(R) -1- [ 5-tert-butyl-2- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -3-methyl-pyrrolidin-3-ol;
- Λ/- { (S) -1- [2- (2-chloro-benzyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (3-chloro-pyridin-2-ylmethyl) -5- (2, 2-dimethyl-propoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2-methanesulfonyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
tert-butyl- [7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-5-yl ] -amine;
- Λ/- { (S) -1- [2- (2-chloro-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (2-trifluoromethyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [2- (2-methanesulfonyl-benzyl) -5- ((S) -2,2, 2-trifluoro-1-methyl-ethoxy) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide;
- Λ/- { (S) -1- [ 5-tert-butylamino-2- (2-chloro-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-yl } -acetamide; and
(S) -1- [ 5-tert-butylamino-2- (1-methyl-1H-tetrazol-5-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol.
14. A compound according to claim 1 or 2, selected from
5-tert-butyl-2- (2-chloro-benzyl) -7-morpholin-4-yl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2-cyclohexylmethyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-pyridin-4-ylmethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2,2, 2-trifluoro-ethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- (2-bromo-benzyl) -5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
2- [ 5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) - [1,2,3] triazolo [4,5-d ] pyrimidin-2-ylmethyl ] -benzonitrile;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2-phenethyl-2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- [ (R) -1- (2-chloro-phenyl) -ethyl ] -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (4-chloro-pyridin-3-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-2-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-7- (3, 3-difluoro-pyrrolidin-1-yl) -2- (4-methyl-furazan-3-ylmethyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine;
5-tert-butyl-2- (3-chloro-pyridin-4-ylmethyl) -7- (3, 3-difluoro-pyrrolidin-1-yl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidine; and
(S) -1- [ 5-tert-butyl-2- (2-trifluoromethyl-benzyl) -2H- [1,2,3] triazolo [4,5-d ] pyrimidin-7-yl ] -pyrrolidin-3-ol.
15. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (a)
At R1In the presence of A-X and a base, or in the presence of R1Reaction in the presence of A-OH under three conditions, in which A and R1To R3As defined in claim 1 and whereinX is halogen or SO2。
16. A compound according to any one of claims 1 to 14, when manufactured according to a process of claim 15.
17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a therapeutically inert carrier.
18. The use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, diabetes mellitus, 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, keloids, gingivitis pyrexia, liver cirrhosis or tumors, regulation of bone mass, neurodegeneration, stroke, transient ischemic attack or uveitis.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11190777.0 | 2011-11-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1196361A HK1196361A (en) | 2014-12-12 |
| HK1196361B true HK1196361B (en) | 2017-11-03 |
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