HK1214245B - Purine derivatives as cb2 receptor agonists - Google Patents
Purine derivatives as cb2 receptor agonists Download PDFInfo
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- HK1214245B HK1214245B HK16102012.2A HK16102012A HK1214245B HK 1214245 B HK1214245 B HK 1214245B HK 16102012 A HK16102012 A HK 16102012A HK 1214245 B HK1214245 B HK 1214245B
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Description
The present invention relates to organic compounds useful for therapy and/or prophylaxis in mammals, and in particular to compounds which are preferential agonists of cannabinoid receptor 2.
The invention relates in particular to compounds of the formula (I),
wherein
A is CH2，CH2CH2，CH2CO or absent;
R1is tert-butyl, tert-butylamino, 2, 2-dimethylpropoxy or halogen;
R2and R3Together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa-7-azaspiro [3.4]]Octyl, 2-oxa-6-azaspiro [3.3]Heptyl, azetidinyl, substituted azetidinyl, 2, 2-dioxo-2. lamda.6-thia-6-azaspiro [3.3]Heptyl or halo-5-azaspiro [2.4]]A heptyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from the group consisting of: halogen, hydroxy, alkyl, hydroxyalkyl, cyano, alkylcarbonylamino, alkylcarbonyloxy and haloalkyl, and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from: halogen, hydroxy, alkyl and haloalkyl; and is
R4Is hydrogen, phenyl, halophenyl, alkylphenyl, haloalkylphenyl, pyridyl, halopyridyl, cycloalkyl, alkylOxadiazolyl, oxolanyl, alkylTetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl, haloalkyl-1H-pyrazolyl or cycloalkylalkyltetrazolyl;
or a pharmaceutically acceptable salt or ester thereof.
The compounds of formula (I) are particularly useful for the treatment or prophylaxis of, for example, pain (pain), atherosclerosis (atherosclerosis), age-related macular degeneration, diabetic retinopathy (diabetic retinopathy), glaucoma (glaucoma), retinal vein occlusion (chronic retinal occlusion), retinopathy of prematurity (retinopathy of prematurity), ocular ischemic syndrome (ischemic syndrome), geographic atrophy (geographic atrophy), diabetes mellitus (diabetes mellitus), inflammation (inflammation), inflammatory bowel disease (inflammatory bowel disease), ischemia-reperfusion injury (ischemic-reperfusion injury), acute failure (acute liver failure), liver fibrosis (fibrosis), acute kidney failure (acute kidney transplant), chronic renal fibrosis (fibrosis), diabetic nephropathy (diabatic nephopathopathy), glomerulonephropathy (glomeronephopathopathy), cardiomyopathy (cardiomyopopathopathy), heart failure (heart failure), myocardial ischemia (myo-ischemic), myocardial infarction (myo-ischemic attack), systemic sclerosis (systemic sclerosis), thermal injury (thermal injury), burn (burning), hypertrophic scars (hypertrophic scars), keloids (keloids), gingivitis pyrexia, liver cirrhosis (liver cirrhosis) or tumors (tumors), regulation of bone mass (bone), amyotrophic lateral sclerosis (amyotropic sclerosis), multiple sclerosis (multiple sclerosis), Alzheimer's disease, Parkinson's disease, stroke (ischemic stroke), uveitis, multiple sclerosis (Parkinson's disease), Parkinson's disease, stroke (ischemic stroke).
The compounds of formula (I) are particularly useful for the treatment or prevention of diabetic retinopathy, retinal vein occlusion or uveitis.
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 Neuropharmacol 2007, 5(2), 73-80; Miller, A.M. et al, Br J Pharmacol2008, 153(2), 299-308; Centonze, D., et al, Curr PharmDes 2008, 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 J Pharmacol2008, 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/year) due to the fact that several of the early compounds have been shown to have beneficial effects in preclinical models of many human diseases, including chronic pain (Beltramo, m.mini Rev Med Chem 2009, 9(1), 11-25), atherosclerosis (Mach, f. et al J neuroendinor 2008, 20 Suppl 1, 53-7), regulation of bone mass (Bab, i. et al Br J Pharmacol2008, 153(2), 182-8), neuroinflammation (Cabral, g.a. et al J leukobio 2005, 78(6), 1192-7), ischemia/reperfusion injury (Pacher, p. et al Br J Pharmacol2008, 153(2), 252-62), systemic (hmetashishi, a. athena et al, rherit, 60 um (60), 4 m), akh), 1129-36; Garcia-Gonzalez, e, et al, rheumatology (oxford)2009, 48(9), 1050-6), liver fibrosis (Julien, b, et al, Gastroenterology 2005, 128(3), 742-55; Munoz-Luque, J. et al J Pharmacol Exp 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 Metab 2007, 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 Int 2009, 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 the CB2 receptor has been shown to be a key target in experimental dermal fibrosis (akhmmetshina, a. et al Arthritis Rheum 2009, 60(4), 1129-36) and in liver pathophysiology, including fibrosis associated with chronic liver disease (Lotersztajn, s. et al gastroentreol Clin Biol 2007, 31(3), 255-8; Mallat, a. et al Expert Opin Theragrets 2007, 11(3), 403-9; Loersztajn, s. 2008 et al Br J (2), 286-9).
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. A particular example of an alkyl group is methyl.
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, cyclobutaneyl, cyclopentyl and cyclohexyl, cycloheptyl and cyclooctyl. Particular examples of "cycloalkyl" are cyclopropyl and cyclohexyl, especially cyclohexyl.
The term "alkoxy", alone or in combination, denotes a group of formula alkyl-O-, wherein the term "alkyl" has the previously given meaning, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. A particular "alkoxy" group is methoxy.
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 "halogen" are fluorine and chlorine. At R2And R3In the definition of (1), fluorine is a particular halogen.
The term "haloalkyl", alone or in combination, denotes an alkyl substituted by at least one halogen, especially by 1 to 5 halogens, especially 1 to 3 halogens. A particular "haloalkyl" is trifluoromethyl.
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 "oxy", alone or in combination, denotes an-O-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-). A particular amino group is-NH-.
The term "aminocarbonyl", alone or in combination, denotes NH2-C(O) -, -NH-C (O) -or-N-C (O) -groups.
The term "carbonylamino", alone or in combination, denotes a-C (O) -NH-or-C (O) -N-group. A particular carbonylamino group is-C (O) -N-.
The term "sulfonyl", alone or in combination, signifies-S (O)2-a group.
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 the Cahn-Ingold-Prelog rule, the asymmetric carbon atom may be in either the "R" or "S" configuration.
The invention relates in particular to compounds of formula (I) wherein:
a is CH2，CH2CH2，CH2CO or absent;
R1is tert-butyl, tert-butylamino or 2, 2-dimethylpropoxy;
R2and R3Together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, alkylpiperazinyl, 2-oxa-7-azaspiro [3.4]]Octyl or 2-oxa-6-azaspiro [3.3]A heptyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from the group consisting of: halogen, hydroxy, alkyl, hydroxyalkyl, cyano andan alkylcarbonylamino group; and is
R4Is phenyl, halophenyl, alkylphenyl, haloalkylphenyl, pyridyl, halopyridyl, cycloalkyl, alkylOxadiazolyl, oxolanyl, alkyltetrazolyl, alkoxy, alkylsulfonylphenyl, haloalkyl, alkoxyphenyl, dioxothietanyl, cycloalkyltetrazolyl or haloalkyl-1H-pyrazolyl;
or a pharmaceutically acceptable salt or ester thereof.
The invention also relates in particular to:
a compound of formula (I) wherein A is CH2；
A compound of formula (I) wherein R1Is tert-butyl or 2, 2-dimethylpropoxy;
a compound of formula (I) wherein R1Is a tert-butyl group;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl group, a substituted pyrrolidinyl group, or a substituted azetidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from: halogen, hydroxy, hydroxyalkyl and cyano, and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from: halogen, hydroxy and haloalkyl;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl group, a substituted pyrrolidinyl group, or a substituted azetidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from: fluoro, hydroxy, hydroxymethyl and cyano, and wherein substituted azetidinyl is nitrogen heterocycle substituted with one or two substituents selected from the group consisting ofButyl group: fluorine, hydroxy and trifluoromethyl;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl, difluoropyrrolidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, cyanopyrrolidinyl, difluoroazetidinyl or (hydroxy) (trifluoromethyl) azetidinyl group;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form a substituted pyrrolidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from the group consisting of: halogen and hydroxy;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form a substituted pyrrolidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from the group consisting of: fluorine and hydroxyl;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached, form difluoropyrrolidinyl or hydroxypyrrolidinyl;
a compound of formula (I) wherein R2And R3Together with the nitrogen atom to which they are attached form difluoropyrrolidinyl, hydroxypyrrolidinyl, tetrafluoropyrrolidinyl, methylcarbonylamino, thiazolidinyl, methylpiperazinyl, 2-oxa-7-azaspiro [3.4]]Octyl or 2-oxa-6-azaspiro [3.3]Heptyl, (methyl) (hydroxy) pyrrolidinyl, hydroxyalkyl pyrrolidinyl, or cyanopyrrolidinyl;
a compound of formula (I) wherein R4Is halophenyl, haloalkylphenyl, halopyridyl, oxolanyl, alkylsulfonylphenyl, pyridyl or cycloalkyltetrazolyl;
a compound of formula (I) wherein R4Is chlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridyl, oxolanyl, methylsulfonylphenyl, pyridyl or cycloPropyl tetrazolyl;
a compound of formula (I) wherein R4Is halophenyl, haloalkylphenyl, halopyridyl, oxolanyl, alkylsulfonylphenyl or pyridyl;
a compound of formula (I) wherein R4Is chlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridyl, oxolanyl, methylsulfonylphenyl or pyridyl; and is
A compound of formula (I) wherein R4Is phenyl, chlorophenyl, chlorofluorophenyl, methylphenyl, trifluoromethylphenyl, chloropyridyl, oxolanyl, methylsulfonylphenyl, pyridyl, methylOxadiazolyl, cyclohexyl, methyl, oxolanyl, methyltetrazolyl, methoxy, trifluoromethyl, methoxyphenyl, thietanyl, trifluoromethyl-1H-pyrazolyl or cyclopropyltetrazolyl.
The invention also relates to compounds of formula (I) selected from:
2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methylphenyl) methyl ] purine;
2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
5- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
2-tert-butyl-9- (cyclohexylmethyl) -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-ethylpurine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-propylpurine;
2- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (oxolane-3-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-phenylethyl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-methoxyethyl) purine;
3- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methoxyphenyl) methyl ] purine;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-pyridin-3-ylethyl) purine;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1-pyridin-2-yl ethanone;
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
3- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] thietane 1, 1-dioxide;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methoxyphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- (2-tert-butyl-9-ethylpurin-6-yl) pyrrolidin-3-ol;
1- (2-tert-butyl-9-propylpurin-6-yl) pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-phenylethyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (cyclohexylmethyl) purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purine;
1- [ 2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (oxocyclopent-3-yl) purin-6-yl ] pyrrolidin-3-ol;
2- [ 2-tert-butyl-6- (3-hydroxypyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
n- { (S) -1- [ 2-tert-butyl-9- (2-chloro-benzyl) -9H-purin-6-yl ] -pyrrolidin-3-yl } -acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
N- [ (S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]An acetamide;
7- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-7-azaspiro [3.4]Octane;
7- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -3-methylpyrrolidin-3-ol;
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (3-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
n- [ (S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
n- [1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
2- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
5- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
3- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
2-tert-butyl-9- (2-methoxyethyl) -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
7- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
(3S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine;
(3S) -1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -3-methylpyrrolidin-3-ol;
n- [ (3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
n-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (5-methyl-1, 3, 4-)Oxadiazol-2-yl) methyl]Purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-2-amine;
n-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-2-amine;
(3S) -1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
5- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (1-methyltetrazol-5-yl) methyl ] purine;
(3S) -1- [2- (tert-butylamino) -9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (2, 2-dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [9- [ (3-chloropyridin-2-yl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol;
1-[2-(22-dimethylpropoxy) -9- [ (4-methyl-1, 2,5-Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
n-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine;
n-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (2-oxa-6-azaspiro [3.3] hept-6-yl) purin-2-amine;
(3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
3- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
n-tert-butyl-9- [ (3-methyl-1, 2,4-Oxadiazol-5-yl) methyl]-6- (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) purin-2-amine;
n-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine;
6- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -2-oxa-6-azaspiro [3.3] heptane;
3- [ [ 2-tert-butyl-6- (4-methylpiperazin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
[(2R)-1-[2-tert-butyl-9- [ (4-methyl-1, 2,5-Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-2-yl radical]Methanol;
[ (2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
(2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile;
(2R) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidine-2-carbonitrile;
6- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-6-azaspiro [3.3]Heptane; and
3- [ [ 2-tert-butyl-6- (1, 3-thiazolidin-3-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazole.
The invention also relates in particular to compounds of formula (I) selected from:
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9H-purine;
[ (3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]Acetate ester;
[1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-yl]Acetate ester;
9-benzyl-2-chloro-6- (3, 3-difluoropyrrolidin-1-yl) purine;
(3S) -1- [ 2-tert-butyl-9- [ (1-propan-2-yltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
[ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
(3S) -1- [ 2-tert-butyl-9- [ (1-propyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(2R,3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2- (hydroxymethyl) pyrrolidin-3-ol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoroazetidin-1-yl) purine;
3- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -1, 3-thiazolidine;
6- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2 λ 6-thia-6-azaspiro [3.3] heptane 2, 2-dioxide;
(2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile;
(3S) -1- [ 2-tert-butyl-9- [ [1- (cyclopropylmethyl) tetrazol-5-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (1-tert-butyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) azetidin-3-ol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (2, 2-difluoro-5-azaspiro [2.4] hept-5-yl) purine; and
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylazetidin-3-ol.
The invention also relates to compounds of formula (I) selected from:
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (oxolane-3-yl) purine;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-pyridin-3-ylethyl) purine;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine; and
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine.
The invention also relates in particular to compounds of formula (I) selected from:
2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
[ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoroazetidin-1-yl) purine;
3- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -1, 3-thiazolidine;
(2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile; and
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) azetidin-3-ol.
The invention also relates in particular to:
use of a compound of formula (I) for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney 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, amyotrophic lateral sclerosis, multiple sclerosis, alzheimer's disease, parkinson's disease, stroke, transient ischemic attack or uveitis;
the use of a compound according to formula (I) for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney 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, amyotrophic lateral sclerosis, multiple sclerosis, alzheimer's disease, parkinson's disease, 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, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney 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, amyotrophic lateral sclerosis, multiple sclerosis, alzheimer's disease, parkinson's disease, stroke, transient ischemic attack or uveitis; and
a method for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney 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, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, stroke, transient ischemic attack or uveitis, the method comprises administering to a patient in need thereof an effective amount of a compound of formula (I).
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 relates in particular to compounds of formula (I) for use in the treatment or prevention of myocardial infarction.
The invention also relates inter alia to compounds of formula (I) for use in the treatment or prevention of age related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy or uveitis.
The invention also relates inter alia to compounds of formula (I) for use in the treatment or prevention of amyotrophic lateral sclerosis or multiple sclerosis.
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 pH 5. 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. Philadelphia: lippincott, Williams & Wilkins, 2004; gennaro, Alfonso r., et al Remington: the Science and Practice of pharmacy. Philadelphia: lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C, Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, 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 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 invention is shown in the following scheme. The techniques required to carry out the reaction and to purify the resulting product are known to those skilled in the art. Unless indicated to the contrary, the substituents and indices used in the following description of the methods have the meanings given above. In more detail, the compounds of formula (I) may be prepared by the methods given below, by the methods given in the examples, or by analogous methods. The reaction conditions suitable for the individual reaction steps are known to the person skilled in the art. Also, for reaction conditions described in the literature to effect the reaction, see, for example: comprehensive organic transformations A Guide to Functional Group Preparations (organic transformation: A Guide for the preparation of Functional groups), 2 nd edition, Richard C.Larock, John Wiley & Sons, New York, N.Y.1999. We 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 to be used, provided that it has no adverse effect on the reaction or the reagents involved and that it is capable of dissolving 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-78 ℃ to reflux. The time required for the reaction may also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5h to several days will generally be sufficient to produce the intermediates and compounds. The reaction sequence is not limited to the sequence shown in the scheme, however, it depends on the starting materials and their respective reactivities. The order of the reaction steps can be freely changed. The starting materials are commercially available or can be prepared by methods analogous to those given below, by the methods described in the literature cited in the description or in the examples, or by methods known in the art.
The synthesis of the compounds of formula (I) can be achieved, for example, according to the following scheme.
Scheme 1
a) 2-tert-butyl-6-chloro-9H-purine II can be conveniently reacted with an amine (commercially available, or known in the art) in the presence or absence of a base to provide intermediate III.
b) Intermediate III can be conveniently reacted with an electrophile (commercially available, or known in the art) in the presence or absence of a base to yield the title compound I. This may be the final desired compound, however R may be conveniently cleaved off under appropriate conditions3Or NR2R3Any protecting groups on to give the desired final compound I.
Scheme 2
a) 6-chloro-2-fluoro-9H-purine II is either commercially available (any other suitable substituted purine serves as an equivalent starting material) or can be obtained by methods known in the art and can be conveniently reacted with a nucleophile (1. amine 2. alcohol, alternatively: 1. amine 2. amine, depending on the nature and reactivity of the corresponding amine) to give substituted imidazopyrimidine derivatives III. Depending on the nature and reactivity of the reagents, the use of protecting groups is optionally suggested.
b) Intermediate III may be conveniently reacted with an electrophile (commercially available, or known in the art) in the presence or absence of a base to yield the title compound I. This may be the final desired compound, however R may be conveniently cleaved off under appropriate conditions4Or NR2R3Any protecting groups on to give the desired final compound I.
The 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 Y-A-R4Reaction in the presence of
Wherein Y is a leaving group and wherein A and R1To R4Is as defined above.
In the process of the invention, suitable leaving groups are, for example, chlorine or bromine.
The process of the invention may be carried out in the presence of a base. Examples of suitable bases are NaH or KOtBu.
The process of the invention can be carried out, for example, in NMP (N-methyl-2-pyrrolidone), DMF (dimethylformamide) or THF (tetrahydrofuran).
The invention also relates to compounds of formula (I) prepared according to the process of the invention.
The invention will now be illustrated by the following examples which are not to be construed as limiting in nature.
Examples
Example 1
2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
a)5- (2, 2-dimethyl-propionylamino) -1H-imidazole-4-carboxamide
To a solution of 5-amino-1H-imidazole-4-carboxamide (10g, 79.36mmol) and DMAP (291mg, 2.38mmol) in anhydrous pyridine (200mL) was slowly added 2, 2-dimethyl-propionyl chloride (10.74mL, 87.30mmol) and the reaction mixture was stirred at 80 ℃ for 8H. The solvent was evaporated under reduced pressure and the residue was diluted with cold water (50 mL). The precipitate was filtered, washed with water (30mL) and dried to give the title compound (9g, 54%) as a grey solid. MS (M/e):211.4(M + H).
b) 2-tert-butyl-1, 9-dihydro-purin-6-one
5- (2, 2-dimethyl-propionylamino) -1H-imidazole-4-carboxamide (22g, 174.6mmol) in KHCO3Solutions in aqueous solution (0.5N, 400mL)Heated to reflux for 48 h. The reaction mixture was concentrated under reduced pressure, the residue was cooled to 0 ℃ and the pH was adjusted to 6 using 10% aqueous HCl. The precipitate was filtered, washed with water and azeotroped with toluene to give a brown solid which was purified by column chromatography over silica gel (2-5% MeOH/DCM) to give the title compound (12g, 36%) as a light yellow solid. MS (M/e) 191.0(M + H).
c) 2-tert-butyl-6-chloro-9H-purine
To 2-tert-butyl-5, 9-dihydro-purin-6-one (4g, 20.83mmol) in CHCl3(100mL) solution DMF (4mL) was added followed by SOCl2(3.04mL, 41.66mmol) and the reaction mixture was refluxed for 3 h. The volatiles were removed in vacuo and the residue was diluted with water (50mL), stirred at 25 ℃ for 10min and filtered. The precipitate was washed with water and pentane to give the title compound (3.6g, 82%) as an off-white solid. MS (M/e) 211.2(M + H).
d) 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine
To a solution of 2-tert-butyl-6-chloro-9H-purine (970mg, 4.62mmol) and 3, 3-difluoro-pyrrolidine (995mg, 6.93mmol) in EtOH (10mL) was added DIPEA (2.29mL, 13.86mmol) and the reaction mixture was stirred at 100 ℃ for 16H. The solvent was evaporated and the residue was dissolved in DCM (60mL) and washed with water. The organic layer was washed with Na2SO4Dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (25-30% EtOAc/hexanes) to give (1g, 77%) as an off-white solid. MS (M/e):282.2(M + H).
e) 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
To a solution of 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (50mg, 0.178mmol) in anhydrous DMF (3mL) at 0 deg.C was added NaH (60% in mineral oil) (10mg, 0.214mmol) and the reaction mixture was stirred at 25 deg.C for 45 min. 1-bromomethyl-4-chloro-benzene (54.7mg, 0.267mmol) was added to the reaction mixture at 0 ℃ and the reaction mixture was heated to 60 ℃ for 16 h. The mixture was quenched with water (10mL) and extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with Na2SO4Dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (20-30% EtOAc/hexanes) to give (54.7mg, 61%) as a light yellow liquid. MS (M/e):406.4(M + H).
Example 2
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-2-chloro-benzene. MS (M/e):406.4(M + H).
Example 3
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methylphenyl) methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-4-methyl-benzene. MS (M/e):386.0(M + H).
Example 4
2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-2-chloro-4-fluoro-benzene. MS (M/e):424.0(M + H).
Example 5
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-2-trifluoromethyl-benzene. MS (M/e) 440.0(M + H).
Example 6
2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 2-chloro-3-chloromethyl-pyridine. MS (M/e):407.0(M + H).
Example 7
5- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Diazoles
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for 6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 5-chloromethyl-3-methyl- [1,2,4]Diazole. MS (M/e):378.2(M + H).
Example 8
2-tert-butyl-9- (cyclohexylmethyl) -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and bromomethyl-cyclohexane. MS (M/e):378.2(M + H).
Example 9
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-ethylpurine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and iodo-ethane. MS (M/e):310.2(M + H).
Example 10
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-propylpurine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-iodo-propane. MS (M/e):324.0(M + H).
Example 11
2- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidine)-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Diazoles
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for 6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 2-chloromethyl-5-methyl- [1,3,4]Diazole. MS (M/e):378.2(M + H).
Example 12
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (oxocyclopent-3-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 3-bromo-tetrahydro-furan. MS (M/e):352.0(M + H).
Example 13
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-phenylethyl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 2-bromo-ethyl) -benzene. MS (M/e):386.0(M + H).
Example 14
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 5-chloromethyl-1-methyl-1H-tetrazole. MS (M/e):378.2(M + H).
Example 15
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-methoxyethyl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-iodo-2-methoxy-ethane. MS (M/e):340.0(M + H).
Example 16
3- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazoles
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 3-chloromethyl-4-methyl-furazan. MS (M/e):378.2(M + H).
Example 17
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 2-bromo-1- (2-chloro-phenyl) -ethanone. MS (M/e):434.0(M + H).
Example 18
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):450.0(M + H).
Example 19
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1,1, 1-trifluoro-3-iodo-propane. MS (M/e):378.2(M + H).
Example 20
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methoxyphenyl) methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 1-bromomethyl-4-methoxy-benzene. MS (M/e):402.2(M + H).
Example 21
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 3-chloro-2-chloromethyl-pyridine. MS (M/e):407.0(M + H).
Example 22
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
a) Acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester
To a solution of 2-tert-butyl-6-chloro-9H-purine (1.2g, 5.71mmol) and pyrrolidin-3-yl acetate (1.66g, 6.85mmol) in EtOH (7mL) at 25 deg.C was added Et3N (2.37mL, 17.14mmol) and the reaction mixture was stirred at 100 ℃ for 5 h. The solvent was evaporated and the residue was purified by column chromatography over silica (30-45% EtOAc/hexanes) to give the title compound (1.1g, 63%) as an off-white solid. MS (M/e) 304.0(M + H).
b)1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-2-chloro-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.2(M + H).
Example 23
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-pyridin-3-ylethyl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 3- (2-bromo-ethyl) -pyridine. MS (M/e):387.2(M + H).
Example 24
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1-pyridin-2-yl ethanone
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 2-bromo-1-pyridin-2-yl-ethanone. MS (M/e):401.2(M + H).
Example 25
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-3-chloro-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.2(M + H).
Example 26
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-4-chloro-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.2(M + H).
Example 27
3- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] thietane 1, 1-dioxide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 3-bromo-thietane 1, 1-dioxide. MS (M/e):386.2(M + H).
Example 28
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 1-bromomethyl-2-trifluoromethyl-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):420.2(M + H).
Example 29
1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ols
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 5-chloromethyl-3-methyl- [1,2, 4-methyl ] -pyrrolidine]Diazole, and subsequent use of K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.0(M + H).
Example 30
1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 5-chloromethyl-1-methyl-1H-tetrazole and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.2(M + H).
Example 31
1- [ 2-tert-butyl-9- [ (4-methoxyphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (parenchyma)Example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 1-bromomethyl-4-methoxy-benzene and then taken up with K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):382.0(M + H).
Example 32
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 3-chloro-2-chloromethyl-pyridine and subsequently K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e) 387.0(M + H).
Example 33
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 2-chloro-3-chloromethyl-pyridine and subsequently K in MeOH2CO3Treating the crude mixture/residue to remove ester moietiesAnd (4) dividing. MS (M/e) 387.0(M + H).
Example 34
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-2-methanesulfonyl-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):430.0(M + H).
Example 35
1- (2-tert-butyl-9-ethylpurin-6-yl) pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and iodo-ethane and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):290.0(M + H).
Example 36
1- (2-tert-butyl-9-propylpurin-6-yl) pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and iodo-propane and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e) 304.0(M + H).
Example 37
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-iodo-2-methoxy-ethane and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):320.2(M + H).
Example 38
1- [ 2-tert-butyl-9- (2-phenylethyl) purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl)) Methyl radical]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 2- (bromo-ethyl) -benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):365.9(M + H).
Example 39
1- [ 2-tert-butyl-9- [ (4-methylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-4-methyl-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):365.9(M + H).
Example 40
1- [ 2-tert-butyl-9- (cyclohexylmethyl) purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and bromomethyl-cyclohexane and then K in MeOH2CO3Processing crude mixture/residueThe remainder to remove the ester moiety. MS (M/e):358.0(M + H).
EXAMPLE 41
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (example 1, step d) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole. MS (M/e):430.0(M + H).
Example 42
1- [ 2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 1-bromomethyl-2-chloro-4-fluoro-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):404.2(M + H).
Example 43
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ols
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 3-chloromethyl-4-methyl-furazan and subsequent use of K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.4(M + H).
Example 44
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. The trityl-protecting group was subsequently removed with TFA. MS (M/e):410.0(M + H).
Example 45
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 1,1, 1-trifluoro-3-iodo-propane and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.0(M + H).
Example 46
1- [ 2-tert-butyl-9- (Oxetapen-3-yl) purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 22, step a) and 3-bromotetrahydrofuran and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):332.2(M + H).
Example 47
2- [ 2-tert-butyl-6- (3-hydroxypyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for (e) -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 22, step a) and 2-bromo-1- (2-chloro-phenyl) -ethanone and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):414.0(M + H).
Example 48
N- { (S) -1- [ 2-tert-butyl-9- (2-chloro-benzyl) -9H-purin-6-yl ] -pyrrolidin-3-yl } -acetamide
a) N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide
To a solution of 2-tert-butyl-6-chloro-9H-purine (600mg, 2.857mmol) and (S) -N-pyrrolidin-3-yl-acetamide (402.28mg, 3.143mmol) in EtOH (30mL) was added DIPEA (1.49mL, 8.571mmol) and the resulting reaction mixture was stirred at 100 ℃ for 16H. The volatiles were evaporated and the residue was diluted with DCM (200mL) and washed with water (2 × 75 mL). The organic layer was washed with anhydrous Na2SO4Dried, filtered and evaporated. The residue was purified by column chromatography over silica gel (30-40% EtOAc/hexanes) to give the title compound (660mg, 76%) as an off-white solid. MS (M/e):303.0(M + H).
b) N- { (S) -1- [ 2-tert-butyl-9- (2-chloro-benzyl) -9H-purin-6-yl ] -pyrrolidin-3-yl } -acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 4, step a) and 1-bromomethyl-2-chloro-benzene. MS (M/e):427.4(M + H).
Example 49
N- [ (S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 1-bromomethyl-3-chloro-benzene. MS (M/e):427.4(M + H).
Example 50
N- [ (S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 1-bromomethyl-4-chloro-benzene. MS (M/e):427.0(M + H).
Example 51
N- [ (S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 1-bromomethyl-2-trifluoromethyl-benzene. MS (M/e) 461.2(M + H).
Example 52
N- [ (S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):471.2(M + H).
Example 53
N- [ (S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 2-chloro-3-chloromethyl-pyridine. MS (M/e):428.2(M + H).
Example 54
N- [ (S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 3-chloro-2-chloromethyl-pyridine. MS (M/e):428.2(M + H).
Example 55
N- [ (S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]Acetamide
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl]Acetamide (example 48, step a) and 2-chloromethyl-5-methyl- [1,3,4]Diazole. MS (M/e):399.0(M + H).
Example 56
7- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
a) 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine
In analogy to the procedure described for the synthesis of N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, a) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine and 2-oxa-6-aza-spiro [3.4] octane. MS (M/e):288.0(M + H).
b)7- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromomethyl-2-chloro-benzene. MS (M/e):412.4(M + H).
Example 57
7- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromomethyl-3-chloro-benzene. MS (M/e):412.2(M + H).
Example 58
7- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromomethyl-4-chloro-benzene. MS (M/e):412.2(M + H).
Example 59
7- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromomethyl-2-trifluoromethyl-benzene. MS (M/e):446.0(M + H).
Example 60
7- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e) 456.0(M + H).
Example 61
7- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 2-chloro-3-chloromethyl-pyridine. MS (M/e):413.2(M + H).
Example 62
7- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-7-azaspiro [3.4]Octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 3-chloromethyl-4-methyl-furazan. MS (M/e):384.2(M + H).
Example 63
7- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromo-2-methoxy-ethane. MS (M/e):346.0(M + H).
Example 64
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
a) Acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, a) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine and 3-methyl-pyrrolidin-3-yl acetate. MS (M/e) 317.8(M + H).
b)1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromomethyl-2-chloro-benzene. MS (M/e):400.0(M + H).
Example 65
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromomethyl-3-chloro-benzene. MS (M/e):400.0(M + H).
Example 66
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromomethyl-4-chloro-benzene. MS (M/e):400.0(M + H).
Example 67
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromomethyl-2-trifluoromethyl-benzene. MS (M/e):434.0(M + H).
Example 68
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 2-chloro-3-chloromethyl-pyridine. MS (M/e):401.0(M + H).
Example 69
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 3-chloro-2-chloromethyl-pyridine. MS (M/e):401.0(M + H).
Example 70
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 3-chloromethyl-4-methyl-furazan. MS (M/e):372.2(M + H).
Example 71
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromo-2-methoxy-ethane. MS (M/e):334.0(M + H).
Example 72
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
a) 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine
In analogy to the procedure described for the synthesis of N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, a) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine and 3,3,4, 4-tetrafluoro-pyrrolidine. MS (M/e):318.0(M + H).
b) 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1-bromomethyl-2-chloro-benzene. MS (M/e) 442.3(M + H).
Example 73
2-tert-butyl-9- [ (3-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1-bromomethyl-3-chloro-benzene. MS (M/e):441.2(M + H).
Example 74
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):444.2(M + H).
Example 75
N- [ (S) -1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole and the trityl protecting group was subsequently removed with TFA. MS (M/e) 451.2(M + H).
Example 76
7- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56 step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole and the trityl protecting group was subsequently removed with TFA. MS (M/e):436.2(M + H).
Example 77
N- [ (S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 3-bromomethyl-4-trifluoromethyl-1-trityl-1H-pyrazole and the trityl protecting group was subsequently removed with TFA. MS (M/e):451.0(M + H).
Example 78
7- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56 step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole and the trityl protecting group was subsequently removed with TFA. MS (M/e):436.2(M + H).
Example 79
2- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Diazoles
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for 6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 2-chloromethyl-5-methyl- [1,3,4]Diazole. MS (M/e):413.8(M + H).
Example 80
5- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Diazoles
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for 6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 5-chloromethyl-3-methyl- [1,2,4]Diazole. MS (M/e):414.0(M + H).
Example 81
2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 5-chloromethyl-1-methyl-1H-tetrazole. MS (M/e) 414.2(M + H).
Example 82
3- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazoles
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 3-chloromethyl-4-methyl-furazan. MS (M/e) 414.2(M + H).
Example 83
2-tert-butyl-9- (2-methoxyethyl) -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1-bromo-2-methoxy-ethane. MS (M/e):376.0(M + H).
Example 84
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole, and the trityl protecting group was subsequently removed with TFA. MS (M/e):424.3(M + H).
Example 85
1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 3-bromomethyl-4-trifluoromethyl-1-trityl-1H-pyrazole, and the trityl protecting group was subsequently removed with TFA. MS (M/e):424.0(M + H).
Example 86
(3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
a) Acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, a) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine and (S) -pyrrolidin-3-yl acetate. MS (M/e):303.8(M + H).
b) (3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromomethyl-2-chloro-benzene, and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):420.0(M + H).
Example 87
(3S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromomethyl-3-chloro-benzene and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.0(M + H).
Example 88
(3S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromomethyl-4-chloro-benzene, and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.0(M + H).
Example 89
7- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 1-bromo-2-methoxy-ethane. MS (M/e):384.0(M + H).
Example 90
(3S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):430.2(M + H).
Example 91
(3S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):387.2(M + H).
Example 92
(3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 3-chloro-2-chloromethyl-pyridine. MS (M/e):387.2(M + H).
Example 93
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1,1, 1-trifluoro-3-iodo-propane. MS (M/e) 414.2(M + H).
Example 94
(3S) -1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromo-2-methoxy-ethane. MS (M/e):320.0(M + H).
Example 95
(3S) -1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The title compound was prepared from the procedure described for (E) -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1)a) (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl acetate (example 86, step a) and 5-chloromethyl-1-methyl-1H-tetrazole, and subsequent application of K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.2(M + H).
Example 96
(3S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ols
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 3-chloromethyl-4-methyl-furazan, and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.2(M + H).
Example 97
(3S) -1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for (E) -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1-bromoMethyl-2-chloro-benzene, and then K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):386.4(M + H).
Example 98
(3S) -1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 4-bromomethyl-3-trifluoromethyl-1-trityl-1H-pyrazole and then K in MeOH and subsequently used2CO3The crude mixture/residue was treated to remove the ester moiety. The trityl group was subsequently removed with TFA. MS (M/e):410.4(M + H).
Example 99
(3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 1,1, 1-trifluoro-3-iodo-propane. MS (M/e):358.0(M + H).
Example 100
(3S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 3-bromomethyl-4-trifluoromethyl-1-trityl-1H-pyrazole and then K in MeOH and2CO3the crude mixture/residue was treated to remove the ester moiety. The trityl group was subsequently removed with TFA. MS (M/e):410.2(M + H).
Example 101
(3S) -1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ols
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]The procedure described for (E) -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) acetic acid (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 86, step a) and 5-chloromethyl-3-methyl- [1,2,4]Diazole, and subsequent use of K in MeOH2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):358.0(M + H).
Example 102
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -3-methylpyrrolidin-3-ol
Analogously to the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl]-6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from acetic acid 1- (2-tert-butyl-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 64, step a) and 1,1, 1-trifluoro-3-iodo-propane and then K in MeOH and then used2CO3The crude mixture/residue was treated to remove the ester moiety. MS (M/e):372.2(M + H).
Example 103
N- [ (3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-yl ] acetamide
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from N- [ (S) -1- (2-tert-butyl-9H-purin-6-yl) -pyrrolidin-3-yl ] -acetamide (example 48, step a) and 1,1, 1-trifluoro-3-iodo-propane. MS (M/e):399.0(M + H).
Example 104
7- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from a) 2-tert-butyl-6- (2-oxa-6-aza-spiro [3.4] oct-6-yl) -9H-purine (example 56, step a) and 3-chloro-2-chloromethyl-pyridine. MS (M/e):413.0(M + H).
Example 105
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1-bromomethyl-2-trifluoromethyl-benzene. MS (M/e):476.0(M + H).
Example 106
2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine
In analogy to the procedure described for the synthesis of 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine (example 1) the title compound was prepared from 2-tert-butyl-6- (3,3,4, 4-tetrafluoro-pyrrolidin-1-yl) -9H-purine (example 72, step a) and 1-bromomethyl-2-methanesulfonyl-benzene. MS (M/e):485.8(M + H).
Example 107
N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine
a)6- (3, 3-difluoro-pyrrolidin-1-yl) -2-fluoro-9H-purine
To a solution of 6-chloro-2-fluoro-9H-purine (500mg 2.89mmol) in tBuOH (10mL) was added DIPEA (0.68mL, 3.76mmol), followed by 3, 3-difluoro-pyrrolidine hydrochloride (415.5mg 2.89mmol) and the reaction mixture was heated in a sealed tube at 80 ℃ for 22H. The solvent was removed under reduced pressure and the residue was purified by Combi-Flash column chromatography (40g, hexanes/EtOAc 1/6) to give the title compound (500 mg; 71%) as a brown solid MS (M/e):244.2(M + H).
b) Tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine
In a sealed tube, a solution of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2-fluoro-9H-purine (500mg, 2.058mmol) in t-BuOH (10mL) and tert-butylamine (1.5g, 20.57mmol) was heated at 160 ℃ for 24H. The reaction mixture was cooled to 25 ℃ and the solvent was evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40g, hexanes/EtOAc 1/7) to yield the title compound (214 mg; 35%) as a white solid. MS (M/e):297.2(M + H).
c) N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine
To 2-tert-butyl-4- (2-oxa-6-aza-spiro [3.3] at 0 deg.C]Hept-6-yl) -7H-pyrrolo [2,3-d]A stirred solution of pyrimidine (30mg, 0.11mmol) in DMF (5mL) was added NaH (10mg, 0.132mmol) and stirred at 25 ℃ for 1 h. To this was added 1-bromomethyl-2-chloro-benzene (30mg, 0.143mmol) in one portion and the mixture was stirred at 25 ℃ for 12 h. Reacting the mixture with NH4Cl quench, remove solvent under reduced pressure, dissolve the residue in H2O (10mL), extracted with EtOAc, washed with brine and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (25mg, 59%) as an off-white solid. MS (M/e):421(M + H).
Example 108
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e):455(M + H).
Example 109
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (5-methyl-1, 3, 4-)Oxadiazol-2-yl) methyl]Purine-2-amines
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e) 393(M + H).
Example 110
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e) 393(M + H).
Example 111
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purine-2-amines
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e) 393(M + H).
Example 112
N-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e):422(M + H).
Example 113
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e) 393(M + H).
Example 114
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e):465(M + H).
Example 115
N-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purine-2-amines
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b). MS (M/e) 393(M + H).
Example 116
(3S) -1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
a) Acetic acid (S) -1- (2-fluoro-9H-purin-6-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2-fluoro-9H-purine (example 107, step a) the title compound was prepared from 6-chloro-2-fluoro-9H-purine and (S) -pyrrolidin-3-yl acetate. MS (M/e) 266.1(M + H).
b) Acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b) the title compound was prepared from (S) -1- (2-fluoro-9H-purin-6-yl) -pyrrolidin-3-yl acetate and tert-butylamine. MS (M/e):318.8(M + H).
c) (3S) -1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 108, step b) and 1-bromomethyl-2-chloro-benzene. MS (M/e) 401.3(M + H).
Example 117
(3S) -1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 116, step b). MS (M/e):435.2(M + H).
Example 118
(3S) -1- [2- (tert-butylamino) -9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 116, step b). MS (M/e) 401.8(M + H).
Example 119
(3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ols
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 116, step b). MS (M/e):373.4(M + H).
Example 120
1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
a) Acetic acid 1- (2-fluoro-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2-fluoro-9H-purine (example 107, step a) the title compound was prepared from 6-chloro-2-fluoro-9H-purine and acetic acid 3-methyl-pyrrolidin-3-yl ester. MS (M/e):280.1(M + H).
b) Acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b) the title compound was prepared from acetic acid 1- (2-fluoro-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester and tert-butylamine. MS (M/e) 333.2(M + H).
c)1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 120, step b) and 1-bromomethyl-2-chloro-benzene. MS (M/e):415.2(M + H).
Example 121
1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 120, step b). MS (M/e):449.2(M + H).
Example 122
(3S) -1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 116, step b) and trityl was deprotected with TFA. MS (M/e):425(M + H).
Example 123
1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methanesBase of]Purin-6-yl]-3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 120, step b). MS (M/e) 387.3(M + H).
Example 124
9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine
a)6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine
To a solution of 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (1g, 4.12mmol) in EtOAc (5mL) at 25 deg.C was added dihydropyran (0.75mL, 8.23mmol) and pTSA (39 mg; 0.21mmol) and the reaction mixture was heated at 50 deg.C for 5H. The reaction mixture was diluted with EtOAc, washed with water and saturated NaHCO at 25 deg.C3Washing, washing with brine, and washing with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 20/80) to yield 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine (1.0 g; 74%) as a white solid. LC-MS:344(M + H).
A mixture of 2, 2-dimethyl-propan-1-ol (1.9g, 21.81mmol) and NaH (60% in oil; 116mg2.90mmol) was heated at 50 ℃ and 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine (500mg 1.45mmol) was added. The reaction mixture was heated at 80 ℃ for 12 h. The mixture was quenched with water, extracted with DCM, washed with brine, and washed with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 30/70) to yield 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9- (tetrahydro-pyran-2-yl) -9H-purine (250 mg; 35%) as an off-white solid. LC-MS:396(M + H).
To a solution of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9- (tetrahydro-pyran-2-yl) -9H-purine (500mg, 1.26mmol) in EtOH (5mL) was added pTSA (12 mg; 0.064mmol) and the reaction mixture was heated at 80 ℃ for 4H. The mixture was evaporated at 25 ℃. The residue was dissolved in EtOAc, and washed with water, saturated NaHCO3Washed with brine and then with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 20/80) to yield the title compound (350 mg; 89%) as a white solid. LC-MS:312(M + H).
b)9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a) and 1-bromomethyl-2-chloro-benzene. MS (M/e):436(M + H).
Example 125
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e):470(M + H).
Example 126
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e):479.8(M + H).
Example 127
2- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Diazoles
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e) 408(M + H).
Example 128
5- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Diazoles
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e) 408(M + H).
Example 129
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (1-methyltetrazol-5-yl) methyl ] purine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e) 408(M + H).
Example 130
(3S) -1- [2- (tert-butylamino) -9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol
a) Acetic acid (S) -1- (2-fluoro-9H-purin-6-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2-fluoro-9H-purine (example 107, step a) the title compound was prepared from 6-chloro-2-fluoro-9H-purine and (S) -pyrrolidin-3-yl acetate. MS (M/e) 266.1(M + H).
b) Acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester
In analogy to the procedure described for the synthesis of tert-butyl- [6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purin-2-yl ] -amine (example 107, step b) the title compound was prepared from (S) -1- (2-fluoro-9H-purin-6-yl) -pyrrolidin-3-yl acetate and tert-butylamine. MS (M/e):277(M + H).
c) (3S) -1- [2- (tert-butylamino) -9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 130, step b). MS (M/e):373.3(M + H).
Example 131
1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine (example 124), intermediate 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol was prepared from acetic acid 1- (2-fluoro-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester by the following method: n1 was protected with THP, followed by nucleophilic substitution at C7 with 2, 2-dimethyl-propan-1-ol, and finally deprotection at N1 with p-TSA. LC-MS:306.4(M + H).
The free alcohol moiety was protected with TBDMS by reaction of 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol with tert-butyldimethylsilyl chloride and imidazole in DMF.
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from TBDMS-protected 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol and 1-bromomethyl-2-chloro-benzene. Deprotection of the silyl protecting group using TBAF yields the title compound. MS (M/e):430(M + H).
Example 132
1- [2- (2, 2-Dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol (example 131) the title compound was prepared from TBDMS-protected 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol and 1-bromomethyl-2-trifluoromethyl-benzene and the TBDMS group was removed with TBAF. MS (M/e):463.8(M + H).
Example 133
1- [2- (2, 2-Dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol (example 131) the title compound was prepared from TBDMS-protected 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol and 1-bromomethyl-2-methanesulfonyl-benzene and the TBDMS group was removed with TBAF. MS (M/e):474.0(M + H).
Example 134
1- [9- [ (3-Chloropyridin-2-yl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol (example 131) the title compound was prepared from TBDMS-protected 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol and 2-bromomethyl-3-chloro-pyridine and the TBDMS group was removed with TBAF. MS (M/e):430.8(M + H).
Example 135
1- [2- (2, 2-dimethylpropoxy) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of 1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol (example 131) the title compound was prepared from TBDMS-protected 1- [2- (2, 2-dimethyl-propoxy) -9H-purin-6-yl ] -3-methyl-pyrrolidin-3-ol and 3-chloromethyl-4-methyl-furazan and the TBDMS group was removed with TBAF. MS (M/e) 401.8(M + H).
Example 136
1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 120, step b) and the trityl group was removed with TFA. MS (M/e):439.3(M + H).
Example 137
N-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine
a) 2-fluoro-6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine
The title compound was prepared from 6-chloro-2-fluoro-9- (tetrahydro-pyran-2-yl) -9H-purine and protected with THP. LC-MS:320.3(M + H).
b) Tert-butyl- [6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purin-2-yl ] -amine
The title compound was prepared from 2-fluoro-6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine by the following method: nucleophilic substitution with tert-butylamine followed by removal of the THP group with PTSA.
c) N-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purin-2-yl ] -amine (example 137, step b). MS (M/e):446.8(M + H).
Example 138
N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (2-oxa-6-azaspiro [3.3] hept-6-yl) purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purin-2-yl ] -amine (example 137, step b). MS (M/e):413(M + H).
Example 139
(3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
a) 2-tert-butyl-6-chloro-9- (1-cyclopropyl-1H-tetrazol-5-ylmethyl) -9H-purine
A mixture of 2-tert-butyl-6-chloro-9H-purine (200mg, 949. mu. mol), NaH 60% (49.4mg, 1.23mmol) in DMF (8mL) was treated with 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole (226mg, 1.42mmol) and stirred at 60 ℃. The mixture was quenched with water (20mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined and washed with Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by HPLC to give the title compound (203mg, 64%) as an off-white solid.
b) (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
2-tert-butyl-6-chloro-9- ((1-cyclopropyl-1H-tetrazol-5-yl) methyl) -9H-purine (50mg, 150. mu. mol) in acetonitrile (683. mu.L) was treated with DIPEA (29.1mg, 225. mu. mol) and (S) -pyrrolidin-3-ol (14.4mg, 165. mu. mol). The reaction mixture was stirred at rt for 3 h. 1mL of toluene was added to the reaction mixture and the solution was concentrated. The residue was transferred to a separatory funnel, treated with citric acid 10% and extracted. The aqueous phase was extracted a second time with toluene. The combined organic phases are washed with NaHCO3Washing was followed by washing with NaCl. The organic extracts were combined and taken with Na2SO4And (5) drying. Heptane was added with stirring. After 5min, the product started to crystallize and the suspension was stirred overnight. The suspension was filtered, and the crystals were washed with heptane and dried to give the title compound (16mg, 28%) as a white solid. MS (M/e) 384.5(M + H).
Example 140
3- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazoles
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9H-purine (example 124, step a). MS (M/e) 408(M + H).
Example 141
N-tert-butyl-9- [ (3-methyl-1, 2,4-Oxadiazol-5-yl) methyl]-6- (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) purin-2-amines
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purin-2-yl ] -amine (example 137, step b). MS (M/e):385.3(M + H).
Example 142
N-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from tert-butyl- [6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purin-2-yl ] -amine (example 137, step b). MS (M/e):385.2(M + H).
Example 143
6- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -2-oxa-6-azaspiro [3.3] heptane
a)2- (2, 2-dimethyl-propoxy) -6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purine
Protection of 2, 6-dichloro-9H-purine with THP in the presence of PTSA was performed with N1. Followed by nucleophilic substitution first with 2-oxa-6-aza-spiro [3.3] heptane at C5 and second with 2, 2-dimethyl-propan-1-ol at C7 to yield an intermediate that was deprotected with PTSA at N1 to yield the title compound.
b)6- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -2-oxa-6-azaspiro [3.3] heptane
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from 2- (2, 2-dimethyl-propoxy) -6- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -9H-purine (example 143, step a). MS (M/e):428(M + H).
Example 144
3- [ [ 2-tert-butyl-6- (4-methylpiperazin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazoles
Analogously to the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl]Purin-6-yl]Pyrrolidine-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 3- (chloromethyl)-4-methyl-1, 2,5-Oxadiazole and 1-methylpiperazine. MS (M/e):371.7(M + H).
Example 145
[ (2R) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-2-yl radical]Methanol
Analogously to the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl]Purin-6-yl]Pyrrolidine-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 3- (chloromethyl) -4-methyl-1, 2,5-Diazole and (R) -pyrrolidin-2-yl methanol. MS (M/e):372.7(M + H).
Example 146
[ (2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol
In analogy to the procedure described for the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole and (R) -pyrrolidin-2-ylmethanol. MS (M/e):398.5(M + H).
Example 147
(2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile
In analogy to the procedure described for the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole and (R) -pyrrolidine-2-carbonitrile hydrochloride. MS (M/e):393.6(M + H).
Example 148
(2R) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidine-2-carbonitriles
Analogously to the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl]Purin-6-yl]Pyrrolidine-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 3- (chloromethyl) -4-methyl-1, 2,5-Oxadiazole and (R) -pyrrolidine-2-carbonitrile hydrochloride. MS (M/e):367.5(M + H).
Example 149
6- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-6-azaspiro [3.3]Heptane (Heptane)
Analogously to the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl]Purin-6-yl]Pyrrolidine-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 3- (chloromethyl) -4-methyl-1, 2,5-Diazoles and 2-oxa-6-azaspiro [3.3]Heptane oxalate ester. MS (M/e):370.5(M + H).
Example 150
3- [ [ 2-tert-butyl-6- (1, 3-thiazolidin-3-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazoles
Analogously to the synthesis of (3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl]Purin-6-yl]Pyrrolidine-3-ol (example 139) the title compound was prepared from 2-tert-butyl-6-chloro-9H-purine, 3- (chloromethyl) -4-methyl-1, 2,5-Oxadiazoles and thiazolidines. MS (M/e):360.5(M + H).
Example 151
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9H-purine
To a solution of 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (1g, 4.12mmol) in EtOAc (5mL) at 25 deg.C was added dihydropyran (0.75mL, 8.23mmol) and pTSA (39 mg; 0.21mmol) and the reaction mixture was heated at 50 deg.C for 5H. The reaction mixture was diluted with EtOAc, washed with water and saturated NaHCO at 25 deg.C3Washing, washing with brine, and washing with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 20/80) to yield 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine (1.0 g; 74%) as a white solid. LC-MS:344(M + H).
A mixture of 2, 2-dimethyl-propan-1-ol (1.9g, 21.81mmol) and NaH (60% in oil; 116mg2.90mmol) was heated at 50 ℃ and 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9- (tetrahydro-pyran-2-yl) -9H-purine (500mg 1.45mmol) was added. The reaction mixture was heated at 80 ℃ for 12 h. The mixture was quenched with water, extracted with DCM, washed with brine, and washed with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 30/70) to yield 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9- (tetrahydro-pyran-2-yl) -9H-purine (250 mg; 35%) as an off-white solid. LC-MS:396(M + H).
To a solution of 6- (3, 3-difluoro-pyrrolidin-1-yl) -2- (2, 2-dimethyl-propoxy) -9- (tetrahydro-pyran-2-yl) -9H-purine (500mg, 1.26mmol) in EtOH (5mL) was added pTSA (12 mg; 0.064mmol) and the reaction mixture was heated at 80 ℃ for 4H. The mixture was evaporated at 25 ℃. Dissolving the residueIn EtOAc, with water, saturated NaHCO3Washed with brine and then with anhydrous Na2SO4Dried and evaporated under reduced pressure. The residue was purified by Combi-Flash column chromatography (40 g; hexane/EtOAc 20/80) to yield the title compound (350 mg; 89%) as a white solid. LC-MS:312(M + H).
Example 152
[ (3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]Acetic acid ester
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid (S) -1- (2-tert-butylamino-9H-purin-6-yl) -pyrrolidin-3-yl ester (example 108, step b) and 3-chloromethyl-4-methyl-furazan. MS (M/e):415(M + H).
Example 153
[1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-yl]Acetic acid ester
In analogy to the procedure described for the synthesis of N-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine (example 107) the title compound was prepared from acetic acid 1- (2-tert-butylamino-9H-purin-6-yl) -3-methyl-pyrrolidin-3-yl ester (example 120, step b) and 3-chloromethyl-4-methyl-furazan. MS (M/e):428.8(M + H).
Example 154
9-benzyl-2-chloro-6- (3, 3-difluoropyrrolidin-1-yl) purine
To a solution of 2, 6-dichloro-9H-purine (commercially available) (1 g; 5.29mmol) in DMF (10mL) at 25 deg.C was added Et3N (0.8 mL; 5.82mmol) was followed by the addition of (3, 3-difluoropyrrolidine hydrochloride (0.8 g; 5.56mmol) and heating the reaction mixture at 80 ℃ for 12H. the reaction mixture was quenched with ice-cold water and stirred at 0 ℃ for 30 min. the solid was filtered, washed with cold water, and finally dried under high vacuum at 50 ℃ to afford 2-chloro-6- (3, 3-difluoropyrrolidin-1-yl) -9H-purine (1 g; 73%) as a pale yellow solid, which was used directly in the next step without further purification. LC-MS:260.2(M + H.) A solution of crude 2-chloro-6- (3, 3-difluoro-pyrrolidin-1-yl) -9H-purine (200mg, 0.7mmol) in DMF (10mL) was added NaH (70mg, 1.7mmol) and the reaction mixture was stirred at 25 ℃ for 1 h. To this was added benzyl bromide (160mg, 0.92mmol) in one portion, and the mixture was stirred at 25 ℃ for 12 h. Reacting the mixture with NH4Cl quench, remove solvent under reduced pressure, and dissolve the residue in H2O (10mL), extracted with EtOAc; washed with brine and concentrated in vacuo. The crude material was purified by column chromatography (SiO)2(ii) a 100-200 mesh; 20% EtOAc/hexanes) to afford 9-benzyl-2-chloro-6- (3, 3-difluoropyrrolidin-1-yl) -9H-purine (100mg, 59%) as an off-white solid. LC-MS:349.8(M + H).
Example 155
(3S) -1- [ 2-tert-butyl-9- [ (1-propan-2-yltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
a) 2-tert-butyl-6-chloro-9- ((1-isopropyl-1H-tetrazol-5-yl) methyl) -9H-purine
NaH (60%, 49.4mg, 1.23mmol) was added to an ice-cold solution of 2-tert-butyl-6-chloro-9H-purine (CAN733736-31-7, 200mg, 949. mu. mol) in DMF (4 mL). The reaction mixture was stirred at ambient temperature for 45 min. At 0C, 5- (chloromethyl) -1-isopropyl-1H-tetrazole (CAN 187739-97-5, 229mg, 1.42mmol) was added to the reaction mixture and the reaction mixture was stirred at 60 ℃ for 12H. Water (20mL) was added and the mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined and washed with Na2SO4Dried, filtered and concentrated in vacuo to afford 446mg of a brown solid, which was purified by HPLC to afford the title compound (218mg, 69%) as a white solid. MS (M/e):335.2(M + H).
b) (3S) -1- [ 2-tert-butyl-9- [ (1-propan-2-yltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
DIPEA (CAN 7087-68-5, 29.0mg, 38.3. mu.L, 224. mu. mol) and (S) -pyrrolidin-3-ol (CAN100243-39-8, 14.3mg, 13.7. mu.L, 164. mu. mol) were added to a solution of 2-tert-butyl-6-chloro-9- ((1-isopropyl-1H-tetrazol-5-yl) methyl) -9H-purine (50mg, 149. mu. mol) in acetonitrile (679. mu.L). The reaction mixture was stirred at ambient temperature overnight. 10% aqueous citric acid was added and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine, washed with Na2SO4Dried and concentrated in vacuo to afford the title compound (65mg, amount) as a white solid. MS (M/e):386.2(M + H).
Example 156
2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
a) 2-tert-butyl-6-chloro-9- ((1-cyclopropyl-1H-tetrazol-5-yl) methyl) -9H-purine
In analogy to the procedure described in example 155a), 2-tert-butyl-6-chloro-9H-purine (CAN733736-31-7, 400mg, 1.9mmol) was reacted with 5- (chloromethyl) -1-cyclopropyl-1H-tetrazole (CAN949980-56-7, 452mg, 2.85mmol) to give the title compound (348mg, 55%) as off-white solid. MS (M/e) 333.2(M + H).
b) 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine
In analogy to the procedure described in example 155b) 2-tert-butyl-6-chloro-9- ((1-cyclopropyl-1H-tetrazol-5-yl) methyl) -9H-purine (50mg, 150 μmol) was reacted with 3, 3-difluoropyrrolidine hydrochloride (CAN 163457-23-6, 23.7mg, 165 μmol) to give the title compound (28mg, 46%) as white solid. MS (M/e):404.3(M + H).
Example 157
[ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol
a) 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine
In analogy to the procedure described in example 155a), 2-tert-butyl-6-chloro-9H-purine (CAN733736-31-7, 500mg, 2.37mmol) was reacted with 3-chloro-2- (chloromethyl) pyridine hydrochloride (CAN124425-87-2, 707mg, 3.56mmol) to give the title compound (208mg, 26%) as off-white solid. MS (M/e):336.4(M + H).
b) [ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol
In analogy to the procedure described in example 155b) 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (40mg, 119 μmol) was reacted with (R) -pyrrolidin-2-ylmethanol (CAN68832-13-3, 13.2mg, 12.9 μ L, 131 μmol) to give the title compound (16mg, 34%) as colorless solid. MS (M/e):401.2(M + H).
Example 158
(3S) -1- [ 2-tert-butyl-9- [ (1-propyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
a) (S) -1- (2-tert-butyl-9H-purin-6-yl) pyrrolidin-3-ol
DIPEA (CAN 7087-68-5, 123mg, 166. mu.L, 949. mu. mol) was added to 2-tert-butyl-6-chloro-9H-purine (CAN733736-31-7, 100mg, 475. mu. mol) and (S) -pyrrolidin-3-ol (CAN100243-39-8, 74.4mg, 71.0. mu.L, 854. mu. mol) in MeCN (2.5 mL). The reaction was stirred at ambient temperature for 24 h. 10% citric acid was added and the mixture was washed with DCM (2 × 20 mL). The aqueous layer was washed with NaHCO3Basified and extracted with DCM (2 × 20 mL). The combined extracts were washed with brine, washed with Na2SO4Dried and concentrated in vacuo to afford the title compound (50mg, 80%) as a white solid. MS (M/e):262.5(M + H).
b) (3S) -1- [ 2-tert-butyl-9- [ (1-propyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
DBU (CAN 6674-22-2, 93.8mg, 92.9. mu.L, 616. mu. mol) was added to a solution of (S) -1- (2-tert-butyl-9H-purin-6-yl) pyrrolidin-3-ol (46mg, 176. mu. mol) and 5- (chloromethyl) -1-propyl-1H-tetrazole (CAN 848178-47-2, 84.8mg, 528. mu. mol) in DMF (1 mL). The reaction was stirred at ambient temperature for 16 h. Water/1N HCl (1:1), 20mL) was added and the mixture was extracted with EtOAc (2X 20 mL). The combined organic phases were washed successively with water and brine. The organic phase is treated with Na2SO4Dried and concentrated in vacuo to afford the title compound (62mg, 91%) as an off-white foam. MS (M/e):386.6(M + H).
Example 159
(2R,3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2- (hydroxymethyl) pyrrolidin-3-ol
In analogy to the procedure described in example 155b) 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 40mg, 119 μmol) was reacted with (2R,3S) -2- (hydroxymethyl) pyrrolidin-3-ol (CAN105017-31-0, 13.9mg, 119 μmol) to give the title compound (3mg, 6%) as colorless solid. MS (M/e):417.6(M + H).
Example 160
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoroazetidin-1-yl) purine
In analogy to the procedure described in example 155b) 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 40mg, 119 μmol) was reacted with 3, 3-difluoroazetidine hydrochloride (CAN 288315-03-7, 30.8mg, 238 μmol) to give the title compound (13mg, 28%) as white solid. MS (M/e):393.50(M + H).
Example 161
3- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -1, 3-thiazolidine
DIPEA (CAN 7087-68-5, 123mg, 166. mu.L, 949. mu. mol) was added to 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 37mg, 110. mu. mol) and thiazolidine (CAN 504-78-9, 31.0mg, 27.4. mu.L, 330. mu. mol) in dioxaneAlkane (1mL) and N, N-dimethylacetamide (122. mu.L). The reaction was stirred at 120 ℃ for 2.5 h. Water was added and the reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine, and Na2SO4Dried and concentrated in vacuo to afford 39mg of a yellow solid, which was purified by flash chromatography (silica gel, 5g, 0% to 35% EtOAc in heptane) and preparationHPLC purification of form to afford the title compound (13mg, 30%) as an off-white solid. MS (M/e):389.2(M + H).
Example 162
6- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2 lambda 6-thia-6-azaspiro [3.3] heptane 2, 2-dioxide
DIPEA (CAN 7087-68-5, 76.9mg, 102. mu.L, 595. mu. mol) was added to 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 40mg, 119. mu. mol) and 2-thia-6-azaspiro [3.3]Heptane, 2, 2-dioxide (trifluoroacetate salt of CAN 1263182-09-7, 62.2mg, 238 μmol) in dioxaneAlkane (1.1mL) and N, N-dimethylacetamide (131. mu.L). The reaction mixture was stirred at 120 ℃ for 16 h. Water was added and the reaction mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine, and Na2SO4Dried and concentrated in vacuo to afford 55mg of a light brown solid, which was purified by preparative TLC (silica gel, 1.0mm, EtOAc) to afford the title compound (27mg, 51%) as a white solid. MS (M/e):447.2(M + H).
Example 163
(2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile
DIPEA (CAN 7087-68-5, 76.9mg, 102. mu.L, 595. mu. mol) is addedTo 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 40mg, 119. mu. mol) and (R) -pyrrolidine-2-carbonitrile hydrochloride (CAN 675602-84-3, 47.3mg, 357. mu. mol) in dioxaneAlkane (623 μ L). The reaction mixture was heated in a microwave oven at 120 ℃ for 30 min. Water was added and the mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined and washed with Na2SO4Dried and concentrated in vacuo to afford 38mg of crude product, which was purified by preparative TLC (silica gel, 1.0mm, 1:1, heptane/EtOAc) to afford the title compound (3mg, 6%) as a white solid. MS (M/e) 396.2(M + H).
Example 164
(3S) -1- [ 2-tert-butyl-9- [ [1- (cyclopropylmethyl) tetrazol-5-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described in example 158b), (S) -1- (2-tert-butyl-9H-purin-6-yl) pyrrolidin-3-ol (example 158a, 40mg, 153. mu. mol) was reacted with 5- (chloromethyl) -1- (cyclopropylmethyl) -1H-tetrazole (CAN 1341701-60-7, 79.3mg, 459. mu. mol) to give the title compound (45mg, 74%) as white viscous oil. MS (M/e):398.3(M + H).
Example 165
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) pyrrolidin-3-ol
DIPEA (CAN 7087-68-5, 46.1mg, 61.1. mu.L, 357. mu. mol) was added to a solution of 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 30mg, 89.2. mu. mol) and 3- (trifluoromethyl) pyrrolidin-3-ol hydrochloride (CAN 1334147-81-7, 34.2mg, 178. mu. mol) in NMP (1 mL). The reaction mixture was stirred at 100 ℃ for 16 h. Water was added and the mixture was extracted with EtOAc (2 × 20 mL). The organic layers were combined, washed with brine, and Na2SO4Dried and concentrated in vacuo to afford 76mg of a dark brown oil, which was purified by preparative TLC (silica, 2.0mm, 1:1 heptane/EtOAc) to afford the title compound (29mg, 72%) as an off-white viscous oil. MS (M/e):455.3(M + H).
Example 166
(3S) -1- [ 2-tert-butyl-9- [ (1-tert-butyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol
In analogy to the procedure described in example 158b), (S) -1- (2-tert-butyl-9H-purin-6-yl) pyrrolidin-3-ol (example 158a, 40mg, 153. mu. mol) was reacted with 1-tert-butyl-5- (chloromethyl) -1H-tetrazole (CAN 75470-92-7, 88.1mg, 459. mu. mol) to give the title compound (29mg, 47%) as off-white solid. MS (M/e):400.4(M + H).
Example 167
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) azetidin-3-ol
In analogy to the procedure described in example 171a), 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 30mg, 89.2 μmol) was reacted with 3- (trifluoromethyl) azetidin-3-ol hydrochloride (CAN848192-96-1, 31.7mg, 178 μmol) to give the title compound (26mg, 66%) as white solid. MS (M/e):441.3(M + H).
Example 168
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (2, 2-difluoro-5-azaspiro [2.4] hept-5-yl) purine
In analogy to the procedure described in example 171a) 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 29mg, 86.3 μmol) was reacted with 1, 1-difluoro-5-azaspiro [2.4] heptane hydrochloride (CAN1215071-12-7, 29.3mg, 173 μmol) to give the title compound (29mg, 78%) as off-white solid. MS (M/e):433.3(M + H).
Example 169
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylazetidin-3-ol
In analogy to the procedure described in example 171a), 2-tert-butyl-6-chloro-9- ((3-chloropyridin-2-yl) methyl) -9H-purine (example 157a, 30mg, 89.2 μmol) was reacted with 3-methylazetidin-3-ol hydrochloride (CAN 124668-46-8, 22.1mg, 178 μmol) to give the title compound (11mg, 32%) as colorless solid. MS (M/e) 387.3(M + H).
Example 170
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 total volume of 0.2ml binding buffer (50 mM Tris, 5mM MgCl for CB1 receptor)22.5mM EDTA, and 0.5% (wt/vol) fatty acid free BSA, pH 7.4, and 50mM Tris, 5mM MgCl for the CB2 receptor22.5mM EGTA, and 0.1% (wt/vol) fatty acid free BSA, pH 7.4), 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 Businesssolution, 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.
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％NaN3) And 50 μ l of detection solution (20 μ M mAb Alexa700-cAMP 1:1, and 48 μ M Ruthenium-2-AHA-cAMP) stop the assay and oscillate 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 0.13nM 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.
The compounds of the present invention are CB2 receptor agonists, the EC thereof50Less than 1 μ M and at least 10-fold selective in the corresponding assay relative to CB 1. Particular compounds of the invention are CB2 receptor agonists, the EC thereof50Less than 0.05 μ M and at least 500-fold selective 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:
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 |
| Povidone (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 pH 5.0 |
| 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 (16)
1. A compound of the formula (I),
wherein
A is CH2，CH2CH2，CH2CO or absent;
R1is tert-butyl, tert-butylamino, 2, 2-dimethylpropoxy or halogen;
R2and R3Together with the nitrogen atom to which they are attached, form pyrrolidinyl, substituted pyrrolidinyl, thiazolidinyl, 2-oxa-7-azaspiro [3.4]]Octyl, 2-oxa-6-azaspiro [3.3]Heptyl, azetidinyl, substituted azetidinyl, 2, 2-dioxo-2. lamda.6-thia-6-azaspiro [3.3]Heptyl or halo-5-azaspiro [2.4]]A heptyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one to four substituents independently selected from the group consisting of: halogen, hydroxy, C1-8Alkyl, hydroxy C1-8Alkyl, cyano, C1-8Alkylcarbonylamino, C1-8Alkylcarbonyloxy and halo C1-8And wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from: halogen, hydroxy, C1-8Alkyl and halo C1-8An alkyl group; and is
R4Is hydrogen, phenyl, halophenyl, C1-8Alkylphenyl, halogeno C1-8Alkylphenyl, pyridyl, halopyridyl, C3-8Cycloalkyl radical, C1-8Alkyl radical, C1-8Alkyl radicalOxadiazolyl, oxacyclopentyl, C1-8Alkyl tetrazolyl, C1-8Alkoxy radical, C1-8Alkylsulfonylphenyl, halo C1-8Alkyl radical, C1-8Alkoxyphenyl, dioxothietanyl, C3-8Cycloalkyl tetrazolyl, halo C1-8alkyl-1H-pyrazolyl or C3-8Cycloalkyl radical C1-8An alkyl tetrazolyl group;
or a pharmaceutically acceptable salt thereof;
provided that the following are excluded:
2-chloro-6- (1-pyrrolidinyl) -9H-purine;
2-chloro-9- (phenylmethyl) -6- (1-pyrrolidinyl) -9H-purine; and
1- [ 2-chloro-9- (1-methylethyl) -9H-purin-6-yl ] -3-pyrrolidinol.
2. The compound of claim 1, whereinA is CH2。
3. The compound of claim 1 or 2, wherein R1Is tert-butyl or 2, 2-dimethylpropoxy.
4. The compound of claim 1 or 2, wherein R1Is a tert-butyl group.
5. The compound of claim 1 or 2, wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl group, a substituted pyrrolidinyl group, or a substituted azetidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from: halogen, hydroxy C1-8Alkyl and cyano, and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from: halogen, hydroxy and halogeno C1-8An alkyl group.
6. The compound of claim 1 or 2, wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl group, a substituted pyrrolidinyl group, or a substituted azetidinyl group, wherein substituted pyrrolidinyl is pyrrolidinyl substituted with one or two substituents independently selected from: fluoro, hydroxy, hydroxymethyl and cyano and wherein substituted azetidinyl is azetidinyl substituted with one or two substituents selected from: fluorine, hydroxyl and trifluoromethyl.
7. The compound of claim 1 or 2, wherein R2And R3Together with the nitrogen atom to which they are attached, form a thiazolidinyl, difluoropyrrolidinyl, hydroxypyrrolidinyl, hydroxymethylpyrrolidinyl, cyanopyrrolidinyl, difluoroazetidinyl or (hydroxy) (trifluoromethyl) azacycloA butyl group.
8. The compound of claim 1 or 2, wherein R4Is halophenyl, halo C1-8Alkylphenyl, halopyridyl, oxolanyl, C1-8Alkylsulfonylphenyl, pyridyl or C3-8A cycloalkyl tetrazolyl group.
9. The compound of claim 1 or 2, wherein R4Is chlorophenyl, chlorofluorophenyl, trifluoromethylphenyl, chloropyridyl, oxolanyl, methylsulfonylphenyl, pyridyl or cyclopropyltetrazolyl.
10. A compound according to claim 1 or 2 selected from
2-tert-butyl-9- [ (4-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methylphenyl) methyl ] purine;
2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
5- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
2-tert-butyl-9- (cyclohexylmethyl) -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-ethylpurine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9-propylpurine;
2- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (oxolane-3-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-phenylethyl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-methoxyethyl) purine;
3- [ [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methoxyphenyl) methyl ] purine;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-pyridin-3-ylethyl) purine;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1-pyridin-2-yl ethanone;
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
3- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] thietane 1, 1-dioxide;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methoxyphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- (2-tert-butyl-9-ethylpurin-6-yl) pyrrolidin-3-ol;
1- (2-tert-butyl-9-propylpurin-6-yl) pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-phenylethyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (cyclohexylmethyl) purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purine;
1- [ 2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (oxocyclopent-3-yl) purin-6-yl ] pyrrolidin-3-ol;
2- [ 2-tert-butyl-6- (3-hydroxypyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
n- { (S) -1- [ 2-tert-butyl-9- (2-chloro-benzyl) -9H-purin-6-yl ] -pyrrolidin-3-yl } -acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
n- [ (S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide
N- [ (S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]An acetamide;
7- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
7- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-7-azaspiro [3.4]Octane;
7- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] -3-methylpyrrolidin-3-ol;
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (3-chlorophenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
n- [ (S) -1- [ 2-tert-butyl-9- [ [3- (M-fluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
n- [ (S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
2- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
5- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
3- [ [ 2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
2-tert-butyl-9- (2-methoxyethyl) -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (4-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
7- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
(3S) -1- [ 2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purine;
(3S) -1- [ 2-tert-butyl-9- (2-methoxyethyl) purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (1-methyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [4- (trifluoromethyl) -1H-pyrazol-3-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-methyl-1, 2, 4-)Oxadiazol-5-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] -3-methylpyrrolidin-3-ol;
n- [ (3S) -1- [ 2-tert-butyl-9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-yl ] acetamide;
7- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2-oxa-7-azaspiro [3.4] octane;
2-tert-butyl-6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-methylsulfonylphenyl) methyl ] -6- (3,3,4, 4-tetrafluoropyrrolidin-1-yl) purine;
n-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (5-methyl-1, 3, 4-)Oxadiazol-2-yl) methyl]Purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-2-amine;
n-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (1-methyltetrazol-5-yl) methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purin-2-amine;
n-tert-butyl-6- (3, 3-difluoropyrrolidine)-1-yl) -9- [ (3-methyl-1, 2,4-Oxadiazol-5-yl) methyl]Purin-2-amine;
(3S) -1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ (2-chlorophenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
(3S) -1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-5-methyl-1, 3,4-Oxadiazole;
5- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-3-methyl-1, 2,4-Oxadiazole;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ (1-methyltetrazol-5-yl) methyl ] purine;
(3S) -1- [2- (tert-butylamino) -9- (3,3, 3-trifluoropropyl) purin-6-yl ] pyrrolidin-3-ol;
1- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (2, 2-dimethylpropoxy) -9- [ (2-methylsulfonylphenyl) methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [9- [ (3-chloropyridin-2-yl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -3-methylpyrrolidin-3-ol;
1- [2- (2, 2-dimethylpropoxy) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-ol;
1- [2- (tert-butylamino) -9- [ [3- (trifluoromethyl) -1H-pyrazol-4-yl ] methyl ] purin-6-yl ] -3-methylpyrrolidin-3-ol;
n-tert-butyl-6- (2-oxa-6-azaspiro [3.3] hept-6-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-2-amine;
n-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (2-oxa-6-azaspiro [3.3] hept-6-yl) purin-2-amine;
(3S) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
3- [ [6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
n-tert-butyl-9- [ (3-methyl-1, 2,4-Oxadiazol-5-yl) methyl]-6- (2-oxa-6-azaspiro [ 3.3)]Hept-6-yl) purin-2-amine;
n-tert-butyl-6- (2-oxa-6-azaspiro [33] hept-6-yl) -9- (3,3, 3-trifluoropropyl) purin-2-amine;
6- [9- [ (2-chlorophenyl) methyl ] -2- (2, 2-dimethylpropoxy) purin-6-yl ] -2-oxa-6-azaspiro [3.3] heptane;
[ (2R) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-2-yl radical]Methanol;
[ (2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
(2R) -1- [ 2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile;
(2R) -1- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidine-2-carbonitrile;
6- [ 2-tert-butyl-9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-2-oxa-6-azaspiro [3.3]Heptane;
3- [ [ 2-tert-butyl-6- (1, 3-thiazolidin-3-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Oxadiazole;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9H-purine;
[ (3S) -1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]Pyrrolidin-3-yl radical]Acetate ester;
[1- [2- (tert-butylamino) -9- [ (4-methyl-1, 2, 5-)Oxadiazol-3-yl) methyl]Purin-6-yl]-3-methylpyrrolidin-3-yl]Acetate ester;
9-benzyl-2-chloro-6- (3, 3-difluoropyrrolidin-1-yl) purine;
(3S) -1- [ 2-tert-butyl-9- [ (1-propan-2-yltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
[ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
(3S) -1- [ 2-tert-butyl-9- [ (1-propyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(2R,3S) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2- (hydroxymethyl) pyrrolidin-3-ol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoroazetidin-1-yl) purine;
3- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -1, 3-thiazolidine;
6- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -2 λ 6-thia-6-azaspiro [3.3] heptane 2, 2-dioxide;
(2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile;
(3S) -1- [ 2-tert-butyl-9- [ [1- (cyclopropylmethyl) tetrazol-5-yl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (1-tert-butyltetrazol-5-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) azetidin-3-ol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (2, 2-difluoro-5-azaspiro [2.4] hept-5-yl) purine; and
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3-methylazetidin-3-ol.
11. A compound according to claim 1 or 2 selected from
2-tert-butyl-9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (oxolane-3-yl) purine;
2- [ 2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) purin-9-yl ] -1- (2-chlorophenyl) ethanone;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- [ (2-methylsulfonylphenyl) methyl ] purine;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
2-tert-butyl-6- (3, 3-difluoropyrrolidin-1-yl) -9- (2-pyridin-3-ylethyl) purine;
1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
1- [ 2-tert-butyl-9- [ (2-chloro-4-fluorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ [2- (trifluoromethyl) phenyl ] methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (3-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chloropyridin-3-yl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
(3S) -1- [ 2-tert-butyl-9- [ (2-chlorophenyl) methyl ] purin-6-yl ] pyrrolidin-3-ol;
9- [ (2-chlorophenyl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) purine;
6- (3, 3-difluoropyrrolidin-1-yl) -2- (2, 2-dimethylpropoxy) -9- [ [2- (trifluoromethyl) phenyl ] methyl ] purine;
2-tert-butyl-9- [ (1-cyclopropyltetrazol-5-yl) methyl ] -6- (3, 3-difluoropyrrolidin-1-yl) purine;
[ (2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidin-2-yl ] methanol;
2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] -6- (3, 3-difluoroazetidin-1-yl) purine;
3- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -1, 3-thiazolidine;
(2R) -1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] pyrrolidine-2-carbonitrile; and
1- [ 2-tert-butyl-9- [ (3-chloropyridin-2-yl) methyl ] purin-6-yl ] -3- (trifluoromethyl) azetidin-3-ol.
12. A compound which is
3- [ [ 2-tert-butyl-6- (4-methylpiperazin-1-yl) purin-9-yl]Methyl radical]-4-methyl-1, 2,5-Diazole.
13. A process for the preparation of a compound according to any one of claims 1 to 12, which process comprises reacting a compound of formula (a) at Y-a-R4In the presence of a catalyst, reacting the mixture,
wherein Y is a leaving group and wherein A and R1To R4Is as defined in any one of claims 1 to 9.
14. A compound according to claim 1 or 2, when manufactured according to a process of claim 13.
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a therapeutically inert carrier.
16. Use of a compound according to any one of claims 1 to 12 for the preparation of a medicament for the treatment or prophylaxis of pain, atherosclerosis, age-related macular degeneration, diabetic retinopathy, glaucoma, retinal vein occlusion, retinopathy of prematurity, ocular ischemic syndrome, geographic atrophy, diabetes mellitus, inflammation, inflammatory bowel disease, ischemia-reperfusion injury, acute liver failure, liver fibrosis, lung fibrosis, kidney 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, amyotrophic lateral sclerosis, multiple sclerosis, inflammatory bowel disease, acute liver failure, liver fibrosis, chronic allograft nephropathy, diabetic nephropathy, cardiomyopathy, heart failure, myocardial ischemia, myocardial infarction, systemic sclerosis, thermal injury, burning, hypertrophic scars, keloids, gingivitis pyrexia fever, liver cirrhosis, Alzheimer's disease, parkinson's disease, stroke, transient ischemic attack or uveitis.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13166293 | 2013-05-02 | ||
| EP13166293.4 | 2013-05-02 | ||
| PCT/EP2014/058545 WO2014177490A1 (en) | 2013-05-02 | 2014-04-28 | Purine derivatives as cb2 receptor agonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1214245A1 HK1214245A1 (en) | 2016-07-22 |
| HK1214245B true HK1214245B (en) | 2019-07-26 |
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