US2004224960A1PendingUtilityA1
Pharmaceutical compositions and methods for their use
Est. expiryFeb 21, 2023(expired)· nominal 20-yr term from priority
Inventors:Allen BorchardtPeter DragovichJavier GonzalezHui LiMaria Angelica LintonJohn Howard Tatlock
A61P 31/14A61P 43/00A61P 1/16C07D 417/12C07D 285/06C07D 495/04C07D 513/04C07D 409/06C07D 263/58C07D 405/06C07D 471/04C07D 473/30C07D 413/14C07D 413/06C07D 405/12C07D 407/12C07D 413/10C07D 407/10C07D 309/32C07D 417/10C07D 405/10C07D 407/06C07D 409/10C07D 413/12C07D 487/04C07D 417/06C07D 405/14C07D 473/36
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Claims
Abstract
The present invention relates to pharmaceutical compositions and to methods for their use in decreasing cytochrome P450 (CYP450) enzyme activity. The present invention also relates to methods of increasing the bioavailability of a compound in a mammal. Additionally, the present invention relates to methods of decreasing the metabolism of certain compounds in a mammal that are metabolized by the cytochrome P450 enzyme. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound metabolized by at least one cytochrome P450 enzyme and a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I).
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of increasing the bioavailability in a mammal of a first compound which is metabolized by cytochrome P450, comprising administering to said mammal said first compound and a cytochrome P450-inhibiting amount of a compound of formula (I),
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
2 . A method according to claim 1 , wherein the cytochrome P450 is the 2D6 isoform.
3 . A method according to claim 1 , wherein said first compound is selected from alprenolol, amiflamine, amitryptyline, aprindine, atomoxetine, bisoprolol, brofaromine, bufuralol, bunitrolol, bupronolol, captopril, chlorpheniramine, chlorpromazine, cilostazol, cinnarizine, citalopram, clomipramine, clozapine, codeine, cyclobenzprine, debrisoquine, desipramine, desmethylcitalopram, dexfenfluramine, dextromethorphan, dihydrocodine, dolasetron, donezepil, doxepin, encainide, ethylmorphine, fenfluramine, flecainide, flunarizine, fluvoxamine, fluoxetine, fluphenazine, guanoxan, haloperidol, hydrocodone, imipramine, indoramin, labetalol, lidocaine, loratidine, maprotiline, (R)-methadone, meperidine, methamphetamine, methoxyamphetamine, 5-methoxyindoleethylamine, methoxyphenamine, methylenedioxymethamphetamine, metoprolol, mexiletine, mianserin, minaprine, morphine, nefazodone, nelfinavir, norcodeine, nortryptyline, ondansetron, omeprazole, oxycodone, paclitaxel, paroxetine, perhexiline, perphenazine, phenformin, procodeine, promethazine, N-propylajmaline, propafenone, propanolol, retinoic acid, quinidine, risperidone, ritonavir, RU-486, sparteine, tamoxifen, testosterone, thioridazine, timolol, tolterodine, tomoxatene, tramadol, trazodone, trifluperidol, trimipramine, tropisetron, venlafaxine, vinblastine, and zuclopenthixol..
4 . A method of inhibiting cytochrome P450 activity in a mammal, comprising administering to said mammal a cytochrome P450 activity-inhibiting amount of a compound of formula (I),
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
5 . A method according to claim 4 , wherein the cytochrome P450 enzyme is the 2D6 isoform.
6 . A method of inhibiting cytochrome P450 enzyme activity, comprising contacting said cytochrome P450 enzyme with a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I),
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
7 . A method according to claim 6 , wherein the cytochrome P450 enzyme is the 2D6 isoform.
8 . A method of decreasing the metabolism in a mammal of a first compound which is metabolized by cytochrome P450 enzyme, comprising administering to said mammal said first compound and a cytochrome P450 enzyme-inhibiting amount of a compound of formula (I),
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
9 . A method according to claim 8 , wherein the cytochrome P450 enzyme is the 2D6 isoform.
10 . A method according to claim 8 , wherein said first compound is selected from alprenolol, amiflamine, amitryptyline, aprindine, atomoxetine, bisoprolol, brofaromine, bufuralol, bunitrolol, bupronolol, captopril, chlorpheniramine, chlorpromazine, cilostazol, cinnarizine, citalopram, clomipramine, clozapine, codeine, cyclobenzprine, debrisoquine, desipramine, desmethylcitalopram, dexfenfluramine, dextromethorphan, dihydrocodine, dolasetron, donezepil, doxepin, encainide, ethylmorphine, fenfluramine, flecainide, flunarizine, fluvoxamine, fluoxetine, fluphenazine, guanoxan, haloperidol, hydrocodone, imipramine, indoramin, labetalol, lidocaine, loratidine, maprotiline, (R)-methadone, meperidine, methamphetamine, methoxyamphetamine, 5-methoxyindoleethylamine, methoxyphenamine, methylenedioxymethamphetamine, metoprolol, mexiletine, mianserin, minaprine, morphine, nefazodone, nelfinavir, norcodeine, nortryptyline, ondansetron, omeprazole, oxycodone, paclitaxel, paroxetine, perhexiline, perphenazine, phenformin, procodeine, promethazine, N-propylajmaline, propafenone, propanolol, retinoic acid, quinidine, risperidone, ritonavir, RU-486, sparteine, tamoxifen, testosterone, thioridazine, timolol, tolterodine, tomoxatene, tramadol, trazodone, trifluperidol, trimipramine, tropisetron, venlafaxine, vinblastine, and zuclopenthixol..
11 . A method according to claim 1 , wherein in the compound of formula (I):
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN; each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen; X is —CH 2 —; m is an integer from 0 to 3; n is 1 or 2; t is an integer from 0 to 3; and pharmaceutically acceptable salts and solvates thereof.
12 . A method according to claim 11 , wherein in the compound of formula (I):
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN; each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen; X is —CH 2 —; m is 1, 2or 3; n is 1; t is 0, 1, or 2; and pharmaceutically acceptable salts and solvates thereof.
13 . A method according to claim 1 , wherein the compound of formula (I) is selected from those of formula (Ia):
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
14 . A method according to claim 1 , wherein the compound of formula (I) is selected from those of formula (Ib):
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
15 . A method according to claim 1 , wherein the compound of formula (I) is selected from 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1 2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
16 . A method according to claim 1 , wherein the compound of formula (I) is selected from the (R)-enantiomers of 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1 H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-(2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-(2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
17 . A method according to claim 1 , wherein the compound of formula (I) is selected from the (S)-enantiomers of 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
18 . A method according to claim 1 , wherein the compound of formula (I) is substantially enantiomerically pure.
19 . A method according to claim 1 , wherein the compound of formula (I) is enantiomerically pure.
20 . A composition, comprising a first compound that is metabolized by at least one cytochrome P450 enzyme and a cytochrome P450 enzyme activity-inhibiting amount of a compound of formula (I),
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
21 . A composition according to claim 20 , wherein said at least one cytochrome P450 enzyme is the 2D6 isoform.
22 . A composition according to claim 20 , wherein said first compound is selected from alprenolol, amiflamine, amitryptyline, aprindine, atomoxetine, bisoprolol, brofaromine, bufuralol, bunitrolol, bupronolol, captopril, chlorpheniramine, chlorpromazine, cilostazol, cinnarizine, citalopram, clomipramine, clozapine, codeine, cyclobenzprine, debrisoquine, desipramine, desmethylcitalopram, dexfenfluramine, dextromethorphan, dihydrocodine, dolasetron, donezepil, doxepin, encainide, ethylmorphine, fenfluramine, flecainide, flunarizine, fluvoxamine, fluoxetine, fluphenazine, guanoxan, haloperidol, hydrocodone, imipramine, indoramin, labetalol, lidocaine, loratidine, maprotiline, (R)-methadone, meperidine, methamphetamine, methoxyamphetamine, 5-methoxyindoleethylamine, methoxyphenamine, methylenedioxymethamphetamine, metoprolol, mexiletine, mianserin, minaprine, morphine, nefazodone, nelfinavir, norcodeine, nortryptyline, ondansetron, omeprazole, oxycodone, paclitaxel, paroxetine, perhexiline, perphenazine, phenformin, procodeine, promethazine, N-propylajmaline, propafenone, propanolol, retinoic acid, quinidine, risperidone, ritonavir, RU-486, sparteine, tamoxifen, testosterone, thioridazine, timolol, tolterodine, tomoxatene, tramadol, trazodone, trifluperidol, trimipramine, tropisetron, venlafaxine, vinblastine, and zuclopenthixol..
23 . A composition according to claim 20 , wherein in the compound of formula (I):
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN; each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen; X is —CH 2 —; m is an integer from 0 to 3; n is 1 or 2; t is an integer from 0 to 3; and pharmaceutically acceptable salts and solvates thereof.
24 . A composition according to claim 20 , wherein in the compound of formula (I):
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN; each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen; X is —CH 2 —; m is 1, 2 or 3; n is 1; t is 0, 1, or 2; and pharmaceutically acceptable salts and solvates thereof.
25 . A composition according to claim 20 , wherein the compound of formula (I) is selected from those of formula (Ia):
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
26 . A composition according to claim 20 , wherein the compound of formula (I) is selected from those of formula (Ib):
wherein:
each R 1 is independently selected from fluorine, —C(CH 3 ) 2 CN, -cyclopropyl-CN, and -cyclobutyl-CN;
each R 2 is independently selected from hydrogen, C 1 -C 4 alkyl, and halogen;
X is —CH 2 — or —O—;
m is an integer from 0 to 5;
n is 1 or 2;
t is an integer from 0 to 3; and
pharmaceutically acceptable salts and solvates thereof.
27 . A composition according to claim 20 , wherein the compound of formula (I) is selected from 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
28 . A composition according to claim 20 , wherein the compound of formula (I) is selected from the (R)-enantiomers of 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile, 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
29 . A composition according to claim 20 , wherein the compound of formula (I) is selected from the (S)-enantiomers of 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-[2-(3-ethyl-4-hydroxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 6-[2-(3-chloro-5-ethyl-4-hydroxyphenyl)ethyl]-6-cyclopentyl-3-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 2-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(4-methyl-1H-imidazol-5-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-({2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}methoxy)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2,6-difluorophenyl)-2-methylpropanenitrile; 2-(4-{2-[2-cyclopentyl-4-hydroxy-5-(imidazo[1,2-a]pyridin-2-ylmethyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)-2-methylpropanenitrile; 3-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-cyclopentyl-6-{2-[3-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]ethyl}-4-hydroxy-5,6-dihydro-2H-pyran-2-one; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4triazol[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-(4-{2-[2-cyclopentyl-4-hydroxy-6-oxo-5-([1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-3,6-dihydro-2H-pyran-2-yl]ethyl}-2-fluorophenyl)cyclopropanecarbonitrile; 1-[4-(2-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-5-[(6-ethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 1-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]cyclopropanecarbonitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{2-cyclopentyl-4-hydroxy-5-[(6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluoro-5-methoxyphenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2,6-difluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; 2-[4-(2-{5-[(6-chloro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}ethyl)-2-fluorophenyl]-2-methylpropanenitrile; and pharmaceutically acceptable salts and solvates thereof.
30 . A composition according to claim 20 , wherein the compound of formula (I) is substantially enantiomerically pure.
31 . A composition according to claim 20 , wherein the compound of formula (I) is enantiomerically pure.
32 . A method according to claim 1 ,wherein said first compound is chosen from antagonists of the N-methyl-D-aspartate receptor.
33 . A method according to claim 32 , wherein said antagonist of the N-methyl-D-aspartate receptor is (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, or a pharmaceutically acceptable salt or solvate thereof.
34 . A method according to claim 8 , wherein said first compound is chosen from antagonists of the N-methyl-D-aspartate receptor.
35 . A method according to claim 34 , wherein said antagonist of the N-methyl-D-aspartate receptor is (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, or a pharmaceutically acceptable salt or solvate thereof.
36 . A composition according to claim 20 , wherein said first compound is chosen from antagonists of the N-methyl-D-aspartate receptor.
37 . A composition according to claim 36 , wherein said antagonist of the N-methyl-D-aspartate receptor is (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol, or a pharmaceutically acceptable salt or solvate thereof.Join the waitlist — get patent alerts
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