US2013079354A1PendingUtilityA1
Pyridyl derivatives and their use as therapeutic agents
Est. expiryJul 29, 2023(expired)· nominal 20-yr term from priority
Inventors:Melwyn AbreoDaniel F. HarveyMikhail A. KondratenkoWenbao LiRajender KambojVishnumurthy KodumuruMichael D. WintherHeinz W. GschwendNagasree ChakkaShifeng LiuSerguei SviridovShaoyi Sun
A61P 43/00A61P 9/12A61P 9/10A61P 3/10A61P 9/00A61P 3/06A61P 7/02A61P 9/14A61P 35/00A61P 3/04A61P 3/00A61P 17/10C07D 213/76C07D 401/04A61K 31/501C07D 213/75A61K 31/444A61P 1/16C07D 213/81C07D 401/14A61P 19/06A61K 31/496C07D 213/71A61K 31/00
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Claims
Abstract
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): wherein W, V, x, y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I):
wherein:
x and y are each independently 1, 2 or 3;
W is —O—, —N(R 1 )—, —C(O)—, —S(O) t —; (where t is 0, 1 or 2), —N(R 1 )S(O) 2 —, —S(O) 2 N(R 1 )—, —OS(O) 2 N(R 1 )—, —C(O)N(R 1 )—, —OC(O)N(R 1 )—, —C(S)N(R 1 )—, —OC(S)N(R 1 )—, —N(R 1 )C(O)— or —N(R 1 )C(O)N(R 1 )—;
V is —C(O)—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 —, —S(O) 2 N(R 1 )— or —C(R 11 )H—, provided that when x and y are both 1 and W is —C(O)N(R 1 )— or —N(R 1 )C(O)—, then V is not —C(O)—;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
R 11 is hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
2 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula (I):
wherein:
x and y are each independently 1, 2 or 3;
W is —O—, —N(R 1 )—, —C(O)—, —S(O) t —; (where t is 0, 1 or 2), —N(R 1 )S(O) 2 —, —S(O) 2 N(R 1 )—, —C(O)N(R 1 )—, —OC(O)N(R 1 )—, —C(S)N(R 1 )—, —OC(S)N(R 1 )—, —N(R 1 )C(O)— or —N(R 1 )C(O)N(R 1 )—;
V is —C(O)—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 —, —S(O) 2 N(R 1 )— or —C(R 11 )H—, provided that when x and y are both 1 and W is —C(O)N(R 1 )— or —N(R 1 )C(O)—, then V is not —C(O)—;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 and R 10 are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
R 11 is hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
3 . The method of claim 2 wherein the mammal is a human.
4 . The method of claim 3 wherein the disease or condition is selected from the group consisting of Type II diabetes, impaired glucose tolerance, insulin resistance, obesity, fatty liver, non-alcoholic steatohepatitis, acne, dyslipidemia and metabolic syndrome and any combination of these.
5 . The method of claim 4 wherein the disease or condition is Type II diabetes.
6 . The method of claim 4 wherein the disease or condition is obesity.
7 . The method of claim 4 wherein the disease or condition is metabolic syndrome.
8 . The method of claim 4 wherein the disease or condition is fatty liver.
9 . The method of claim 4 wherein the disease or condition is non-alcoholic steatohepatitis.
10 . A compound of formula (IIa):
wherein:
x and y are each independently 1, 2 or 3, provided that x and y are not each 1;
R 1 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 7 -C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 12 hydroxyalkyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 13 -C 19 aralkyl, C 1 -C 12 heteroaryl, C 3 -C 12 heterocyclylalkyl and C 3 -C 12 heteroarylalkyl, provided that R 2 is not pyrazinyl, pyridinonyl, pyrrolidinonyl or imidazolyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 9 and R 9a together, or R 10 and R 10a together form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 7 , R 7a , R 10 and R 10a , together with one of R 8 , R 8a , R 9 and R 9a , form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
11 . The compound of claim 10 wherein:
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 7 -C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 13 -C 19 aralkyl, C 3 -C 12 heterocyclylalkyl, and C 3 -C 12 heteroarylalkyl;
R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each hydrogen; and
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen.
12 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 10 .
13 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 10 .
14 . A compound of formula (IIb):
wherein:
x and y are each independently 1, 2 or 3, provided that x and y are not each 1;
R 1 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 6 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is phenyl optionally substituted with one or more substituents selected from halo and C 1 -C 6 trihaloalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 , —S(O) 2 N(R 12 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 9 and R 9a together, or R 10 and R 10a together form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 7 , R 7a , R 10 and R 10a , together with one of R 8 , R 8a , R 9 and R 9a , form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
15 . The compound of claim 14 wherein:
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 6 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is phenyl optionally substituted with one or more substituents selected from halo and C 1 -C 6 trihaloalkyl;
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 and —S(O) 2 N(R 12 ) 2 ;
R 4 , R 5 and R 6 are each hydrogen;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
16 . The compound of claim 15 wherein:
R 2 is C 7 -C 12 aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 3 alkyl and C 1 -C 6 trihaloalkyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
17 . (canceled)
18 . The compound of claim 15 wherein:
R 2 is C 1 -C 12 alkyl or C 2 -C 12 alkenyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
19 . (canceled)
20 . The compound of claim 15 wherein:
R 2 is C 3 -C 12 heteroarylalkyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 3 alkyl and C 1 -C 6 trihaloalkyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
21 . (canceled)
22 . The compound of claim 15 wherein:
R 2 is phenyl optionally substituted with one or more substituents selected from halo and C 1 -C 6 trihaloalkyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
23 . (canceled)
24 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 14 .
25 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 14 .
26 .- 32 . (canceled)
33 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (III):
wherein:
x and y are each independently 1, 2 or 3′,
V a is —C(O)—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 1 )—;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 6 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, provided that when V a is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
34 .- 41 . (canceled)
42 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (IV):
wherein:
x and y are each independently 1, 2 or 3;
V a is —C(O)—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 1 )—;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, provided that when V a is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
43 . (canceled)
44 . A compound of formula (V):
wherein:
x and y are each independently 1, 2 or 3;
W a is —O—, —N(R 1 )— or —S(O) t — (where t is 0, 1 or 2);
V a is —C(O)—, —C(S)—, —C(O)N(R 1 )—, —C(O)O—, —S(O) 2 — or —S(O) 2 N(R 1 )—;
x and y are each independently 1, 2 or 3;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, provided that when V a is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
45 . The compound of claim 44 wherein:
x and y are each 1;
W a is —O—;
V a is —C(O)—;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each hydrogen; and
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen.
46 . The compound of claim 45 wherein:
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 , —S(O) 2 N(R 12 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
47 . The compound of claim 44 wherein:
x and y are each 1;
W a is —N(R 1 )—;
V a is —C(O)—;
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each hydrogen; and
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen.
48 . The compound of claim 47 wherein:
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 , —S(O) 2 N(R 12 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
49 . The compound of claim 44 wherein:
x and y are each 1;
W a is —S(O) t — (where t is 0, 1 or 2);
V a is —C(O)—;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each hydrogen; and
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen.
50 . The compound of claim 49 wherein:
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 , —S(O) 2 N(R 12 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
51 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 44 .
52 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 44 .
53 . A compound of formula (VIa):
wherein:
x and y are each independently 1, 2 or 3, provided that x and y are not each 1;
R 1 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 7 -C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 13 -C 19 aralkyl, C 3 -C 12 heterocyclylalkyl, and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 5 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to each other;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
including a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
54 . The compound of claim 53 wherein:
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 7 -C 12 alkyl, C 3 -C 12 alkenyl, C 7 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 13 -C 19 aralkyl, C 3 -C 12 heterocyclylalkyl, and C 3 -C 12 heteroarylalkyl;
R 3 is selected from the group consisting of C 3 -C 12 alkyl, C 3 -C 12 alkenyl, C 3 -C 12 hydroxyalkyl, C 3 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxy, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 5 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 4 , R 5 and R 6 are each hydrogen; and
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen.
55 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 53 .
56 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 53 .
57 . A compound of formula (VIb):
wherein:
x and y are each independently 1, 2 or 3, provided that x and y are not each 1;
each R 1 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C 2 -C 12 hydroxyalkyl, C 4 -C 12 cycloalkylalkyl and C 7 -C 19 aralkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, where some or all of the rings may be fused to each other;
R 3 is naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 , —S(O) 2 N(R 12 ) 2 , cycloalkyl, heterocyclyl, heteroaryl and heteroarylcycloalkyl, provided that R 3 is not phenyl substituted with optionally substituted thienyl, and provided that when R 3 is naphthyl, R 2 can not be C 1 -C 6 alkyl, C 2 -C 6 hydroxyalkyl or phenyl substituted by amino;
R 4 , R 5 and R 6 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 13 ) 2 ;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 9 and R 9a together, or R 10 and R 10a together are an oxo group, while the remaining R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 10 , R 10a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 10 , R 10a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl; and
each R 13 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof or a prodrug thereof.
58 . The compound of claim 57 wherein:
R 1 is hydrogen or C 1 -C 6 alkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 3 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 19 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
R 3 is naphthyl or phenyl, each optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 or —S(O) 2 N(R 12 ) 2 ;
R 4 , R 5 and R 6 are each hydrogen;
R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , and R 10a are each hydrogen; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
59 . The compound of claim 58 wherein:
R 2 is C 7 -C 12 aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 3 alkyl and C 1 -C 6 trihaloalkyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
60 . (canceled)
61 . The compound of claim 58 wherein:
R 2 is C 1 -C 12 alkyl or C 2 -C 12 alkenyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
62 . (canceled)
63 . The compound of claim 58 wherein:
R 2 is C 3 -C 12 cycloalkyl or C 4 -C 12 cycloalkylalkyl; and
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
64 . (canceled)
65 . The compound of claim 58 wherein:
R 2 is C 3 -C 12 heterocyclylalkyl optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, C 1 -C 6 trihaloalkoxy, C 1 -C 6 alkylsulfonyl, —N(R 12 ) 2 , —OC(O)R 12 , —C(O)OR 12 and —S(O) 2 N(R 12 ) 2 ;
R 3 is phenyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy; and
each R 12 is independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl or aralkyl.
66 . The compound of claim 65 wherein R 2 is 2-piperazinylethyl optionally substituted by —C(O)OR 12 .
67 . (canceled)
68 . The compound of claim 58 wherein:
R 2 is C 7 -C 12 aralkyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 3 alkyl and C 1 -C 6 trihaloalkyl; and
R 3 is naphthyl optionally substituted by one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl and C 1 -C 6 trihaloalkoxy.
69 . (canceled)
70 . A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 57 .
71 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 57 .Join the waitlist — get patent alerts
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