US 7,456,180 B2
Piperazine derivatives and their use as therapeutic agents
Serguei Sviridov, Burnaby (Canada); Vishnumurthy Kodumuru, Burnaby (Canada); Shifeng Liu, Port Coquitlam (Canada); Melwyn Abreo, Jamul, Calif. (US); Michael D. Winther, Vancouver (Canada); Heinz W. Gschwend, Santa Rosa, Calif. (US); Rajender Kamboj, Burnaby (Canada); Shaoyi Sun, Vancouver (Canada); Mark W. Holladay, San Diego, Calif. (US); Wenbao Li, San Diego, Calif. (US); and Chi Tu, San Diego, Calif. (US)
Assigned to Xenon Pharmaceuticals Inc., Burnaby, British Columbia (Canada)
Appl. No. 10/567,009
PCT Filed Jul. 29, 2004, PCT No. PCT/US2004/024658
§ 371(c)(1), (2), (4) Date Jan. 30, 2006,
PCT Pub. No. WO2005/011657, PCT Pub. Date Feb. 10, 2005.
Claims priority of provisional application 60/491095, filed on Jul. 30, 2003.
Prior Publication US 2006/0252767 A1, Nov. 09, 2006
Int. Cl. A61K 31/497 (2006.01); C07D 241/02 (2006.01)
U.S. Cl. 514—252.11  [544/357] 25 Claims
 
1. 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 (Ia):

OG Complex Work Unit Drawing
wherein:
x and y are each independently 1, 2 or 3;
W is —N(R1)C(O)N(R1)—, —O—, —N(R1)—, —S(O)— (where t is 0, 1 or 2), —N(R1)S(O)2—, —S(O)2N(R1)—, —C(O)O— or —N(R1)C(O)O—;
W is —N(R1)C(O)N(R1)—, —O—, —N(R1)—, —S(O)— (where t is 0, 1 or 2), —N(R1)S(O)2—, —S(O)2N(R1)—, —C(O)O— or —N(R1)C(O)O—;
V is —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)2— or —S(O)2N(R1)—;
G and M are each —N═, and J and L are each —C(R4)═;
each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C2-C19aralkyl;
R2 is selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, and C3-C12heteroarylalkyl;
or R2 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;
R3 is selected from the group consisting of C3-C12alkyl, C2-C12alkenyl, C2-C12hydroxyalkyl, C2-C12hydroxyalkenyl, C2-C12alkoxyalkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl and C3-C12heteroarylalkyl;
or R3 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;
each R4 is independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R9)2;
each R5, R5a, R6, R6a, R7, R7a, R8 and R8a is independently selected from hydrogen, or C1-C3alkyl;
or R5 and R5a together, or R6 and R6a together, or R7 and R7a together, or R8 and R8a together are an oxo group, provided that when V is —C(O)—, R6 and R6a together or R8 and R8a together do not form an oxo group, while the remaining R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or C1-C3alkyl;
or one of R5, R5a, R6, and R6a together with one of R7, R7a, R8 and R8a form an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or C1-C3alkyl;
R10 is hydrogen or C1-C3alkyl; and
each R9 is independently selected from hydrogen or C1-C6alkyl;
a stereoisomer, enantiomer ot tautomer thereof, or a pharmaceutically acceptable salt thereof,
wherein the mammal is a human,
wherein the disease or condition is selected from the group consisting of fatty liver, non-alcoholic steatohepatitis, Type II diabetes, impaired glucose tolerance, insulin resistance, obesity, dyslipidemia, acne, and metabolic syndrome and any combination of these.