Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors

A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I):

• wherein:
• W is selected from —O—, —OC(O)—, —OC(O)N(R5)—, —OS(O)2N(R5)—, —C(O)—, —C(O)O—, —C(O)N(R5)—, —N(R5)—, —N(R5)C(O)—, —N(R5)C(O)O—, —N(R5)C(O)N(R5)—, —N(R5)S(O)2—, —S(O)t— (where t is 0, 1 or 2), or —S(O)2N(R5)—;
• V is selected from —C(O)—, —C(O)N(R5)—, —C(O)O—, —S(O)t— (where t is 1 or 2) or a direct bond;
• R1 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R2 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R3 is selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trihaloalkyl, trihaloalkoxy, cyano, nitro, —OR4, —OC(O)R2, —OC(O)N(R4)(R5), —OS(O)2N(R4)(R5), —S(O)tR2 (where t is 0, 1 or 2), —S(O)tN(R4)(R5) (where t is 1 or 2), —C(O)R2, —C(O)OR2, —C(O)N(R4)(R5), —N(R4)(R5), —N(R5)C(O)R5, —N(R5)C(O)OR5, —N(R5)C(O)N(R4)(R5) or —N(R5)S(O)2R2;
• and
• each R4 and R5 is independently selected from —R6—N(R7)2, —R6—OR7, —R6—C(O)OR7, hydrogen, alkyl, cycloalkylalkyl or aralkyl;
• each R6 is a straight or branched alkylene chain;
• and
• each R7 is hydrogen, alkyl, aryl or aralkyl;
• or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non-racemic mixture thereof,
• or a pharmaceutically acceptable salt or prodrug thereof.

A method of treating a disease or condition mediated by stearoyl-CoA desaturase 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:
• W is selected from —O—, —OC(O)—, —OC(O)N(R5)—, —OS(O)2N(R5)—, —C(O)—, —C(O)O—, —C(O)N(R5)—, —N(R5)—, —N(R5)C(O)—, —N(R5)C(O)O—, —N(R5)C(O)N(R5)—, —N(R5)S(O)2—, —S(O)t— (where t is 0, 1 or 2) or —S(O)2N(R5)—;
• V is selected from —C(O)—, —C(O)N(R5)—, —C(O)O—, —S(O)t— (where t is 1 or 2) or a direct bond;
• R1 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R2 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R3 is selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trihaloalkyl, trihaloalkoxy, cyano, nitro, —OR4, —OC(O)R2, —OC(O)N(R4)(R5), —OS(O)2N(R4)(R5), —S(O)tR2 (where t is 0, 1 or 2), —S(O)tN(R4)(R5) (where t is 1 or 2), —C(O)R2, —C(O)OR2, —C(O)N(R4)(R5), —N(R4)(R5), —N(R5)C(O)R5, —N(R5)C(O)OR5, —N(R5)C(O)N(R4)(R5) or —N(R5)S(O)2R2;
• each R4 and R5 is independently selected from —R6—N(R7)2, —R6—OR7, —R6—C(O)OR7, hydrogen, alkyl, cycloalkylalkyl or aralkyl;
• each R6 is a straight or branched alkylene chain;
• and
• each R7 is hydrogen, alkyl, aryl or aralkyl;
• or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non-racemic mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• wherein the disease or condition is a body weight disorder, metabolic syndrome, fatty liver, non-alcoholic steatohepatitis or a skin disorder.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (I):

• wherein:
• W is selected from —O—, —OC(O)—, —OC(O)N(R5)—, —OS(O)2N(R5)—, —C(O)—, —C(O)O—, —C(O)N(R5)—, —N(R5)—, —N(R5)C(O)—, —N(R5)C(O)O—, —N(R5)C(O)N(R5)—, —N(R5)S(O)2—, —S(O)t— (where t is 0, 1 or 2), or —S(O)2N(R5)—;
• V is selected from —C(O)—, —C(O)N(R5)—, —C(O)O—, —S(O)t— (where t is 1 or 2) or a direct bond;
• R1 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R2 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R3 is selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trihaloalkyl, trihaloalkoxy, cyano, nitro, —OR4, —OC(O)R2, —OC(O)N(R4)(R5), —OS(O)2N(R4)(R5), —S(O)tR2 (where t is 0, 1 or 2), —S(O)tN(R4)(R5) (where t is 1 or 2), —C(O)R2, —C(O)OR2, —C(O)N(R4)(R5), —N(R4)(R5), —N(R5)C(O)R5, —N(R5)C(O)OR5, —N(R5)C(O)N(R4)(R5) or —N(R5)S(O)2R2;
• each R4 and R5 is independently selected from —R6—N(R7)2, —R6—OR7, —R6—C(O)OR7, hydrogen, alkyl, cycloalkylalkyl or aralkyl;
• each R6 is a straight or branched alkylene chain;
• and
• each R7 is hydrogen, alkyl, aryl or aralkyl;
• or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non-racemic mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

A pharmaceutical composition comprising a pharmaceutically acceptable excipient;

• a therapeutically effective amount of a compound of formula (I):
• wherein:
• W is selected from —O—, —OC(O)—, —OC(O)N(R5)—, —OS(O)2N(R5)—, —C(O)—, —C(O)O—, —C(O)N(R5)—, —N(R5)—, —N(R5)C(O)—, —N(R5)C(O)O—, —N(R5)C(O)N(R5)—, —N(R5)S(O)2—, —S(O)t— (where t is 0, 1 or 2), or —S(O)2N(R5)—;
• V is selected from —C(O)—, —C(O)N(R5)—, —C(O)O—, —S(O)t— (where t is 1 or 2) or a direct bond;
• R1 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
• or R1 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R2 is selected from alkyl, alkenyl, —R6—OR7, hydroxyalkenyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;
• or R2 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from cycloalkyl, heterocyclyl, aryl or heteroaryl and where some or all of the rings may be fused to each other;
• R3 is selected from hydrogen, alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, fluoro, chloro, bromo, trihaloalkyl, trihaloalkoxy, cyano, nitro, —OR4, —OC(O)R2, —OC(O)N(R4)(R5), —OS(O)2N(R4)(R5), —S(O)tR2 (where t is 0, 1 or 2), —S(O)tN(R4)(R5) (where t is 1 or 2), —C(O)R2, —C(O)OR2, —C(O)N(R4)(R5), —N(R4)(R5), —N(R5)C(O)R5, —N(R5)C(O)OR5, —N(R5)C(O)N(R4)(R5) or —N(R5)S(O)2R2;
• each R4 and R5 is independently selected from —R6—N(R7)2, —R6—OR7, —R6—C(O)OR7, hydrogen, alkyl, cycloalkylalkyl or aralkyl;
• each R6 is a straight or branched alkylene chain;
• and
• each R7 is hydrogen, alkyl, aryl or aralkyl;
• or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non-racemic mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof;
• and
• a therapeutically effective amount of insulin, insulin derivative, insulin mimetic, insulin secretagogue, insulinotropic sulfonylurea receptor ligand, PPAR ligand, insulin sensitizer, biguanide, alpha-glucosidase inhibitors, GLP-1, GLP-1 analog, GLP-1 mimetic, DPPIV inhibitor, HMG-CoA reductase inhibitor, squalene synthase inhibitor, FXR ligand, LXR ligand, cholestyramine, fibrates, nicotinic acid or aspirin.