Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase

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 0, 1, 2 or 3;
• G is —N═ or —C(R4)═;
• J and K are each independently N or C(R10);
• L and M are each independently —N═ or —C(R4)═, provided that L and M can not both be —C(R4)═ when G is —C(R4)═ and provided that L and M can not both be —N═ when G is —N═;
• V is a direct bond, —N(R1)—, —N(R1)C(O)—, —O—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)t— (where t is 0, 1 or 2) or —S(O)pN(R1)— (where p is 1 or 2);
• W is a direct bond, —N(R1)C(O)—, —C(O)N(R1)—, —OC(O)N(R1)—, —N(R1)C(O)N(R1)—, —O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), —C(O)—, —OS(O)2N(R1)—, —OC(O)—, —C(O)O—, or —N(R1)C(O)O—;
• each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl;
• R2 is selected from the group consisting of C1-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 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 hydrogen, C1-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, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or —N(R9)2;
• or two adjacent R4 groups, together with the carbons to which they are attached, may form an aryl, heteroaryl or heterocyclyl ring system;
• R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or C1-C3alkyl;
• or R5 and R5a together, 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 R1a 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 R1a forms a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or C1-C3alkyl;
• each R9 is independently selected from hydrogen or C1-C6alkyl;
• and
• R10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy;
• as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.

A compound of formula (I):

• wherein:
• x and y are each independently 0, 1, 2 or 3;
• G is —N═ or —C(R4)═;
• J and K are each independently N or C(R10);
• L and M are each independently —N═ or —C(R4)═, provided that L and M can not both be —C(R4)═ when G is —C(R4)═ and provided that L and M can not both be —N═ when G is —N═;
• V is a direct bond, —N(R1)—, —N(R1)C(O)—, —O—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)p— (where p is 0, 1 or 2) or —S(O)pN(R1)— (where p is 1 or 2);
• W is a direct bond, —N(R1)C(O)—, —C(O)N(R1)—, —OC(O)N(R1)—, —N(R1)C(O)N(R1)—, —O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), —C(O)—, —OS(O)2N(R1)—, —OC(O)—, —C(O)O—, or —N(R1)C(O)—2;
• each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl;
• R2 is selected from the group consisting of C1-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 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 hydrogen, C1-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, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or —N(R9)2;
• or two adjacent R4 groups, together with the carbons to which they are attached, may form an aryl, heteroaryl or heterocyclyl ring system;
• R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or C1-C3alkyl;
• or R5 and R5a together, 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 forms a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or C1-C3alkyl;
• each R9 is independently selected from hydrogen or C1-C6alkyl;
• and
• R10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy;
• as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.

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

• wherein:
• x and y are each independently 0, 1, 2 or 3;
• G is —N═ or —C(R4)═;
• J and K are each independently N or C(R10);
• L and M are each independently —N═ or —C(R4)═, provided that L and M can not both be —C(R4)═ when G is —C(R4)═ and provided that L and M can not both be —N═ when G is —N═;
• V is a direct bond, —N(R1)—, —N(R1)C(O)—, —O—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)p— (where p is 0, 1 or 2) or —S(O)pN(R1)— (where p is 1 or 2);
• W is a direct bond, —N(R1)C(O)—, —C(O)N(R1)—, —OC(O)N(R1)—, —N(R1)C(O)N(R1)—, —O—, —N(R1)—, —S(O)t— (where t is 0, 1 or 2), —N(R1)S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), —C(O)—, —OS(O)2N(R1)—, —OC(O)—, —C(O)O—, or —N(R1)C(O)O—;
• each R1 is independently selected from the group consisting of hydrogen, C1-C12alkyl, C2-C12hydroxyalkyl, C4-C12cycloalkylalkyl and C7-C19aralkyl;
• R2 is selected from the group consisting of C1-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 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 hydrogen, C1-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, C1-C12alkyl, C1-C12alkoxy, haloalkyl, cyano, nitro or —N(R9)2;
• or two adjacent R4 groups, together with the carbons to which they are attached, may form an aryl, heteroaryl or heterocyclyl ring system;
• R5, R5a, R6, R6a, R7, R7a, R8 and R8a are each independently selected from hydrogen or C1-C3alkyl;
• or R5 and R5a together, R6 and R6a together, or R7 and R7, 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 forms a direct bond or an alkylene bridge, while the remaining R5, R5a, R6, R6a, R7, R7a, R8, and R8a are each independently selected from hydrogen or C1-C3alkyl;
• each R9 is independently selected from hydrogen or C1-C6alkyl;
• and
• R10 is independently selected from hydrogen, fluoro, chloro, C1-C12alkyl or C1-C12alkoxy;
• as a stereoisomer, enantiomer or tautomer thereof, as a mixture of stereoisomers, as a pharmaceutically acceptable salt thereof, or as a prodrug thereof.