Piperazine derivatives as stearoyl-coa desaturase inhibitors and their use as therapeutic agents

A compound of formula (II):

• wherein:
• x and y are each independently 1;
• W is —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)2—, —S(O)2N(R1)—, —C(O)—, —OS(O)2N(R1)—, —OC(O)—, —C(O)O— or —N(R1)C(O)O—;
• V is —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, or —C(R10)H—;
• J and M are each —C(R4)═;
• 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, Cr—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 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 hydrogen;
• each R5, R5a, R6, R6a, R7, R7a, R8 and R8a is independently selected from hydrogen or C1-C3alkyl;
• and
• R10 is hydrogen or C1-C3alkyl;
• wherein each of C1-C3alkyl, C1-C12alkyl, C2-C12hydroxyalkyl, and C2-C12alkoxyalkyl is optionally substituted by one of the following groups:
• C1-C12alkyl, C2-C12alkenyl, halo, C2-C12haloalkenyl, cyano, nitro, C6-C19aryl, C3-C12cycloalkyl, C3-C12heterocyclyl, C1-C12heteroaryl, —OR14, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)S(O)tR16) (where t is 1 to 2), —S(O)tOR16 (where t is 1 to 2), —S(O)tR16 (where t is 0 to 2), and —S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl (optionally substituted with one or more halo groups), C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• and each R16 is C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• wherein C2-C12alkenyl or C2-C12hydroxyalkenyl is optionally substituted by one of the following groups:
• C1-C12alkyl, C2-C12alkenyl, halo, haloC1-C12alkenyl, cyano, nitro, C6-C19aryl, C7-C19aralkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, C3-C12heteroarylalkyl, —OR14, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)(S(O)tR16) (where t is 1 to 2), —S(O)tOR16 (where t is 1 to 2), —S(O)tR16 (where t is 0 to 2), and —S(O)tN(R14)2 (where t is 1 to 2 where each R14 is independently hydrogen, C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heteroarylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• and each R16 is C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• wherein each of C3-C12cycloalkyl and the cycloalkyl part of C4-C12cycloalkylalkyl is optionally substituted b one or more substituents selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, halo, haloC1-C12alkyl, haloC2-C12alkenyl, cyano, nitro, C6-C19aryl, C7-C19aralkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, C3-C12heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR19 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• each R15 is independently a direct bond or a straight or branched C1-C12alkylene or C2-C12alkenylene chain;
• and each R16 is C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• wherein each of C6-C19aryl or the aryl part of C7-C19aralkyl is optionally substituted by one or more substituents selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, halo, haloC1-C12alkyl, haloC2-C12alkenyl, cyano, nitro, C6-C19aryl, C7-C19aralkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, C3-C12heteroarylalkyl, —R15—OR14, —R15OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2) —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• each R15 is independently a direct bond or a straight or branched C1-C12alkylene or C2-C12alkenylene chain;
• and each R16 is C1-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• wherein each of C3-C12heterocyclyl or the heterocyclyl part of C3-C12heterocyclylalkyl is optionally substituted by one or more substituents selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, halo, haloC1-C12alkyl, haloC2-C12alkenyl, cyano, oxo, thioxo, nitro, C6-C19aryl, C7-C19aralkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, C3-C12heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)(S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14), (where t is 1 to 2) where each R14 is independently hydrogen, C1-C12alkyl, C2-C12alkyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• each R15 is independently a direct bond or a straight or branched C1-C12alkylene or C2-C12alkenylene chain;
• and each R16 is C1-C12alkyl, C2-C12alkenyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• wherein each of C1-C12heteroaryl or the heteroaryl part of C3-C12heteroarylalkyl is optionally substituted by one or more substituents selected from the group consisting of C1-C12alkyl, C2-C12alkenyl, halo, haloC1-C12alkyl, haloC2-C12alkenyl, cyano, oxo, thioxo, nitro, C6-C19aryl, C7-C19aralkyl, C3-C12cycloalkyl, C4-C12heteroalkylalkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl, C3-C12heteroarylalkyl, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, R15—N(R14)S(O)tR16) (where t is 1 to 2), —R15—S(O)tOR16 (where t is 1 to 2), —R15—S(O)tR16 (where t is 0 to 2), and —R15—S(O)tN(R14)2 (where t is 1 to 2) where each R14 is independently hydrogen, C1-C12alkyl, C2-C12alkenyl, haloC1-C12alkyl, —C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl;
• each R15 is independently a direct bond or a straight or branched C1-C12alkylene or C2-C12alkenylene chain;
• and each R16 is C1-C12alkyl, C2-C12alkenyl, haloC1-C12alkyl, C3-C12cycloalkyl, C4-C12cycloalkylalkyl, C6-C19aryl, C7-C19aralkyl, C3-C12heterocyclyl, C3-C12heterocyclylalkyl, C1-C12heteroaryl or C3-C12heteroarylalkyl, and where each of the above substituents is unsubstituted;
• and
• a stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt thereof.