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US 7,547,698 B2Granted
Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coadesaturase (SCD)
AssigneeXenon Pharmaceuticals Inc.
InventorsRajender Kamboj, Jianmin Fu, Vishnumurthy Kodumuru, Shifeng Liu, Kashinath Sadalapure, Nagasree Chakka, Duanjie Hou, Shaoyi Sun
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Abstract
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise, for example, administering to a mammal in need thereof a compound of formula (I): where x, y, J, K, L, M, W, V, R2, R3, R5, R5a, R6, R6a, R7, R7a, R8 and R8a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
Claims9
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;
- J and K are each independently N or C(R11);
- L is N;
- M is —N═;
- 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—, —N(R1)C(O)O— or —C(R1)2—;
- V is —N(R1)—, —N(R1)C(O)—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), or —C(R10)H—;
- 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 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;
- 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;
- R10 is hydrogen or C1-C3alkyl;
- and
- R11 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.
18 more elements
A compound of formula (I):
- wherein:
- x and y are each independently 1, 2 or 3;
- J and K are each independently N or C(R11);
- L is N;
- M is —N═;
- 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—, —N(R1)C(O)O— or —C(R1)2—;
- V is —N(R1)—, —N(R1)C(O)—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), or —C(R10)H—;
- 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 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;
- 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;
- R10 is hydrogen or C1-C3alkyl;
- and
- R11 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.
18 more elements
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 1, 2 or 3;
- J and K are each independently N or C(R11);
- L is N;
- M is —N═;
- 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—, —N(R1)C(O)O— or —C(R1)2—;
- V is —N(R1)—, —N(R1)C(O)—, —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R1)—, —S(O)p— (where p is 1 or 2), —S(O)pN(R1)— (where p is 1 or 2), or —C(R10)H—;
- 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 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;
- 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;
- R10 is hydrogen or C1-C3alkyl;
- and
- R11 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.
18 more elements
Dependencies are inferred from the claim text.