Pyridazine derivatives and their use as therapeutic agents
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (Ia): where x, y, W, V, R 2 , R 3 , R 4 , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 and R 9a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
1. An in vivo method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (Ia)
wherein:
x and y are each independently 1, 2 or 3;
W is —C(O)N(R 1 )—; —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— —N(R 1 )C(O)—, —OC(O)N(R 1 )—, —N(R 1 )S(O) p —(where p is 1 or 2), —S(O) p N(R 1 )— (where p is 1 or 2), —C(O)—, —OS(O) 2 N(R 1 )—, —OC(O)—, —C(O)O—, —N(R 1 )C(O)O—, —N(R 1 )C(═NR 1a )N(R 1 )—, —N(R 1 )C(═S)N(R 1 )—, —N(R 1 )C(═NR 1a )—, or —C(═NR 1a )N(R 1 )—;
V is —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R 1 )—, —S(O) t — (where t is 0, 1 or 2), —S(O) p N(R 1 )— (where p is 1 or 2), —C(R 10 )H—, or —C(═NR 1a )—;
each R 1 is independently selected from the group consisting of hydrogen; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl;
R 1a is selected from the group consisting of hydrogen, —OR 1 , cyano, C 1 -C 6 alkyl and cycloalkylalkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
or R 2 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;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 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;
R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ;
or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 6 , R 6a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
R 10 is hydrogen or C 1 -C 3 alkyl; and
each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof.
2. A compound of formula (la):
wherein:
x and y are each independently 1, 2 or 3;
W is —C(O)N(R 1 )—; —C(O)N[C(O)R 1a ]—, —N(R 1 )C(O)N(R 1 )— —N(R 1 )C(O)—, —OC(O)N(R 1 )—, —N(R 1 )S(O) p (where p is 1 or 2), —S(O) p N(R 1 )— (where p is 1 or 2), —C(O)—, —OS(O) 2 N(R 1 )—, —OC(O)—, —C(O)O—, —N(R 1 )C(O)O—, —N(R 1 )C(═NR 1a )N(R 1 )—, —N(R 1 )C(═S)N(R 1 )—, —N(R 1 )C(═NR 1a )—, or —C(═NR 1a )N(R 1 )—;
V is —C(O)—, —C(O)O—, —C(S)—, —C(O)N(R 1 )—, —S(O) t — (where t is 0, 1 or 2) —S(O) p N(R 1 )— (where p is 1 or 2), —C(R 10 )H—, or —C(═NR 1a )—;
each R 1 is independently selected from the group consisting of hydrogen;
C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, methyl or trifluoromethyl; and C 2 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of methoxy and hydroxyl;
R 1a is selected from the group consisting of hydrogen, —OR 1 , cyano, C 1 -C 6 alkyl and cycloalkylalkyl;
R 2 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl, and C 3 -C 12 heteroarylalkyl;
or R 2 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;
R 3 is selected from the group consisting of C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 hydroxyalkyl, C 2 -C 12 hydroxyalkenyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 3 -C 12 cycloalkyl, C 4 -C 12 cycloalkylalkyl, aryl, C 7 -C 12 aralkyl, C 3 -C 12 heterocyclyl, C 3 -C 12 heterocyclylalkyl, C 1 -C 12 heteroaryl and C 3 -C 12 heteroarylalkyl;
or R 3 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;
R 4 and R 5 are each independently selected from hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro or —N(R 12 ) 2 ;
R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or R 6 and R 6a together, or R 7 and R 7a together, or R 8 and R 8a together, or R 9 and R 9a together are an oxo group, provided that when V is —C(O)—, R 7 and R 7a together or R 8 and R 8a together do not form an oxo group, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
or one of R 6 , R 6a , R 7 , and R 7a together with one of R 8 , R 8a , R 9 and R 9a form an alkylene bridge, while the remaining R 6 , R 6a , R 7 , R 7a , R 8 , R 8a R 9 , and R 9a are each independently selected from hydrogen or C 1 -C 3 alkyl;
R 10 is hydrogen or C 1 -C 3 alkyl; and
each R 12 is independently selected from hydrogen or C 1 -C 6 alkyl;
a stereoisomer, enantiomer or tautomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof.
3. The compound of claim 2 wherein W is —N(R 1 )C(O)— and V is —C(═NH)—.
4. The compound of claim 2 wherein W is —N(R 1 )C(═NR 1a )—.
5. The compound of claim 2 wherein W is —N(R 1 )C(═NR 1a )N(R 1 )— or —N(R 1 )C(═S)N(R 1 )—.
6. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 2 .