WO2006125180B1 - Piperazine derivatives and their uses as therapeutic agents - Google Patents
Piperazine derivatives and their uses as therapeutic agentsInfo
- Publication number
- WO2006125180B1 WO2006125180B1 PCT/US2006/019562 US2006019562W WO2006125180B1 WO 2006125180 B1 WO2006125180 B1 WO 2006125180B1 US 2006019562 W US2006019562 W US 2006019562W WO 2006125180 B1 WO2006125180 B1 WO 2006125180B1
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- alkyl
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- hydrogen
- independently selected
- cycloalkylalkyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
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 (I); where p, G, J, K, L, M, V, R2, R3, R5, R6 and R6a are defined herein. Pharmaceutical compositions comprising the compounds of formula (I) are also disclosed.
Claims
1. A compound of formula (I):
K is selected from N or C(R7); when K is N, V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O)1- (where t is 0, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -C(R8)H- or -C(NR1'3)-; wfejsn K is C(R7), V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R1)-, -N(R1)C(O)-, -S(OX- (where t is 0, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -N(R1)S(O)q- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-;
J is selected from -C(O)-, -S(O)r (where t is 0, 1 or 2), or -C(R6)2-;
G, L and M are independently selected from -N*= or -C(R4)=; each R1 is independently selected from the groiup consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylatkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, CrC6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxy alkenyl, aikoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; 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 alkyl., alkenyl, hydroxyatkyl, hydroxyalkenyl, aikoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 ring$ wherein the rings are independently selected from the group consisting of cycloalkyl heterocyclyl, aryl and heteroaryi and where some or all of the rings may be fused to each other; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2, each R6 is alkyl; 51
or one of R5 together with another one of R6 onja different carbon atom forms an alkylene bridge, while the remaining R5's are each alkyl; each R8 is independently selected from hydrogen or alkyl;
R6a and R6b are each independently selected from hydrogen or alkyl, or R6a and R6b together form an oxo group;
R7 is selected from hydrogen, alkyl, fluoro, or ctfiloro; and
R8 is selected from hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R1)2; or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non- racemic mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof.
2. The compound of Claim 1 wherein: p is 0 to 8;
W is -N(R1)C(O)-, -S(O),- (where t is 0, 1 or 2), -C(O)-, -N(R1)S(O)2-, -OC(O)-, -N(R1)C(NR1a)-, -C(NR1a)N(R1)-, heteroaryl, heterocyclyl or a direct bond;
K is selected from N or C(R7); when K is N1 V is -C(O)-, -C(O)O-, -C(S)-, -C(Oi)N(R1)-, -S(0)r (where t is O, 1 or 2), -S(0)qN(R1)- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-; when K is C(R7), V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where α is 1 or 2), -N(R1)S(O)q- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-;
J is selected from -C(O)-, -S(O),- (where t is O, I or 2), or -C(R6)2-;
G, L and M are independently selected from -Ni= or -C(R4)=; each R1 is independently selected from the groϋiu consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the grφu,p consisting of hydrogen, Ci-C6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyi, alkenyl, hydroxyaikyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro aihd -N(R1)2; each R5 is alkyl; 52
or one of R5 together with another one of R5 on a different carbon atom forms an alkylene bridge, while the remaining R5ls are each alkyl; each R6 is independently selected from hydrogen or alkyl;
R6a and R6b are each independently selected from hydrogen or alkyl, or R6a and R6b together form an oxo group;
R7 is selected from hydrogen, alkyl, fluoro, or chloro; and
R8 is selected from hydrogen, alkyl, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro or -N(R1)2.
3. The compound of Claim 1 wherein: p is 0 to 8;
K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-;
J is selected from -C(O)-, -S(0)r (where t is O, 1 or 2), or -C(R6)2~;
M is -CH2-; at least one of G or L is -N= and the other is -N1= or -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the grotjp consisting of hydrogen, CrC6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, ara kyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R^)2; each R5 is alkyl; each R6 is independently selected from hydrogen or alkyl; and
R6a and Rδb together form an oxo group.
4. The compound of Claim 3 wherein: p is O to 8;
K is N; 53
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O),- (where t is 0, 1 or 2), -S(0)qN(R1)- (where q is 1 or 2) or -C(NR1a)-;
J is -C(O)-;
M is -CH2-; at least one of G or L is -N= and the other is -Nfc or -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, C-ι-C6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2, each R5 is alkyl; and
R8a and R6b together form an oxo group.
5. The compound of Claim 3 wherein: p is O to 8; K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-; 
M is -CH2-; at least one of G or L is -N= and the other is -N= or -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, Ci-C6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2, each R5 is alkyl; each R8 is independently selected from hydrogen or alkyl; and
Rδa and R6b together form an oxo group.
6. The compound of Claim 1 wherein: p is 0 to 8;
K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(Ol),- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-;
J is selected from -C(O)-, -S(O)1- (where t is O, I or 2), or -C(R6)2-;
G1 L and M are each -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyatkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the groqp consisting of hydrogen, CrC6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2; each R5 is alkyl; each R6 is independently selected from hydrogen or alkyl; and
R6a and R6b together form an oxo group.
7. The compound of Claim 6 wherein: p is O to 8;
K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(Ci)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-; 55
J is -C(O)-;
G, L and M are each -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, CrC6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyi, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2l each R5 is alkyl; and
R6a and Reb together form an oxo group.
8. The compound of Claim 6 wherein: p is 0 to 8;
K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(Oj)n (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-; 
G, L and M are each -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alky!, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, CrC6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alky), alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, araϋkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, nitro and -N(R1J2; 56
each R5 is alkyl; each R8 is independently selected from hydrogen or alkyl; and
R6a and R6b together form an oxo group.
9. The compound of Claim 6 wherein: p is 0 to 8;
K is N;
V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2) or -C(NR1a)-;
J is -S-;
G, L and M are each -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyi, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl;
R3 is selected from the group consisting of alkySl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyi, cycloalkyl, cycloalkylalkyl, aryl, ar»a|kyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2; each R5 is alkyi; and
R6a and Rβb together form an oxo group.
10. A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity comprising contacting a source of hSCD with a compound of formula (I):
K is selected from N or C(R7); when K is N, V is -C(O)-, -C(O)O-, -C(S)-, -C(O)N(R1)-, -S(O)1- (where t is 57
0, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -C(R8)H- or -C(NR ia)k when K is C(R7), V is -O-, -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1- (where t is 0, 1 or 2), -S(O)qN(R1)- (where cj is 1 or 2), -N(R1)S(O)q- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-;
J is selected from -C(O)-, -S(O)r (where t is O, 1 or 2), or -C(R6)2-; G, L and M are independently selected from -N1= or -C(R 44s)_=.; each R1 is independently selected from the grouf consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyi and aralkyl; each R1a is independently selected from the group consisting of hydrogen, CrC6alkyl, cycloalkylalkyi, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyi, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 ring$ \|vherein the rings independently selected from the group consisting of cycloalkyll, 
heterocyclyl, aryl heteroaryl and where some or all of the rings may be fused to e ach other;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyi, aryl, arakyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; or R3 is a multi-ring structure having 2 to 4 rings wherein the rings are independently selected from the group consisting of cycloalkyl,, leterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused toieach other; each R4 is independently selected from the groUi consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2; each R5 is alkyl; or one of R5 together with another one of R5 on* ε different carbon atom forms an alkylene bridge, while the remaining R5's are each alkyl; each Rβ is independently selected from hydrogerti or alkyl;
R6a and Rβb are each independently selected from hydrogen or alkyl, or R6a and R8b together form an oxo group;
R7 is selected from hydrogen, alkyl, fluoro, or chlbro; and
R8 is selected from hydrogen, alkyl, fluoro, chlorc , methoxy, trifluoromethyl, cyano, nitro or -N(R1)2; or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non- racemic mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof. 58
11. 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 ejffective amount of a compound of formula (!):
K is selected from N or C(R7); when K is N, V is -C(O)-, -C(O)O-, -C(S)-, -C(CON(R1)-, -S(O)1- (where t is O1 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-; when K is C(R7), V is -O-, -C(O)-, -C(O)O-, -OC(b)-, -C(S)-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O),- (where t is O, 1 or 2), -S(O)qN(R1)- (where \ is 1 or 2), -N(R1)S(O)q- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-;
J is selected from -C(O)-, -S(O)1- (where t is O, i| or 2), or -C(R6)2-;
G, L and M are independently selected from -N=|or -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the gπbϋp consisting of hydrogen, Ci-C6alkyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyatkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, ara kyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; 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 e,ach other;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, ara kyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; 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 e ach other; each R4 is independently selected from the gro'u 3 consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro and -N(R1)2; 59
each R5 is alkyl; or one of R5 together with another one of R5 on a different carbon atom forms an alkylene bridge, while the remaining R5's are each alkyl; each R6 is independently selected from hydrogen or alkyl;
RBa and R6b are each independently selected from hydrogen or alkyl, or R6a and R6b together form an oxo group;
R7 is selected from hydrogen, alkyl, fluoro, or cftipro; and
R8 is selected from hydrogen, alkyl, fluoro, chlorq, methoxy, trifluoromethyl, cyano, nitro or -N(R1)2; or a stereoisomer, enantiomer or tautomer thereαrf, or a racemic or non- racemic mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof.
12. The method of Claim 11 wherein the mammal is a human.
13. The method of Claim 12 wherein the dis'ease or condition is selected selected from the group consisting of Type Il diabetes, impaired glucose tolerance, insulin resistance, obesity, fatty liver, non-alcoholic δteatohepatitis, dyslipidemia, acne and metabolic syndrome and any combination of these.
14. The method of Claim 13 wherein the disease or condition is Type Il diabetes.
15. The method of Claim 13 wherein the disease or condition is obesity.
16. The method of Claim 13 wherein the disease or condition is metabolic syndrome.
17. The method of Claim 13 wherein the disease or condition is ratty liver.
18. The method of Claim 13 wherein the dis'ease or condition is non-alcoholic steatohepatitis.
19. The method of Claim 13 wherein the disease or condition is acne. 60
20. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of formula (I):
K is selected from N or C(R7); when K is N1 V is -C(O)-, -C(O)O-, -C(S)-, -C(O)M(R1)-, -S(O),- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-; when K is C(R7), V is -O-, -C(O)-, -C(O)O-, -OCHQ)-, -C(S)-, -C(O)N(R1)-, -N(R1)C(O)-, -S(O)1- (where t is O, 1 or 2), -S(O)qN(R1)- (where q is 1 or 2), -N(R1)S(O)q- (where q is 1 or 2), -C(R8)H- or -C(NR1a)-;
J is selected from -C(O)-, -S(O)r (where t is O, 1 or 2), or -C(R6)2-;
G, L and M are independently selected from -Nf= or -C(R4)=; each R1 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkylalkyl and aralkyl; each R1a is independently selected from the group consisting of hydrogen, Ci-C6a!kyl, cycloalkylalkyl, -OR1 and cyano;
R2 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; or R2 is a multi-ring structure having 2 to 4 ringst. wherein the rings are independently selected from the group consisting of cycloalkyl., neterocyclyl, aryl and heteroaryl and where some or all of the rings may be fused to sach other;
R3 is selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl; 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 sach other; each R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, cyano, nitro ana -N(R1)2; each R5 is alkyl; or one of R5 together with another one of R5 on a; different carbon atom 61
forms an alkylene bridge, while the remaining R5's are each alkyl; each R6 is independently selected from hydrogem or alkyl;
R6a and R6b are each independently selected frorm hydrogen or alkyl, or R6a and R6b together form an oxo group;
R7 is selected from hydrogen, alkyl, fluoro, or cnluro; and
R8 is selected from hydrogen, alkyl, fluoro, chlorψ, methoxy, trifluoromethyl, cyano, nitro or -N(R1)2; or a stereoisomer, enantiomer or tautomer thereof, or a racemic or non- racemic mixture thereof, or a pharmaceutically acceptable salt or prodrug thereof.
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| US68292605P | 2005-05-19 | 2005-05-19 | |
| US60/682,926 | 2005-05-19 |
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Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101506203B (en) | 2006-08-24 | 2013-10-16 | 诺瓦提斯公司 | 2- (pyrazin-2-yl) -thiazole and 2- (1h-pyraz0l-3-yl) -thiazole derivatives as well as related compounds as stearoyl-coa desaturase (scd) inhibitors for the treatment of metabolic, cardiovascular and other syndromes |
| US8575167B2 (en) | 2007-02-06 | 2013-11-05 | Takeda Pharmaceutical Company Limited | Spiro compounds having stearoyl-CoA desaturase action |
| JP2010518104A (en) * | 2007-02-09 | 2010-05-27 | アストラゼネカ・アクチエボラーグ | Aza-isoindolone and their use as metabotropic glutamate receptor potentiators-613 |
| PA8782701A1 (en) * | 2007-06-07 | 2009-01-23 | Janssen Pharmaceutica Nv | UROTENSIN II RECEIVER ANTAGONISTS |
| US7842696B2 (en) | 2007-06-21 | 2010-11-30 | Forest Laboratories Holdings Limited | Piperazine derivatives as inhibitors of stearoyl-CoA desaturase |
| JP2011516494A (en) * | 2008-04-07 | 2011-05-26 | ギリアード サイエンシーズ， インコーポレイテッド | 2H-benzo [b] [1,4] oxazin-3 (4H) -one derivatives for use as inhibitors of stearoyl-CoA desaturase |
| EP2350029A1 (en) * | 2008-10-15 | 2011-08-03 | Gilead Sciences, Inc. | 3-hydroquinazolin-4-one derivatives for use as stearoyl coa desaturase inhibitors |
| CA2750564A1 (en) | 2009-02-17 | 2010-08-26 | Merck Canada Inc. | Novel spiro compounds useful as inhibitors of stearoyl-coenzyme a delta-9 desaturase |
| US8383643B2 (en) | 2009-07-28 | 2013-02-26 | Merck Canada Inc. | Spiro compounds useful as inhibitors of stearoyl-coenzyme A delta-9 desaturase |
| WO2011030312A1 (en) | 2009-09-10 | 2011-03-17 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | NOVEL INHIBITORS OF STEAROYL-CoA-DESATURASE-1 AND THEIR USES |
| EA201270778A1 (en) | 2010-05-06 | 2013-04-30 | Бристол-Майерс Сквибб Компани | BICYCLIC HETEROARRYAL ANALOGUES AS MODELING GPR119 RECEPTOR MODULATORS |
| WO2013056015A1 (en) | 2011-10-14 | 2013-04-18 | Incyte Corporation | Isoindolinone and pyrrolopyridinone derivatives as akt inhibitors |
| MX2014004426A (en) | 2011-10-15 | 2014-07-09 | Genentech Inc | Scd1 antagonists for treating cancer. |
| BR112014029365A2 (en) | 2012-05-22 | 2017-06-27 | Hoffmann La Roche | selective undifferentiated cell inhibitors |
| WO2017107089A1 (en) | 2015-12-23 | 2017-06-29 | Merck Sharp & Dohme Corp. | 3- (1h-pyrazol-4-yl) pyridineallosteric modulators of the m4 muscarinic acetylcholine receptor |
| US10329289B2 (en) | 2015-12-23 | 2019-06-25 | Merck Sharp & Dohme Corp. | 6,7-dihydro-5H-pyrrolo[3,4-B]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor |
| WO2018112840A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | 6, 5-fused heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
| WO2018112842A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | 6,6-fused heteroaryl piperidine ether allosteric modulators of m4 muscarinic acetylcholine receptor |
| WO2018112843A1 (en) | 2016-12-22 | 2018-06-28 | Merck Sharp & Dohme Corp. | Heteroaryl piperidine ether allosteric modulators of the m4 muscarinic acetylcholine receptor |
| WO2019000237A1 (en) | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | 3-(1h-pyrazol-4-yl)pyridine allosteric modulators of m4 muscarinic acetylcholine receptor |
| WO2019000238A1 (en) | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | 5-(pyridin-3-yl)oxazole allosteric modulators of m4 muscarinic acetylcholine receptor |
| WO2019000236A1 (en) | 2017-06-27 | 2019-01-03 | Merck Sharp & Dohme Corp. | 3-(1h-pyrazol-4-yl)pyridine allosteric modulators of m4 muscarinic acetylcholine receptor |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6165873A (en) * | 1984-09-07 | 1986-04-04 | Mitsui Petrochem Ind Ltd | 2-piperazinopyrimidine derivative |
| JPH0635460B2 (en) * | 1985-04-22 | 1994-05-11 | 三井石油化学工業株式会社 | 2-Piperazinopyrimidine derivative |
| US4959368A (en) * | 1986-02-24 | 1990-09-25 | Mitsui Petrochemical Industries Ltd. | Therapeutic agent for neurological diseases |
| US5304555A (en) * | 1987-08-26 | 1994-04-19 | Mitsui Petrochemical Industries, Ltd. | Pyrimidines and pharmaceutically acceptable salts thereof useful in treatment of neurological disorders |
| US6417362B1 (en) * | 1997-05-30 | 2002-07-09 | Meiji Seika Kaisha, Ltd. | Nitrogenous heterocyclic compounds and hyperlipemia remedy containing the same |
| KR20020005662A (en) * | 1999-04-09 | 2002-01-17 | 기따자또 이찌로 | Nitrogen-containing heterocyclic compounds and benzamide compounds and drugs containing the same |
| ATE556056T1 (en) * | 2003-07-29 | 2012-05-15 | Xenon Pharmaceuticals Inc | PYRIDYL DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS |
| CN101712653A (en) * | 2003-07-30 | 2010-05-26 | 泽农医药公司 | Pyridazine derivatives and their use as therapeutic agents |
| JP4808616B2 (en) * | 2003-07-30 | 2011-11-02 | ゼノン・ファーマシューティカルズ・インコーポレイテッド | Pyridazine derivatives and their use as therapeutic agents |
| BRPI0412348A (en) * | 2003-07-30 | 2006-09-05 | Xenon Pharmaceuticals Inc | piperazine derivatives and their use as therapeutic agents |
| AU2004261267B9 (en) * | 2003-07-30 | 2009-04-09 | Xenon Pharmaceuticals Inc. | Pyridyl derivatives and their use as therapeutic agents |
| TW200613272A (en) * | 2004-08-13 | 2006-05-01 | Astrazeneca Ab | Isoindolone compounds and their use as metabotropic glutamate receptor potentiators |
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