US 2016/0263132 A1 · INHIBITORS OF DIACYLGLYCEROL O-ACYLTRANSFERASE 1 (DGAT-1) AND USES THEREOF

Abstract

The invention pertains to the use of fused bicyclo heterocyclic adducts of thiohydroxy pyridines or pyrimidines as diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitors to treat hyperlipidiemias and various diseases and disorders associated therewith. Other conditions also can be ameliorated or avoided, such as high postprandial triglycerides or diet-related hypertriglyceridemia, cardiovascular risk associated with excessive triglycerides, and insulin resistance/glucose intolerance in overweight patients, those with diabetes or other glucose metabolic disorders such as Syndrome X and/or polycystic ovary disease.

A compound of Formula (I), pharmaceutically acceptable salts or stereoisomers thereof,

Q-G1-G2-G3-G4-Z Formula (I)
wherein Q is Q2, Q3, Q4, Q5, Q8, or Q9;
Q2 is
X is N or C(R4) and when X is C(R4);
E is selected from the group consisting of O and S;
R1 is selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, C(O)Ra, ORa and NRaRb;
optionally, when X is C(R4), R4 may be combined with R1 to form a 5-, 6- or 7-membered fused ring;
Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
R2 and R3 are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, C(O)Ra, CO2Ra, C(O)NRaRb, (C1-C4)alkylene-ORa and (C1-C4)perfluoroalkyl or may be combined with R5 to form a 3-, 4-, 5- or 6-membered spiro ring;
optionally, having from 0 to 3 heteroatoms selected from the group consisting of N, O and S;
R4 is selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, C(O)Ra, CO2Ra and C(O)NRaRb;
and
R5 is H or (C1-C4)alkyl;
Q3 is
wherein R6 is an optionally substituted aryl or optionally substituted heteroaryl group, wherein the optional substituents are one or more groups selected from a group H, (C1-C4)alkyl, halo, halo(C1-C4)alkyl, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, —C(O)xRa, —ORa, —S(O)xRa, —NRaRb, —C(O)NRaRb, —NRaC(O)Rb, —NRaCO NRaRb, —S(O)2NRaRb or —NRaS(O)2NRaRb where x is an integer of 1 or 2;
and
T is N, CH or CMe;
Q4 is
wherein R6 is an optionally substituted aryl or optionally substituted heteroaryl group, wherein the optional substituents are one or more groups selected from a group H, (C1-C4)alkyl, halo, halo(C1-C4)alkyl, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, —C(O)xRa, —ORa, —S(O)xRa, —NRaRb, —C(O)NRaRb, —NRaC(O)Rb, —NRaCO NRaRb, —S(O)2NRaRb or —NRaS(O)2NRaRb where x is an integer of 1 or 2;
and
T is N, CH or CMe;
Q5 is
wherein R6 is an optionally substituted aryl or optionally substituted heteroaryl group, wherein the optional substituents are one or more groups selected from a group H, (C1-C4)alkyl, halo, halo(C1-C4)alkyl, cyano, (C1-C4)alkoxy, (C1-C4)haloalkoxy, —C(O)xRa, —ORa, —S(O)xRa, —NRaRb, —C(O)NRaRb, —NRaC(O)Rb, —NRaCO NRaRb, —S(O)2NRaRb or —NRaS(O)2NRaRb where x is an integer of 1 or 2;
and
T is N, CH or CMe;
Q6 is
R7(V)nC(O)(NH)m—;
R7 is (C1-C6)alkyl, aryl, heteroaryl or cycloalkyl;
wherein each of the aryl, heteroaryl and cycloalkyl is independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of (C1-C6)alkyl, (C2-C8)alkenyl, alkynyl, —CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, —ORa, —O—C(O)(Ra), —S(Ra), —S(O)(Rb), —S(O)2(Rb), —C(O)(Ra), —C(O)(ORa), —N(Ra)2, —N(Ra)—C(O)(Ra), —C(O)N(Ra)2, —S(O)2N(Ra)2, —(CRaRb)tORa, —(CRaRb)t—O—C(O)(Ra), —(CRaRb)tS(Ra), —(CRaRb)tS(O)(Rb), —(CRaRb)tS(O)2(Rb), —(CRaRa)tC(O)(Ra), —(CRaRb)tC(O)(ORa), —(CRaRb)rN(RaRb)—(CRaRb)tN(Ra)—C(O)(Ra), —(CRaRb)tC(O)N(Ra)2, —(CRaRa)tS(O)2N(Ra)2 and —(CRaRb)tRa;
V is —NH—, —O—, —(CRaRb)t—;
Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
t is an integer of 1, 2, 3, or 4;
m is 0 or 1;
and
n is 0 or 1;
Q7 is
D is O, NRc, or S;
Rc is H or (C1-C6)alkyl, hydroxyl(C2-C6)alkyl;
A is a fused ring selected from an aromatic 6-membered ring containing 0 or 2 N atoms and the number of R8 substituents on A ring may be 0, 1 or 2 and when two of said R8 substituents are:
a) found on A ring;
b) (C1-C6)alkyl and c) attached to adjacent carbon atoms of the Ring A, they may be joined together to form a 5 to 7-membered carbocyclic ring;
R8 is independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C8)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, cyano, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —ORa, —O—C(O)(Ra), —S(Ra), —S(O)(Rb), —S(O)2(Rb), —C(O)(Ra), —C(O)(ORa), —N(Ra)2, —N(Ra)—C(O)(Ra), —C(O)N(Ra)2, —S(O)2N(Ra)2, —(CRaRb)tORa, —(CRaRb)t—O—C(O)(Ra), —(CRaRb)tS(Ra), —(CRaRb)tS(O)(Rb), —(CRaRb)tS(O)2(Rb), —(CRaRa)tC(O)(Ra), —(CRaRb)tC(O)(ORa), —(CRaRb)rN(RaRb)—(CRaRb)tN(Ra)—C(O)(Ra), —(CRaRb)tC(O)N(Ra)2, —(CRaRa)tS(O)2N(Ra)2 or —(CRaRb)tRa and wherein t is an integer of 1, 2, 3, or 4;
and
Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
Q8 is
L is N or C(R8);
the number of R8 substituents on A ring may be 0, 1, 2 or 3 and when two of said R8 substituents are:
a) found on A ring;
b) (C1-C6)alkyl and c) attached to adjacent carbon atoms of the Ring A, they may be joined together to form a 5 to 7-membered carbocyclic ring or they may be joined together to form a 5 to 7-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N, S;
R8 is independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, aryl, heteroaryl, (C3-C8)cycloalkyl, cyano, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —ORa, —O—C(O)(Ra), —S(Ra), —S(O)(Rb), —S(O)2(Rb), —C(O)(Ra), —C(O)(ORa), —N(Ra)2, —N(Ra)—C(O)(Ra), —C(O)N(Ra)2, —S(O)2N(Ra)2, —(CRaRb)tORa, —(CRaRb)t—O—C(O)(Ra), —(CRaRb)tS(Ra), —(CRaRb)tS(O)(Rb), —(CRaRb)tS(O)2(Rb), —(CRaRa)tC(O)(Ra), —(CRaRb)tC(O)(ORa), —(CRaRb)rN(RaRb)—(CRaRb)tN(Ra)—C(O)(Ra), —(CRaRb)tC(O)N(Ra)2, —(CRaRa)tS(O)2N(Ra)2 or —(CRaRb)tRa and wherein t is an integer of 1, 2, 3, or 4;
and
Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
or
Q9 is a [5,5], [5,6], [6,5] and [6,6] bicylic heterocycle containing 1 to 4 N atoms where G1 is connected through one of the ring N atoms;
G1 and G3 are independently selected from the group consisting of cyclo(C3-C8)alkylene, heterocyclo(C3-C8)alkylene, arylene and heteroarylene, optionally substituted with one or two groups independently selected from halo, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkoxy, cyano, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C4)perfluoroalkyl;
—N(RaRb), —N(Ra)—C(O)(Ra), —C(O)N(Ra)2, —S(O)2N(Ra)2, —S(O)2(Rb), —C(O)(Ra), wherein Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
G2 is selected from the group consisting of a bond, (C1-C4)alkylene, (C2-C4)alkenylene, O, N(Ra)C(O), S and S(O)2, wherein Ra is selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
G4 is —X—Y—;
wherein X is selected from null, O, NH, CO, CHOH, S or S(O)2;
and Y is selected from (C1-C4)alkylene, C3-C8-cycloalkylene or heterocycloalkylene, —CH(R9)C(R10R11)— or —N(R9)C(R10R11)—;
wherein:
R10 and R11 are both hydrogen, and R9 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, phenoxy-(C2-C6)alkyl, 1-methyl-1H-indol-3-yl, bis[(C1-C6)alkyl]amino-(C2-C6)alkyl, 1-piperidinyl-(C2-C6)alkyl, 1-pyrrolidinyl-(C2-C6)alkyl, or 1-morpholinyl-(C2-C6) alkyl;
or
R10 and R11 are both hydrogen and R9 is R12(CH2)m, where m is 0 to 3, and R12 is phenyl optionally substituted with one or more halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl or cyano;
or
R10 and R11 are both hydrogen and R9 is R12(CH2)m, where m is 0 to 3, and R12 is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, each of which is optionally substituted with halogen, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl or cyano;
or
R9 is hydrogen, and R10 and R11 together with the carbon atom to which they are attached, form a three to five-membered ring, with 0 to 2 heteroatoms independently selected from O, S or N;
or
R10 is hydrogen, and R9 and R11 together with the two carbon atoms to which they are attached, form a three- to six-membered ring with 0 to 2 heteroatoms independently selected from O, S or N;
Z is Z1 or Z2;
and
Z1 is
X1 and X2 are independently selected from null, (C(RaRb))m, O, NRa, S or CO and n is 0 or 1;
W is selected from H, (C1-C6)alkyl, aryl, heteroaryl or (C3-C8)cycloalkyl;
wherein each of the (C1-C6)alkyl, aryl, heteroaryl and cycloalkyl is independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, —CN, halogen, ethylenedioxy, methylenedioxy, haloalkyl, —ORa, —O—C(O)(Ra), —S(Ra), —S(O)(Rb), —S(O)2(Rb), —C(O)(Ra), —C(O)(ORa), —N(Ra)2, —N(Ra)—C(O)(Ra), —C(O)N(Ra)2, —S(O)2N(Ra)2, —(CRaRb)tORa, —(CRaRb)t—O—C(O)(Ra), —(CRaRb)t S(Ra), —(CRaRb)tS(O)(Rb), —(CRaRb)tS(O)2(Rb), —(CRaRa)tC(O)(Ra), —(CRaRb)tC(O)(ORa), —(CRaRb)tN(RaRb)—(CRaRb)tN(Ra)—C(O)(Ra), —(CRaRb)tC(O)N(Ra)2, —(CRaRa)tS(O)2N(Ra)2 and —(CRaRb)tRa, —(CRaRb)tP(O)(OH)2, and —(CRaRb)tP(O)(OH)(Ra), wherein t is an integer of 1, 2, 3, or 4 and Ra and Rb are independently selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
X1 and X2 may be combined to form a 5-, 6- or 7-membered ring having from 0 to 3 heteroatoms selected from the group consisting of NRa, O and S;
or X1 or X2 may be combined with W to form a 5-, 6- or 7-membered fused ring having from 0 to 3 heteroatoms selected from the group consisting of NRa, O and S;
and
Z2 is Z1, H, —OH, CO2Ra or —C(O)N(Ra)2, wherein Ra is selected from the group consisting of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, fluoro(C1-C8)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl and aryl(C1-C4)alkyl;
with a proviso that when X2 is O and Q is Q2, Q3, Q4, Q5, Q6, Q7 or Q9, then X1 is not (C(RaRb))n and when Q is Q8 then Z is Z2 and Z2 is Z1, H, —OH, CO2Ra or —C(O)N(Ra)2.

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Inhibitors of diacylglycerol o-acyltransferase 1 (dgat-1) and uses thereof

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Inhibitors of diacylglycerol o-acyltransferase 1 (dgat-1) and uses thereof

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Abstract

Claims6