| 摘要 |
The invention relates to a DGAT inhibitor of formula;;including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; —C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; —NRx—C(═S)—Z—; Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl; Y represents —C(═O)—NRx or —NRx—C(═O)—; R1 represents adamantanyl, C3-6cycloalkyl; aryl1 or Het1; R2 represents C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or heterocycle may optionally be substituted; R7 represents hydrogen, halo, C1-4alkyl, C1-4alkyl substituted with hydroxyl; provided that the following compounds;;are excluded;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine, as a DGAT inhibitor, of said compounds. |
| 主权项 |
1. A method of treating a warm blooded mammal suffering from a disorder selected from the group consisting of obesity, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty liver disease, liver fibrosis, non-alcoholic steatohepatitis or diabetes, comprising administering to such warm blooded mammal a compound of formulaincluding any stereochemically isomeric form thereof, wherein
A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —O—C(═O)—; —C(═O)—C(═O)—; —NRx—C(═O)—; —Z—C(═O)—; —Z—NRx—C(═O)—; —C(═O)—Z—; —NRx—C(═O)—Z—; —C(═S)—; —NRx—C(═S)—; —Z—C(═S)—; —Z—NRx—C(═S)—; —C(═S)—Z—; or —NRx—C(═S)—Z—; Z represents a bivalent radical selected from C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl; wherein each of said C1-6alkanediyl, C2-6alkenediyl or C2-6alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C1-6alkanediyl may optionally be replaced by C1-6alkanediyl; Rx represents hydrogen or C1-4alkyl; Y represents —C(═O)—NRx— or —NRx—C(═O)—; R1 represents adamantanyl, C3-6cycloalkyl; aryl1 or Het1; R2 represents C3-6cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C3-6cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with hydroxy; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhalo-C1-6alkyloxy; C1-6alkyloxycarbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; C1-4alkylcarbonylamino; —S(═O)p—C1-4alkyl; R4R3N—C(═O)—; R4R3N—C1-6alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—; R3 represents hydrogen; C1-4alkyl optionally substituted with hydroxyl or C1-4alkyloxy; R6R5N—C1-4alkyl; C1-4alkyloxy; Het; Het-C1-4alkyl; aryl; or R6R5N—C(═O)—C1-4alkyl; R4 represents hydrogen or C1-4alkyl; R5 represents hydrogen; C1-4alkyl; or C1-4alkylcarbonyl; R6 represents hydrogen or C1-4alkyl; or R5 and R6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O)p and N; and which heterocycle may optionally be substituted with C1-4alkyl; R7 represents hydrogen; halo; C1-4alkyl; or C1-4alkyl substituted with hydroxyl; aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl; aryl1 represents phenyl, or fluorenyl; each of said phenyl, or fluorenyl optionally substituted with one or two substituents, each substituent independently being selected from the group consisting of oxo; carboxyl; halo; C1-6alkyl optionally substituted with carboxyl or C1-4alkyloxycarbonyl; C1-6alkyloxy; C1-6alkyloxy-carbonyl; and Het; Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with C1-4alkyloxy, amino or mono- or di(C1-4alkyl)amino; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-4alkyl)amino; and —S(═O)p—C1-4alkyl; Het1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O)p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C1-6alkyl optionally substituted with aryl-C(═O)—; hydroxyC1-6alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC1-6alkyl; C1-6alkyloxy optionally substituted with C1-4alkyloxy; C1-6alkylthio; polyhaloC1-6alkyloxy; C1-6alkyloxy-carbonyl wherein C1-6alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C1-4alkyl)aminocarbonyl; C1-6alkylcarbonyl; nitro; amino; mono- or di(C1-6alkyl)amino; R4R3N—C1-6alkyl C3-6cycloalkyl-NRx—; aryl-NRx—; Het-NRx—; C3-6cycloalkylC1-4alkyl-NRx—; arylC1-4alkyl-NRx—; HetC1-4alkyl-NRx—; —S(═O)p—C1-4alkyl; C3-6cycloalkyl; C3-6cycloalkylC1-4alkyl; C3-6cycloalkyl-C(═O)—; aryl; aryloxy; arylC1-4alkyl; aryl-C(═O)—C1-4alkyl; aryl-C(═O)—; Het; HetC1-4alkyl; Het-C(═O)—C1-4alkyl; Het-C(═O)—; and Het-O—; p represents 1 or 2; provided that the following compoundsare excluded;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. |
