Aryl ethene derivative and pharmaceutical composition containing same as active ingredient
The present invention relates to an aryl ethene derivative, for inhibiting an estrogen-related receptor gamma (ERRγ) activity, a prodrug of same, a solvate of same, a stereoisomer of same or pharmaceutically acceptable salts of same, and a pharmaceutical composition containing same as an active ingredient.
1. A compound represented by the following Chemical Formulae 2 to 5, or a stereoisomer, or pharmaceutically acceptable salt thereof:
wherein
denotes a single bond or a double bond;
R 1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH 2 ) m R 11 , —(CH 2 ) m —R 12 , —NH—(CH 2 ) m —R 13 , —NHCO—(CH 2 ) n —R 14 , or —SiR 16 R 17 —(CH 2 ) m —R 15 ;
R 11 is selected from the following structures:
wherein R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is S;
R 12 to R 15 are independently of one another (C3-C20)heterocycloalkyl;
R 16 and R 17 are independently of each other (C1-C20)alkyl;
m is an integer of 1 to 3; and
n is an integer of 0 or 1;
Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, —NR 21 R 22 , (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO 2 —R 23 and —OSO 2 —R 24 ;
R 21 and R 22 are independently of each other hydrogen, (C1-C20)alkylsulfonyl, or (C3-C20)cycloalkylsulfonyl;
R 23 and R 24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
R 2 is hydroxy, fluoro, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy;
the heterocycloalkyl or heteroaryl of R 1 and the heterocycloalkyl of R 12 to R 15 may be further substituted by one or more selected from the group consisting of (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino, (C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl;
the heterocycloalkyl is a monovalent radical of a non-aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and is a saturated or unsaturated mono-, bi-, or spirocycle having a carbon atom or nitrogen atom in a ring as a binding site; and
the heteroaryl is a monovalent radical of a heteroaromatic ring which is an aryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S as an aromatic ring backbone atom, and carbons as remaining aromatic ring backbone atoms.
2. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein
R 1 is (C3-C10)heterocycloalkyl, (C3-C10)heteroaryl, —O—(CH 2 ) m —R 11 , —(CH 2 ) m —R 12 , —NH—(CH 2 ) m —R 13 , —NHCO—(CH 2 ) n —R 14 , or —SiR 16 R 17 —(CH 2 ) m —R 11 ;
R 12 to R 15 are independently of one another (C3-C10)heterocycloalkyl;
R 16 and R 17 are independently of each other (C1-C10)alkyl;
m is an integer of 1 to 3;
n is an integer of 0 or 1;
Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy;
R 2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy; and
the heterocycloalkyl or heteroaryl of R 1 and the heterocycloalkyl of R 12 to R 15 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.
3. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 2 , wherein R 1 is (C3-C10)heterocycloalkyl or —O—(CH 2 ) m —R 11 ; m is an integer of 1 to 3; and the heterocycloalkyl of R 1 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.
4. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the heterocycloalkyl of R 1 and R 12 to R 15 is independently of each other selected from the following structures:
wherein R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
5. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the compound is represented by the following Chemical Formula 6:
wherein
R 1 is (C3-C10)heterocycloalkyl or —O—(CH 2 ) m —R 11 ;
m is an integer of 1 to 3;
the heterocycloalkyl of R may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl;
Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and
R 2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy.
6. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 5 , wherein R 2 is hydroxy; and R is heterocycloalkyl selected from the following structures:
wherein R 31 and R 32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.
7. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 5 , wherein R 2 is hydroxy; R 1 is —O—(CH 2 ) m —R 11 ; m is an integer of 1 or 2.
8. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the compound is selected from the following structures:
9. The compound, or stereoisomer, or pharmaceutically acceptable salt thereof, of claim 5 , wherein the compound is selected from the following structures: