Aromatic ring or heteroaromatic ring derivatives, preparation method therefor and use thereof
The present invention relates to aromatic ring or heteroaromatic ring derivatives, a preparation method therefor and applications thereof in medicine. Specifically, the present invention relates to aromatic ring or heteroaromatic ring derivatives represented by general formula (I), a preparation method therefor and pharmaceutically acceptable salts thereof, as well as a use thereof as therapeutic agents, especially uses as angiotensin II type 2 receptor (AT 2 R) antagonists, wherein the definition of each substituent in the general formula (I) is the same as the definition thereof in the description.
1 . A compound represented by general formula (I):
wherein W, Y and Z are each independently selected from CR n and N, and there are at most 2 N atoms contained among W, Y, and Z;
R 1 is selected from —COOR a and tetrazolyl;
R 2 is selected from 8- to 10-membered heteroaryl and —NR b R c , wherein the heteroaryl is optionally further substituted with one or more substituents selected from R d ;
R 3 is selected from —NR e R f and the group
Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CR j and N, and there are at most 3 N atoms contained among Y 1 , Y 2 , Y 3 and Y 4 ;
ring A is selected from 6- to 8-membered monocyclic heterocyclyl and 5-membered heteroaryl, wherein the monocyclic heterocyclyl contains one or more N, O or S(O) n therein, and the 6- to 8-membered heterocycle is optionally further substituted by one or more R 10 ;
R a is selected from hydrogen atom and alkyl, wherein the alkyl is optionally further substituted with one or more halogens;
R b is the group:
R c is alkyl;
R e is selected from hydrogen atom and alkyl, wherein the alkyl is optionally further substituted with one or more substituents selected from hydroxyl, alkoxy and halogen;
R f is selected from -L-R k ,
L is selected from C 1-6 alkylene;
wherein the C 1-6 alkylene is substituted or unsubstituted, when the C 1-6 alkylene is substituted, the C 1-6 alkylene is substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic ester groups, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
R g and R h are each independently selected from hydrogen atom, alkyl, alkoxy, halogen and cyano, wherein the alkyl or alkoxy is optionally further substituted with one or more halogen or alkoxy;
R k is selected from aryl and heteroaryl, wherein the aryl or heteroaryl is optionally further substituted with one or more R m ;
R d , R j , R m , R n and R 10 are the same or different, and are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —S(O) n NR 5 R 6 and —NR 5 C(O)R 6 , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
R 4 , R 5 and R 6 are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
or, R 5 and R 6 , together with the N atom connected thereto, form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocycle contains one or more N, O or S(O) n , and the 4- to 8-membered heterocycle is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
R 7 , R 8 and R 9 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and carboxylic ester groups;
m is selected from 0, 1, 2, 3, 4 and 5;
n is selected from 0, 1 and 2; and
q is 0, 1, 2, 3, 4 or 5;
a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.
2 . A compound represented by general formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
wherein W, Y and Z are each independently selected from CH and N, and there is at most 1 N atom contained among W, Y, and Z;
Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from CR j and N, and there is at most 1 N atom contained among Y 1 , Y 2 , Y 3 and Y 4 ;
ring A is selected from 6- to 8-membered monocyclic heterocyclyl, wherein the monocyclic heterocyclyl contains one or more N, O or S(O) n therein, and the 6- to 8-membered heterocycle is optionally further substituted with one or more R 10 ;
R 10 are the same or different, and are each independently selected from halogen, alkyl, alkoxy and ═O, wherein the alkyl or alkoxy is optionally further substituted with halogen;
R j are the same or different, and are each independently selected from hydrogen atom, alkyl, alkoxy and halogen, wherein the alkyl or alkoxy is optionally further substituted with halogen;
q is 0, 1, 2 or 3;
R 1 is selected from —COOR a and tetrazolyl;
R 2 is selected from 8- to 10-membered heteroaryl and —NR b R c , wherein the heteroaryl is optionally further substituted with one or more substituents selected from R d ;
R a is selected from hydrogen atom and alkyl, wherein the alkyl is optionally further substituted with one or more halogens;
R b is the group:
R c is alkyl;
R d is selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —S(O) n NR 5 R 6 and —NR 5 C(O)R 6 , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
R 4 , R 5 and R 6 are each independently selected from hydrogen atom, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
or, R 5 and R 6 , together with the N atom connected thereto, form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocycle contains one or more N, O or S(O) n , and the 4- to 8-membered heterocycle is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ═O, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —NR 8 R 9 , —C(O)NR 8 R 9 , —SO 2 NR 8 R 9 and —NR 8 C(O)R 9 ;
R 7 , R 8 and R 9 are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl and carboxylic ester groups;
R g and R h are each independently selected from hydrogen atom, alkyl, alkoxy, halogen and cyano, wherein the alkyl or alkoxy is optionally further substituted with one or more halogen or alkoxy;
m is selected from 0, 1, 2, 3, 4 and 5; and
n is selected from 0, 1 and 2.
3 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , which is a compound represented by general formula (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof,
wherein W, Y and Z are each independently selected from CH and N, and there is at most 1 N atom contained among W, Y, and Z;
R e is selected from hydrogen atom and alkyl;
R f is selected from -L-R k ,
L is selected from C 1-6 alkylene;
wherein the C 1-6 alkylene is substituted or unsubstituted, when the C 1-6 alkylene is substituted, the C 1-6 alkylene is substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic ester groups, —C(O)R 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 5 R 6 , —C(O)NR 5 R 6 , —SO 2 NR 5 R 6 and —NR 5 C(O)R 6 ;
R k is selected from aryl; wherein the aryl is optionally further substituted with one or more substituents selected from halogen, alkyl and alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more halogen; and
R 1 and R 2 are defined as described in claim 1 .
4 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is selected from the groups:
R d are the same or different, and are each independently selected from hydrogen atom, alkyl, cyano, alkoxy and halogen, wherein the alkyl or alkoxy is optionally further substituted with halogen; and
m is 0, 1, 2, 3 or 4.
5 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is the group:
and
R g , R h and m are defined as described in claim 1 .
6 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is selected from the groups:
and
R d is selected from hydrogen atom, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl and trifluoromethoxy.
7 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 5 ,
wherein R g and R h are each independently selected from hydrogen atom, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl and trifluoromethoxy; and
m is 1.
8 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 2 , wherein
is selected from the groups:
R j are the same or different, and are each independently selected from hydrogen atom, alkyl, alkoxy and halogen, wherein the alkyl or alkoxy is optionally further substituted with halogen; and
p is 0, 1, 2, 3 or 4.
9 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from:
10 . A pharmaceutical composition, comprising an effective dose of the compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier, excipient or combinations thereof.
11 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R e is methyl; or L is propylidene.
12 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 3 , wherein R e is selected from hydrogen atom and methyl; or L is propylidene; or the aryl for R k is phenyl.
13 . The compound or the stereoisomer, the tautomer or the pharmaceutically acceptable salt thereof according to claim 7 , wherein R g and R h are each independently a hydrogen atom or fluorine.