N-(benzoyl)-phenylalanine compound, pharmaceutical composition containing same, and use thereof
The present invention belongs to the field of pharmaceutical chemistry, and relates to an N-(benzoyl)-phenylalanine compound used as an α4β7 integrin antagonist, including the pharmaceutical composition and the use, and in particular to a compound represented by general formula (1). The compound exhibits good α4β7 integrin binding inhibitory activity, can be used as a high-efficiency α4β7 integrin antagonist, and used for preventing and/or treating α4β7 integrin-related diseases such as autoimmune diseases and inflammatory diseases.
1 . A compound as shown in general formula (1) or a pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof,
wherein:
R 3 is hydrogen;
each R 4 is independently hydrogen;
each X 1 is independently fluorine, chlorine, or bromine;
X 2 is hydrogen, halogen, di (C 1-6 alkyl) amino, or 3-7-membered heterocyclic alkyl;
each X 3 is independently hydrogen;
A is a group as shown in general formula (2-1), (2-2), or (2-3),
ring H is C 3-6 cyclic alkylene or 3-7 membered heterocyclic alkylene;
Y is O or S;
each Z is independently CR 1 or N;
if present, each R 1 is independently hydrogen, halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino;
if present, each R 2 is independently C 1-6 alkyl, C 3-6 cyclic alkyl or 3-7 membered heterocyclic alkyl.
2 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 , wherein each X 1 is independently fluorine or chlorine.
3 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 , wherein X 2 is hydrogen or 3-7 membered heterocyclic alkyl.
4 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 ,
wherein:
A is a group as shown in the general formula (2-1-1) or (2-1-1′),
ring H is C 3-6 cyclic alkylene or 3-7-membered heterocyclic alkylene;
Y is O or S;
when A is a group as shown in general formula (2-1-1),
two of the four R 1 are independently halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
alternatively, one of the four R 1 is halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
alternatively, all four R 1 are hydrogen;
when A is a group as shown in general formula (2-1-1′),
two of the three R 1 are independently halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and one is hydrogen;
alternatively, one of the three R 1 is halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
alternatively, all three R 1 are hydrogen.
5 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 , wherein:
A is a group as shown in general formula (2-2-1),
Y is O or S;
two of the four R 1 are independently halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
alternatively, one of the four R 1 is halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
R 2 is C 1-6 alkyl, C 3-6 cyclic alkyl or 3-7-membered heterocyclic alkyl.
6 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 ,
wherein:
A is a group as shown in general formula (2-3-1),
Y is O or S;
one of the four R 1 is halogen, C 1-6 alkoxy, or di (C 1-6 alkyl) amino, and the rest are hydrogen;
each R 2 is independently C 1-6 alkyl, C 3-6 cyclic alkyl or 3-7-membered heterocyclic alkyl.
7 . A compound or pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof having a structure selected from the group consisting of:
8 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 .
9 . A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 7 .
10 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 1 , wherein
is selected from the group consisting of:
11 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 4 , wherein
is selected from the group consisting of:
12 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 5 , wherein
is selected from the group consisting of:
13 . The compound or the pharmaceutically acceptable salt, ester, solvate, optical isomer, tautomer, isotope marker, or prodrug thereof according to claim 6 , wherein
is selected from the group consisting of: