Pyrazolamide derivative, preparation method therefor, and application thereof
The present invention relates to a compound of chemical Formula (I), a preparation method therefor, and an application thereof, as well as a pharmaceutical composition comprising the compound as an active ingredient, or a pharmaceutically acceptable salt thereof. The present invention further relates to a use of the compound of Formula (I) in the treatment and prevention of EP 4 -mediated diseases.
1 . A compound of Formula I or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof;
wherein,
R 1 and R 2 are each independently selected from the group consisting of: H, unsubstituted or halogen-substituted C 1 -C 4 alkyl;
or R 1 and R 2 form a C 3 -C 6 cycloalkyl together with the carbon atom to which they are connected;
R 3 is unsubstituted or halogen-substituted C 1 -C 4 alkyl;
R 4 is unsubstituted or halogen-substituted C 1 -C 4 alkyl;
R 5 is selected from the group consisting of: hydrogen, halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; and
R 6 is absent or selected from the group consisting of: halogen, unsubstituted or halogen-substituted C 1 -C 4 alkyl, and unsubstituted or halogen-substituted C 1 -C 4 alkoxy,
X is O.
2 . The compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , wherein one of R 1 and R 2 is H, and the other is unsubstituted or halogen-substituted C 1 -C 4 alkyl.
3 . The compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , wherein R 3 is methyl, monofluoromethyl, difluoromethyl or trifluoromethyl.
4 . The compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , wherein R 4 is methyl.
5 . The compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , wherein the prodrug is an ester formed by the compound of Formula I and C 1 -C 4 alkyl-OH.
6 . The compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , wherein the compound of Formula I is selected from the group consisting of:
7 . A pharmaceutical composition, comprising the compound or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, an isotopic compound or a prodrug thereof according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
8 . A method for inhibiting EP 4 receptor activity in a cell or a subject, comprising administering to the subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof according to claim 1 , or contacting an effective amount of the compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof according to claim 1 with the cell.
9 . A method for preventing and/or treating a disease associated with an EP 4 receptor, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, isotopic compound or prodrug thereof according to claim 1 .
10 . The method according to claim 9 , wherein the disease associated with EP 4 receptor is selected from the group consisting of acute and chronic pain, osteoarthritis, rheumatoid arthritis and cancer.