THRβ receptor agonist compound and preparation method and use thereof
The present invention discloses a compound represented by the following Formula (I) and a pharmaceutically acceptable salt thereof. The compound improves the THRα selectivity while maintaining good THRβ agonistic activity, thereby improving properties of the finished drug.
1. A compound of Formula (II), or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of hydrogen, cyano, substituted or unsubstituted C 1-6 alkyl, and substituted or unsubstituted C 3-6 cycloalkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy;
R 2 and R 3 are each independently selected from the group consisting of halogen and substituted or unsubstituted C 1-6 alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy;
L is not present from the group consisting of —CH 2 — and —CH 2 CH 2 —;
R 4 is selected from the group consisting of hydrogen, halogen atoms, hydroxy, —OCF 3 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , C 1-6 alkyl, C 1-6 alkoxy and C 3-6 cycloalkyl;
n is an integer from the range 2 to 4;
m is an integer from the range 1 to 4; and
when L is not present, the ring may have two or more substituents R 4 ; and
the halogen is selected from the group consisting of F, Cl and Br.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl;
L is not present or is selected from the group consisting of —CH 2 — or —CH 2 CH 2 —;
n is 1, 2 or 3; and
m is 1 or2.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl;
L is not present;
n is 2 or 3; and
m is 1 or 2.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl;
L is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —;
n is 2 or 3; and
m is 1 or 2.
5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of hydrogen, cyano, and substituted or unsubstituted C 1-6 alkyl, wherein the substituent is selected from the group consisting of halogen, hydroxy, and C 1-6 alkoxy; and
the halogen is selected from the group consisting of F, Cl and Br.
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of cyano and C 1-3 alkyl.
7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is cyano.
8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 and R 3 are each independently selected from the group consisting of F, Cl and Br.
9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 2 and R 3 are each Cl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
12. A method for treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, non-alcoholic steatohepatitis (NASH), steatosis of liver, atherosclerosis, hypothyroidism, and thyroid cancer.
13. The method of claim 12 , wherein the disease is selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, type 2 diabetes, NASH, steatosis of liver, hypothyroidism, and thyroid cancer.
14. The method of claim 12 , wherein the disease is selected from the group consisting of NASH, hypothyroidism, and thyroid cancer.
15. The method of claim 12 , wherein the disease is NASH.
16. The method of claim 12 , wherein the disease is hypothyroidism.
17. The method of claim 12 , wherein the disease is thyroid cancer.