Diarylthiohydantoin compound as androgen receptor antagonist

Patent metadata

Field	Value
Publication number	US-11866433-B2
Application number	US-202117503141-A
Country	US
Kind code	B2
Filing date	Oct 15, 2021
Priority date	Aug 7, 2017
Publication date	Jan 9, 2024
Grant date	Jan 9, 2024

Abstract

The present application belongs to the field of medicine. In particular, the present application relates to a diarylthiohydantoin compound as an androgen receptor antagonist or a pharmaceutically acceptable salt thereof, a preparation method of the same, a pharmaceutical composition comprising the compound, and a use thereof in treating a cell proliferative disease mediated by androgen. The compound of the present application has good antagonistic effect on androgen receptor and exhibits excellent antitumor effect.

First claim

What is claimed is:

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof,

wherein,
T is selected from the group consisting of CH and N;
R 1 is selected from the group consisting of hydrogen, halogen, C 1-12 alkyl, and halogen-substituted C 1-12 alkyl;
the ring A is selected from the group consisting of

R 2 and R 3 are each independently selected from C 1-12 alkyl, or R 2 and R 3 are connected to each other to form a 3- to 6-membered cycloalkyl together;
X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of CH and N, and at least one of them is N;
n is 0, 1, 2, or 3;
each R 4 is independently selected from C 1-12 alkyl;
the ring B is

R 5 is selected from the group consisting of hydrogen, C 1-12 alkyl, C 1-12 alkoxy, and halogen;
R 6 is selected from C 1-12 alkylaminocarbonyl;
one of X 5 , X 6 , and X 7 is N(—R a ), and the others are CH or N;
R a is selected from 5-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-4 alkoxy, hydroxyl, or amino;
X 8 , X 9 , X 10 , and X 11 are each independently selected from the group consisting of CH, C(═O), N, and NH, and three of X 8 , X 9 , X 10 , and X 11 are C(═O), N, and NH, respectively;
R b is selected from C 1-12 alkyl, wherein the C 1-12 alkyl is optionally substituted by halogen;
Y 8 , Y 9 , Y 10 , and Y 11 are each independently selected from the group consisting of CH and N, and at least two of Y 8 , Y 9 , Y 10 , and Y 11 are N;
m is 0, 1, or 2;
each R 7 is independently selected from the group consisting of halogen, C 1-12 alkyl, hydroxyl, C 1-12 alkoxy, amino, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and C 1-12 alkylamino, wherein the C 1-12 alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, or C 1-12 alkylamino is optionally substituted by halogen, and wherein the hydroxyl is substituted by: —C 1-12 alkyl-OH, —C 1-12 alkyl-(3- to 10-membered heterocycloalkyl), —C 1-12 alkyl-S(═O) 2 R c , —C 1-12 alkyl-NR d R e , —C 1-12 alkyl-C(═O)NR f R g , —C 1-12 alkyl-(3- to 10-membered cycloalkyl) optionally substituted by halogen or hydroxyl, or 3- to 10-membered heterocycloalkyl optionally substituted by halogen or hydroxyl;
Z 8 , Z 9 , Z 10 , and Z 11 are each independently selected from the group consisting of CH, C(═O), and N;
j is 0, 1, or 2;
each R 9 is independently selected from the group consisting of halogen, C 1-12 alkyl, C 1-12 alkoxy, and hydroxyl, wherein the C 1-12 alkyl is optionally substituted by halogen or C 1-12 alkoxy, and wherein the hydroxyl is optionally substituted by: —C 1-12 alkyl-O—C 1-12 alkyl, —C 1-12 alkyl-OH, or —C 1-12 alkyl-C(═O)NR f R g ;
R c , R d , R e , R f , and R g are each independently selected from the group consisting of hydrogen, C 1-12 alkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, C 1-12 alkoxy, hydroxyl, and amino;
two of X 12 , X 13 , X 14 , X 15 , and X 16 are NH and C(═O), respectively, and the others are CH 2 , O, or S;
q is 0, 1, 2, 3, or 4; and
each R 8 is independently selected from the group consisting of halogen, C 1-12 alkyl, hydroxyl, amino, 3- to 10-membered cycloalkyl, C 1-12 alkoxy, 3- to 10-membered heterocycloalkyl, and C 1-12 alkylamino;
provided that: when the ring A is selected from

the ring B is not

and when R 7 is selected from C 1-12 alkoxy, R 7 substitutes the hydrogen on Y 9 , Y 10 , or Y 11 .

2. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 and R 3 are each independently selected from C 1-6 alkyl, or R 2 and R 3 are connected to each other to form a 3- to 6-membered cycloalkyl together.

3. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, and halogen-substituted C 1-6 alkyl.

4. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, and halogen.

5. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Y 8 , Y 9 , Y 10 , and Y 11 are each independently selected from the group consisting of CH and N, and two of Y 8 , Y 9 , Y 10 , and Y 11 are N, and the others are CH.

6. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R c , R d , R e , R f , and R g are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocycloalkyl, C 1-6 alkoxy, hydroxyl, and amino.

7. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Z 8 , Z 9 , Z 10 , and Z 11 are each independently selected from the group consisting of CH, C(═O), and N, and wherein at least one of them is selected from N.

8. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

9. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein each R 9 is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy, and hydroxyl, wherein the C 1-6 alkyl is optionally substituted by halogen or C 1-6 alkoxy, and wherein the hydroxyl is optionally substituted by: —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-OH, or —C 1-6 alkyl-C(═O)NR f R g .

10. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 9 , wherein each R 9 is independently selected from the group consisting of halogen, methyl, ethyl, methoxy, ethoxy, and hydroxyl, wherein the methyl or ethyl is optionally substituted by halogen or methoxy, and wherein the hydroxyl is optionally substituted by: -ethyl-O-methyl, -ethyl-OH, or -methyl-C(═O)NR f R g .

11. The compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from the group consisting of

wherein each R 91 is independently selected from the group consisting of C 1-12 alkyl, C 1-12 alkoxy, and hydroxyl, wherein the C 1-12 alkyl is optionally substituted by C 1-12 alkoxy or halogen, and wherein the hydroxyl is optionally substituted by —C 1-1

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Shen Chunli
• Wu Chengde
• Chen Shenglin
• Chen Shuhui
• Zhang Xiquan
• Tian Xin

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title