Biaryl urea derivative or salt thereof and preparation process and use for the same

Patent metadata

Field	Value
Publication number	US-10851050-B2
Application number	US-202016850882-A
Country	US
Kind code	B2
Filing date	Apr 16, 2020
Priority date	Jun 22, 2016
Publication date	Dec 1, 2020
Grant date	Dec 1, 2020

Abstract

The present disclosure discloses a biaryl urea RORγt inhibitor, and specifically relates to a biaryl urea derivative, as represented by formula I, with an RORγt inhibiting activity, and a preparation process thereof, and a pharmaceutical composition comprising the compound. Further disclosed is use of the compound for treating an RORγt-related disease.

First claim

The invention claimed is:

1. A method for inhibiting RORγt activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound shown by formula II or a pharmaceutically acceptable salt thereof:

wherein:
B is phenyl or pyridyl;
R 1 is optionally selected from a group consisting of hydrogen, methyl, halogen, cyano, hydroxyl, —CF 3 , —CHF 2 , and —CH 2 F;
R 1 ′ is selected from a group consisting of hydrogen, —OCF 3 , —OCHF 2 , —CF 3 and heteroaryl;
R 2 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C(O)OR a or cycloalkyl substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 oxo(azo)heterocycloalkyl, C 1 -C 6 alkoxyl, halogen-substituted C 1 -C 6 alkoxyl, hydroxyl or C 1 -C 3 alkoxyl substituted C 1 -C 3 alkyl, phenyl, substituted heteroaryloxyl, C 2 -C 6 alkenyl, halogen substituted aromatic ketone group, carboxyl or cyano substituted heteroaryl, —C(O)R a , —(CH 2 ) n NR a1 R a2 , —(CH 2 ) n C(O)OR a , —C(O)NR a1 R a2 ;
R 3 and R 4 is hydrogen or C 1 -C 3 alkyl;
R 5 and R 6 is hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl hydroxyl;
R 7 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C(O)OR a or cycloalkyl substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 oxo(azo)heterocycloalkyl, C 1 -C 6 alkoxyl, halogen-substituted C 1 -C 6 alkoxyl, hydroxyl or C 1 -C 3 alkoxyl substituted C 1 -C 3 alkyl, phenyl, substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl, heterocyclooxyl, heteroaryl, heteroaryloxyl, C 2 -C 6 alkenyl, halogen-substituted aromatic ketone group, carboxyl or cyano substituted heteroaryl, —C(O)R a , —(CH 2 ) n NR a1 R a2 , —(CH 2 ) n C(O)OR a and —C(O)NR a1 R a2 ;
Y is a covalent bond,
When R 8 is

wherein Z is O, and R 9 is methyl, ethyl, or —NH 2 ; or
Y is —CR a1 CR a2 , R 8 is

R a , R a1 and R a2 are each independently selected from hydrogen or C 1 -C 3 alkyl;
m, r, t and n are each independently selected from any integer value of 0˜2.

2. The method according to claim 1 , wherein m is 1 and R 1 is selected from a group consisting of —H, —Cl, —F, and —CH 3 .

3. The method according to claim 2 , wherein r is 1 and R 2 is selected from a group consisting of —H, —Cl, —F, —CF 3 , —OCF 3 , —CN, C 1 -C 3 alkyl and heteroaryl.

4. The method according to claim 2 , wherein r is 2 and R 2 is selected from a group consisting of —Cl, —F, —CF 3 , —OCF 3 , —CN, and C 1 -C 3 alkyl.

5. The method according to claim 1 , wherein R 7 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, and C 1 -C 6 alkyl.

6. The method according to claim 1 , wherein the compound is as shown in Formula III:

wherein:
X is CH or N;
R 1 is optionally selected from a group consisting of —H, —Cl, —F, and —CH 3 ;
R 1 ′ is optionally selected from a group consisting of —H, —OCF 3 , —OCHF 2 and —CF 3 ;
R 2 is optimally selected from a group consisting of —H, —Cl, —F, —CF 3 , —OCF 3 , —CN and C 1 -C 3 alkyl;
R 3 and R 4 each is hydrogen;
R 5 and R 6 each is hydrogen;
R 7 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, and C 1 -C 6 alkyl;
Y is a covalent bond,
When R 8 is

wherein Z is O, and R 9 is methyl, ethyl, or —NH 2 ; or
Y is-CR a1 R a2 , R 8 is

R a , R a1 and R a z are each independently selected from hydrogen or C 1 -C 3 alkyl; and
r and t are each independently selected from 1 or 2.

7. The method according to claim 1 , wherein the compound is selected from:

8. The method according to claim 1 , wherein the subject has RORγt receptor related diseases.

9. The method according to claim 8 , wherein the diseases are multiple sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel disease, encephalomyelitis, clonal disease, asthma, or cancer.

10. The method according to claim 9 , wherein the cancer is prostate cancer.

11. A method for preparing RORγt receptor inhibitors, comprising applying of the compound shown by formula II or a pharmaceutically acceptable salt thereof:

wherein:
B is phenyl or pyridyl;
R 1 is optionally selected from a group consisting of hydrogen, methyl, halogen, cyano, hydroxyl, —CF 3 , —CHF 2 , and —CH 2 F;
R 1 ′ is selected from a group consisting of hydrogen, —OCF 3 , —OCHF 2 , —CF 3 and heteroaryl;
R 2 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C(O)OR a or cycloalkyl substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 oxo(azo)heterocycloalkyl, C 1 -C 6 alkoxyl, halogen-substituted C 1 -C 6 alkoxyl, hydroxyl or C 1 -C 3 alkoxyl substituted C 1 -C 3 alkyl, phenyl, substituted heteroaryloxyl, C 2 -C 6 alkenyl, halogen substituted aromatic ketone group, carboxyl or cyano substituted heteroaryl, —C(O)R a , —(CH 2 ) n NR a1 R a2 , —(CH 2 ) n C(O)OR a , —C(O)NR a1 R a2 ;
R 3 and R 4 is hydrogen or C 1 -C 3 alkyl;
R 5 and R 6 is hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl hydroxyl;
R 7 is optionally selected from a group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C(O)OR a or cycloalkyl substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 oxo(azo)heterocycloalkyl, C 1 -C 6 alkoxyl, halogen-substituted C 1 -C 6 alkoxyl, hydroxyl or C 1 -C 3 alkoxyl substituted C 1 -C 3 alkyl, phenyl, substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl, heterocyclooxyl, heteroaryl, heteroaryloxyl, C 2 -C 6 alkenyl, halogen-substituted aromatic ketone group, carboxyl or cyano substituted heteroaryl, —C(O)R a , —(CH 2 ) n NR a1 R a2 , —(CH 2 ) n C(O)OR a and —C(O)NR a1 R a2 ;
Y is a covalent bond,
When R 8 is

wherein Z is O, and R 9 is methyl, ethyl, or —NH 2 ; or
Y is —CR a1 CR a2 , R 8 is

R a , R a1 an

Assignees

• Univ Fudan

Inventors

• Wang Yonghui
• Huang Yafei
• Yu Fazhi
• Tang Ting

Classifications

• C07D213/71 Primary

  to which a second hetero atom is attached · CPC title

• C07C311/47

  Y being a hetero atom · CPC title

• C07D213/70

  Sulfur atoms · CPC title

• C07C311/51

  Y being a hydrogen or a carbon atom · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title