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

Patent metadata

Field	Value
Publication number	US-10647665-B2
Application number	US-201716312436-A
Country	US
Kind code	B2
Filing date	Jun 19, 2017
Priority date	Jun 22, 2016
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The present invention 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 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 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, 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 R a2 , when 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 compound or the pharmaceutically acceptable salt thereof 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 compound or the pharmaceutically acceptable salt thereof 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 compound or the pharmaceutically acceptable salt thereof 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 compound or the pharmaceutically acceptable salt thereof 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 compound or the pharmaceutically acceptable salt thereof according 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 , when R 8 is

R a , R a1 and R a2 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. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from:

8. A pharmaceutical composition as a RORγt receptor inhibitor, comprising the compound or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient, and one or more pharmaceutically acceptable carriers.

9. A 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 each is hydrogen, one of R 5 and R 6 is hydrogen, the other of R 5 and R 6 is C 1 -C 3 alkyl or C 1 -C 3 alkyl hydroxyl; or
one of R 3 and R 4 is hydrogen, the other one of R 3 and R 4 is C 1 -C 3 alkyl, R 5 and R 6 each is hydrogen;
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 or ethyl; or
Y is —CR a1 R a2 , when 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 in

Assignees

• Univ Fudan

Inventors

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

Classifications

• A61K31/18

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

• C07C275/00 Primary

  Derivatives of urea, i.e. compounds containing any of the groups [IMAGE cpc-sch-C07C-0967.gif], the nitrogen atoms not being part of nitro or nitroso groups · CPC title

• C07C317/32

  with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title