Fused tricyclic compounds as Raf kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9273046-B2
Application number	US-201114369379-A
Country	US
Kind code	B2
Filing date	Dec 31, 2011
Priority date	Dec 31, 2011
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

Provided are certain fused tricyclic compounds and salts thereof, compositions thereof, and methods of use therefor.

First claim

What is claimed is:

1. At least one compound selected from compounds of Formula (II)

stereoisomers thereof, and pharmaceutically acceptable salts thereof,
wherein:
Q is selected from C and N;
X is O;
Y is NR 12 ;
Z is selected from O, S, NR 13 , CO, SO, SO 2 , and CR 13 R 14 ;
R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R 10 and R 11 , which may be the same or different, are each selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , and —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are each optionally substituted with at least one substituents R 16 , or (R 1 and R 2 ), and/or (R 3 and R 4 ), and/or (R 8 and R 9 ), and/or (R 9 and R 10 ), and/or (R 10 and R 11 ) together with the ring to which they are attached, form a fused ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ; provided that R 1 is absent when Q is N;
R 7 is selected from hydrogen, halogen, alkyl, —O-alkyl, and —S-alkyl;
R 12 is selected from hydrogen and alkyl;
R 13 , R 14 and R 15 , which may be the same or different, are each selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or (R 13 and R 14 ), and/or (R 14 and R 15 ) together with the atom(s) to which they are attached, each form a ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ;
R 16 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, and —NR′SO 2 aryl, wherein R′, R″, and R′″ are independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a ring selected from heterocyclyl, and heteroaryl rings.

2. The at least one compound of claim 1 , which is selected from compounds of Formula (III)

stereoisomers thereof, and pharmaceutically acceptable salts thereof,
wherein:
X is O;
Z is selected from O, S, NR 13 , CO, SO, SO 2 , and CR 13 R 14 ;
A is selected from —CH 2 —, —CH 2 CH 2 —, —CH═CH—, ═CH—, —NR 13 —, —CH 2 —O—, —O—, and —S—;
M is selected from ═CH— and —C(O)—; or M is absent;
R 1 , R 2 , R 8 , R 9 , R 10 and R 11 , which may be the same or different, are each selected from hydrogen, halogen, halo-alkyl, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —SO 2 aryl, —NR 13 SO 2 NR 14 R 15 , and —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are each optionally substituted with at least one substituent R 16 ,
or (R 1 and R 2 ), and/or (R 8 and R 9 ), and/or (R 9 and R 10 ), and/or (R 10 and R 11 ) together with the ring to which they are attached, form a fused ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ;
R 12 is selected from hydrogen and alkyl;
R 13 , R 14 and R 15 , which may be the same or different, are each selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or (R 13 and R 14 ), and/or (R 14 and R 15 ) together with the atom(s) to which they are attached, each form a ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ;
R 16 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, and —NR′SO 2 aryl, wherein R′, R″, and R′″ are independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a ring selected from heterocyclyl, and heteroaryl rings.

3. The at least one compound of claim 2 , which is selected from compounds of Formula (IV)

stereoisomers thereof, and pharmaceutically acceptable salts thereof,
wherein:
B is selected from CH 2 , O, and NR 13 ;
X is O;
R 1 , R 2 , R 8 , R 9 , R 10 and R 11 , which may be the same or different, are each selected from hydrogen, halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —SO 2 aryl, —NR 13 SO 2 NR 14 R 15 , and —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are each optionally substituted with at least one substituent R 16 , or (R 1 and R 2 ), and/or (R 8 and R 9 ), and/or (R 9 and R 10 ), and/or (R 10 and R 11 ) together with the ring to which they are attached, form a fused ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ;
R 12 is selected from hydrogen and alkyl;
R 13 , R 14 and R 15 , which may be the same or different, are each selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; or (R 13 and R 14 ), and/or (R 14 and R 15 ) together with the atom(s) to which they are attached, each form a ring selected from heterocyclyl, and heteroaryl rings optionally substituted with at least one substituent R 16 ;
R 16 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, and —NR′SO 2 aryl, wherein R′, R″, and R′″ are independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or (R′ and R″), and/or (R″ and R′″) together with the atoms to which they are attached, form a ring selected from heterocyclyl, and heteroaryl rings.

4. The at least one compound of claim 3 , which is selected from compounds of Formula (V)

stereoisomers thereof, and pharmaceutically acceptable salts thereof,
wherein:
X is O;
R 8 , R 9 , R 10 and R 11 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —SO 2 aryl, —NR 13 SO 2 NR 14 R 15 , and —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are each optionally substituted with at least one substituent R 16 , or (R 8 and R 9 ), and/or (R 9 and R 10 ), and/or

Assignees

• Zhou Changyou
• Wang Shaohui
• Zhang Guoliang
• Beigene Ltd

Inventors

• Zhou Changyou
• Wang Shaohui
• Zhang Guoliang

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/52

  Purines, e.g. adenine · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title