Fused tricyclic urea compounds as Raf kinase and/or Raf kinase dimer inhibitors

Patent metadata

Field	Value
Publication number	US-10562899-B2
Application number	US-201916243301-A
Country	US
Kind code	B2
Filing date	Jan 9, 2019
Priority date	Jun 28, 2013
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

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

First claim

The invention claimed is:

1. A method of treating cancer comprising administering to a subject in need thereof a compound of formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
Q is selected from C or N;
R 1 , R 2 , R 3 , and R 4 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —CN, —NR 6 R 7 , —OR 6 , —COR 6 , —CO 2 R 6 , —CONR 6 R 7 , —C(═NR 6 )NR 7 R 8 , —NR 6 COR 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —SO 2 R 6 , —NR 6 SO 2 NR 7 R 8 , —NR 6 SO 2 R 7 , or NR 6 SO 2 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are independently optionally substituted with at least one substituent R 9 , or (R 1 and R 2 ), and/or (R 3 and R 4 ), together with the ring to which they are attached, form a fused ring selected from heterocyclyl or heteroaryl rings optionally substituted with at least one substituent R 9 ; provided that R 1 is absent when Q is N;
R 5 is selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl rings, each of which is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 6 and R 7 , or R 7 and R 8 together with the atom(s) to which they are attached, each form a ring selected from heterocyclyl or heteroaryl rings optionally substituted with at least one substituent R 9 ; and
R 9 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, or —NR'SO 2 aryl, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl group are each independently optionally substituted with one, two or three substituents selected from halo, alkyl or haloalkyl, wherein R′, R″, and R′″ are independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R′ and R″ or R″ and R′″ together with the atoms to which they are attached, form a ring selected from heterocyclyl optionally substituted with halogen or alkyl, and heteroaryl rings optionally substituted with halogen or alkyl;
wherein the cancer is selected from melanomas, thyroid cancer, Barret's adenocarcinoma, breast cancer, cervical cancer, colorectal cancer, gastric cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancers, cancer of biliary tract, non-small cell lung cancer, endometrium cancer, blood cancer, lung adenocarcinoma, or glioblastoma.

2. The method of claim 1 , wherein the compound has the structure of formula (II):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein:
Q is selected from C or N;
R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkynyl, —CN, —NR 6 R 7 , —OR 6 , —COR E , —CO 2 R 6 , —CONR 6 R 7 , —C(═NR 6 )NR 7 R 8 , —NR 6 COR 7 , —NR 6 CONR 7 R 8 , —NR 6 CO 2 R 7 , —SO 2 R 6 , —NR 6 SO 2 NR 7 R 8 , —NR 6 SO 2 R 7 , or NR 6 SO 2 aryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and heterocyclyl are independently optionally substituted with at least one substituent R 9 , or (R 1 and R 2 ) together with the ring to which they are attached, form a fused ring selected from heterocyclyl or heteroaryl rings optionally substituted with at least one substituent R 9 ; provided that R 1 is absent when Q is N;
X is selected from —O—, —NR′— or —CR′R″, wherein R′ and R″ are independently selected from H, haloalkyl, or alkyl;
R 5 is each selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl rings, each of which is optionally substituted with at least one substituent R 9 ;
R 6 , R 7 and R 8 , which may be the same or different, are each selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or R 6 and R 7 or R 7 and R 8 together with the atom(s) to which they are attached, each form a ring selected from heterocyclyl or heteroaryl rings optionally substituted with at least one substituent R 9 ;
R 9 is selected from halogen, haloalkyl, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkynyl, oxo, -alkyl-NR′R″, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, nitro, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, NR′SO 2 R″, or —NR'SO 2 aryl, wherein the cycloalkyl, aryl, heteroaryl, and heterocyclyl group are each independently optionally substituted with one, two or three substituents selected from halo, alkyl or haloalkyl, wherein R′, R″, and R′″ are independently selected from H, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R′ and R″ or R″ and R′″ together with the atoms to which they are attached, form a ring selected from heterocyclyl ring optionally substituted with halogen or alkyl, or a heteroaryl ring optionally substituted with halogen or alkyl.

3. The method of claim 2 , wherein Q is C.

4. The method of claim 2 , wherein R 1 and R 2 , which may be the same or different, are each selected from hydrogen, halogen, or alkyl, wherein alkyl is optionally substituted with at least one substituent R 9 .

5. The method of claim 4 , wherein R 1 and R 2 are each hydrogen.

6. The method of claim 2 , wherein R 5 is aryl, heteroaryl, heterocyclyl, or cycloalkyl, each of which is optionally substituted with at least one substituent R 9 .

7. The method of claim 6 , wherein R 5 is aryl selected from phenyl, naphthyl or indanyl, each of which is optionally substituted with one, two, or three substituent R 9 .

8. The method of claim 7 , wherein R 9 is each independently selected from halogen, haloalkyl, alkyl, alkenyl, alkynyl, -alkyl-NR′R″, —CN, —OR′, —NR′R″, or nitro, wherein R′ and R″ are independently selected from H, haloalkyl, or alkyl.

9. The method of claim 8 , wherein R 9 is halogen.

10. The method of claim 6 , wherein R 5 is heteroaryl selected from pyridinyl or pyrimidinyl, each of which is optionally substituted with one, two, or three substituent R 9 .

11. The method of claim 10 , wherein R 9 is each independently selected from halogen, haloalkyl, alkyl, alkenyl, alkynyl, -alkyl-NR′R″, —CN, —OR′, —NR′R″, or nitro, wherein R′ and R″ are independently selected from H, haloalkyl, or alkyl.

12. The method of claim 6 , wherein R 5 is heterocyclyl selected from tertrahydropyranyl or piperidinyl, each of which is optionally substituted with one, two, or three substituent R 9 ;
wherein R 9 is each independently selected from halogen, haloalkyl, alkyl, alkenyl, alkynyl, -alkyl-NR′R″, —CN, —OR′, —NR′R″, or nitro, wherein R′ and R″ are independently selected from H, haloalkyl, or alkyl.

13. The method of claim 6 , wherein R 5 is cycloalkyl, wherein cycloalkyl is:
monocyclic cycloalkyl group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, each of which is optionally substituted with one, two or three substituent R 9 selected from halogen, haloalkyl, alkyl, alkenyl, alkynyl, -alkyl-NR′R″, —CN, —OR′, —NR′R″, or nitro, wherein R′ and R″ are independently

Assignees

• Beigene Ltd

Inventors

• Zhou Changyou
• Zhang Guoliang

Classifications

• A61P43/00

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

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P17/00

  Drugs for dermatological disorders · CPC title