Novel bi-ring phenyl-pyridines/pyrazines for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-2015266878-A1
Application number	US-201514735348-A
Country	US
Kind code	A1
Filing date	Jun 10, 2015
Priority date	Dec 10, 2012
Publication date	Sep 24, 2015
Grant date	—

Abstract

The invention provides novel compounds having the general formula:

wherein R 1 , R 2 and R 3 are as described herein, compositions including the compounds and methods of using the compounds.

First claim

1 . Compounds of formula (I)

wherein
R 1 is selected from

R 2 is aminocarbonyl, C 1-6 alkoxy-C y H 2y -amino-C x H 2x —, C 1-6 alkoxy-C x H 2x -sulfonylamino-C x H 2x —, C 1-6 alkylcarbonylamino-C x H 2x —, C 1-6 alkylsulfonylamino-C x H 2x —, cycloalkylcarbonylamino-C x H 2x —, cycloalkylsulfonylamino-C x H 2x —, hydroxy-C x H 2x —, hydroxy-C y H 2y -amino-C x H 2x —, hydroxy-C x H 2x -carbonylamino-C x H 2x — or phenylcarbonylamino-C x H 2x —;
R 3 is phenyl, which is unsubstituted or substituted by halogen;
R 4 is hydrogen, C 1-6 alkyl or halogen;
R 5 is hydrogen, C 1-6 alkyl or halogen;
or R 4 and R 5 , together with the carbon atom, to which they are attached, form cycloalkyl;
R 6 is hydrogen or halogen;
R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, amino or halogen;
x is 1-6;
y is 2-6;

or pharmaceutically acceptable salt thereof.

2 . A compound according to claim 1 , wherein
R 1 is selected from

R 2 is aminocarbonyl, C 1-6 alkoxy-C y H 2y -amino-C x H 2x —, C 1-6 alkoxy-C x H 2x -sulfonylamino-C x H 2x —, C 1-6 alkylcarbonylamino-C x H 2x —, C 1-6 alkylsulfonylamino-C x H 2x —, cycloalkylcarbonylamino-C x H 2x —, cycloalkylsulfonylamino-C x H 2x —, hydroxy-C x H 2x —, hydroxy-C y H 2y -amino-C x H 2x —, hydroxy-C x H 2x -carbonylamino-C x H 2x — or phenylcarbonylamino-C x H 2x —;
R 3 is phenyl, which is unsubstituted or once substituted by halogen;
R 4 is hydrogen, C 1-6 alkyl or halogen;
R 5 is hydrogen, C 1-6 alkyl or halogen;
or R 4 and R 5 , together with the carbon atom, to which they are attached, form cycloalkyl;
R 6 is hydrogen or halogen;
R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, amino or halogen;
x is 1-6;
y is 2-6;

or pharmaceutically acceptable salt thereof.

3 . A compound according to claim 1 , wherein
R 1 is selected from

R 2 is aminocarbonyl, methoxyethylaminomethyl, methoxyethylsulfonylaminomethyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, isopropylcarbonylaminomethyl, methylsulfonylaminomethyl, cyclohexylcarbonylaminomethyl, cyclopropylsulfonylaminomethyl, hydroxymethyl, hydroxyethylaminomethyl, hydroxymethylcarbonylaminomethyl or phenylcarbonylaminomethyl;
R 3 is phenyl or chlorophenyl;
R 4 is hydrogen, methyl or fluoro;
R 5 is hydrogen, methyl or fluoro;
or R 4 and R 5 , together with the carbon atom, to which they are attached, form cyclopropyl;
R 6 is hydrogen or fluoro;
R 7 is hydrogen, methyl, ethyl, methylsulfanyl, methylsulfonyl, amino, fluoro or chloro;

or pharmaceutically acceptable salt thereof.

4 . A compound according to claim 1 , wherein
R 1 is

R 2 is aminocarbonyl, C 1-6 alkylcarbonylamino-C x H 2x — or hydroxy-C x H 2x —;
R 3 is phenyl, which is unsubstituted or once substituted by halogen;
R 4 is hydrogen, C 1-6 alkyl or halogen;
R 5 is hydrogen, C 1-6 alkyl or halogen;
or R 4 and R 5 , together with the carbon atom, to which they are attached, form cycloalkyl;
R 6 is hydrogen or halogen;
x is 1-6.

5 . A compound according to claim 4 , wherein
R 1 is

R 2 is aminocarbonyl, methylcarbonylaminomethyl or hydroxymethyl;
R 3 is phenyl or chlorophenyl;
R 4 is hydrogen, methyl or fluoro;
R 5 is hydrogen, methyl or fluoro;
or R 4 and R 5 , together with the carbon atom, to which they are attached, form cyclopropyl;
R 6 is hydrogen or fluoro.

6 . A compound according to claim 1 , wherein
R 1 is

R 2 is aminocarbonyl, C 1-6 alkoxy-C y H 2y -amino-C x H 2x —, C 1-6 alkoxy-C x H 2x -sulfonylamino-C x H 2x —, C 1-6 alkylcarbonylamino-C x H 2x —, C 1-6 alkylsulfonylamino-C x H 2x —, cycloalkylcarbonylamino-C x H 2x —, cycloalkylsulfonylamino-C x H 2x —, hydroxy-C x H 2x —, hydroxy-C y H 2y -amino-C x H 2x —, hydroxy-C x H 2x -carbonylamino-C x H 2x — or phenylcarbonylamino-C x H 2x —;
R 3 is phenyl;
R 7 is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfanyl, C 1-6 alkylsulfonyl, amino or halogen;
x is 1-6;
y is 2-6.

7 . A compound according to claim 6 , wherein
R 1 is

R 2 is aminocarbonyl, methoxyethylaminomethyl, methoxyethylsulfonylaminomethyl, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, isopropylcarbonylaminomethyl, methylsulfonylaminomethyl, cyclohexylcarbonylaminomethyl, cyclopropylsulfonylaminomethyl, hydroxymethyl, hydroxyethylaminomethyl, hydroxymethylcarbonylaminomethyl or phenylcarbonylaminomethyl;
R 3 is phenyl;
R 7 is hydrogen, methyl, ethyl, methylsulfanyl, methylsulfonyl, amino, fluoro or chloro.

8 . A compound according to claim 1 , selected from
5-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-indol-2-one; 5-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-3,3-dimethyl-1,3-dihydro-indol-2-one; 5-{5-[(R)-1-(2-Chloro-phenyl)-2-hydroxy-ethylamino]-pyridin-3-yl}-1,3-dihydro-indol-2-one; 5-{5-[(S)-1-(2-Chloro-phenyl)-2-hydroxy-ethylamino]-pyridin-3-yl}-1,3-dihydro-indol-2-one; 5-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-benzoimidazol-2-one; (R)-5′-(5-((2-hydroxy-1-phenylethyl)amino)pyridin-3-yl)-spiro[cyclopropane-1,3′-indolin]-2′-one; 5-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one; 3,3-Difluoro-5-[5-((R)-2-hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-indol-2-one; 5-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-pyrrolo[3,2-b]pyridin-2-one; 6-Fluoro-5-[5-((R)-2-hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-indol-2-one; 7-Fluoro-5-[5-((R)-2-hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-1,3-dihydro-indol-2-one; 6-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-3H-benzooxazol-2-one; 6-[5-((R)-2-Hydroxy-1-phenyl-ethylamino)-pyridin-3-yl]-3H-benzothiazol-2-one; (R)-2-(5-Benzo[1,3 ]dioxol-5-yl-pyridin-3-ylamino)-2-phenyl-ethanol; (R)-2-[5-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(1H-Indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(1H-Indol-4-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Amino-1H-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Fluoro-1H-indazol-5-yl-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Methyl-1H-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Ethyl-1H-indazol-5 -yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Methylsulfanyl-1H-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-[5-(3-Methanesulfonyl-1H-indazol-5-yl)-pyridin-3-ylamino]-2-phenyl-ethanol; (R)-2-Phenyl-2-[5-(1H-pyrazolo[3,4-b]pyridin-5-yl)-pyridin-3-ylamino]-ethanol;

Assignees

• Hoffmann La Roche

Inventors

• Yang Song
• Cheng Zhanling
• Zhou Chengang
• Jiang Min
• Wang Jianhua
• Wang Min
• Han Xingchun

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title