Compounds and compositions as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9573969-B2
Application number	US-201514851249-A
Country	US
Kind code	B2
Filing date	Sep 11, 2015
Priority date	Sep 12, 2014
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

The present invention provides a compound of Formula I:

wherein X, Y, Z, R 1 and R 2 are as described herein, and salts thereof and therapeutic uses of these compounds for treatment of disorders associated with RAF kinase activity. The invention further provides pharmaceutical compositions comprising these compounds, and compositions comprising these compounds and a therapeutic co-agent.

First claim

We claim:

1. A compound of formula I:

in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
X and Y are independently selected from N and C—OCH 2 CHR 3 R 4 ; wherein R 3 is selected from hydrogen and OH; and R 4 is selected from 2-(phosphonooxy)methyl and phosphonooxy; with the proviso that if X is N, Y is C—OCH 2 CHR 3 R 4 ; and if Y is N, X is C—OCH 2 CHR 3 R 4 ; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 of formula Ia:

in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
R 3 is selected from hydrogen and OH;
R 4 is selected from 2-(phosphonooxy)methyl and phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, selected from:

4. The compound of claim 1 of formula Ib:

in which:
R 1 is selected from hydrogen and methyl;
R 2 is selected from pyridinyl and phenyl; wherein phenyl or pyridinyl can be substituted with a group selected from trifluoromethyl, 1,1-difluoroethyl and 2-fluoropropan-2-yl;
R 3 is selected from hydrogen and OH;
R 4 selected from 2-(phosphonooxy)methyl and phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, selected from:

6. A compound, or a pharmaceutically acceptable salt thereof, of formula:

7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

8. A combination comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

Assignees

• Burger Matthew T
• Ramurthy Savithri
• Taft Benjamin R
• Novartis Ag

Inventors

• Burger Matthew T
• Ramurthy Savithri
• Taft Benjamin R

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P15/08

  for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title