Compounds and compositions as kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9809610-B2
Application number	US-201715397787-A
Country	US
Kind code	B2
Filing date	Jan 4, 2017
Priority date	Sep 12, 2014
Publication date	Nov 7, 2017
Grant date	Nov 7, 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 method of treating a proliferative disorder selected from ovarian cancer, non-small cell lung cancer and cancers driven by Ras mutations, comprising administering to a subject having said proliferative disorder a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof;
wherein
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 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.

2. The method of claim 1 , wherein the compound has 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 phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the compound has 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 is phosphonooxy; and
Z is selected from N and CH; or a pharmaceutically acceptable salt thereof.

5. The method of claim 4 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

6. A method of treating a proliferative disorder selected from ovarian cancer, non-small cell lung cancer and cancers driven by Ras mutations, comprising administering to a subject in need thereof having said proliferative disorder a therapeutically effective amount of a compound of

or a pharmaceutically acceptable salt thereof.

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

• C07F9/65583 Primary

  each of the hetero rings containing nitrogen as ring hetero atom · CPC title