Compounds and compositions as RAF kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10167279-B2
Application number	US-201515510609-A
Country	US
Kind code	B2
Filing date	Sep 11, 2015
Priority date	Sep 12, 2014
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present invention provides compounds of Formula (I) and (II) 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, or a pharmaceutically acceptable salt thereof, of formula I or II:

in which:
L is selected from NHC(O)— and —C(O)NH—;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from N and CH;
Y 4 is selected from N and CR 8 ; wherein R 8 is selected from H, hydroxy-ethoxy, 3-hydroxyoxetan-3-yl, 2,3-dihydroxypropoxy, bis(hydroxy-ethyl)-amino, 4-hydroxy-piperidin1-yl, hydroxy-ethyl-amino, 4-amino-4-methylpiperidin-1-yl, 2-oxooxazolidin-3-yl, methoxy and methyl;
Y 5 is selected from N and CR 1 ;
or R 1 and the nitrogen of Y 4 form a 5 member unsaturated ring containing and additional heteroatom selected from N, O and S;
or R 1 and R 8 together with the ring to which they are both attached form 2H-benzo[b][1,4]oxazin-3(4H)-one substituted with one to two R 20 groups independently selected from methyl and hydroxy-ethyl;
or R 8 and Y 3 together with the ring to which they are both attached form 1H-benzo[d]imidazole substituted with methyl;
R 1 is selected from H, ethoxy, isopropoxy, methoxy-ethyl-amino, (2-hydroxyethyl)(methyl)amino, (1-hydroxypropan-2-yl)amino, methoxy-ethoxy, hydroxy-ethoxy, methoxy, (2-hydroxypropyl)amino, (tetrahydro-2H-pyran-4-yl)oxy, (tetrahydro-2H-pyran-4-yl)oxy, (1-ethylpiperidin-4-yl)oxy and pyrazolyl; wherein said pyrazolyl can be unsubstituted or substituted with 1 to 2 methyl groups; each
R 2a is independently selected from hydrogen and OH;
R 2b is selected from H, methyl, halo, fluoro-methyl, hydroxy, hydroxymethyl, difluoromethyl, formyl, methoxy and cyano;
R 3 is selected from:

wherein

indicates the point of attachment with L;
R 4 is selected from H, methyl, hydroxy-ethyl, hydroxy-propyl and 2,3-dihydroxypropyl;
R 15 is selected from —CF 3 , methoxy, —C(CH 3 ) 2 F, —CF 2 CH 2 F, —C(CH 3 ) 2 CN, —C(CH 3 )F 2 , —CHF 2 , —C(CH 3 ) 2 OH, t-butyl, 1-cyanocyclopropyl, 2-(trifluoromethyl)cyclopropyl, —C(F 2 )C 2 H 5 , methyl-sulfonyl, 4-ethylpiperazin-1-yl, —C(CH 3 ) 2 NH 2 and dimethyl-amino-methyl;
R 16 is selected from H, halo, hydroxy, dimethyl-amino, hydroxy-methyl, amino-methyl, —C(CH 3 ) 2 NH 2 and —CF 3 ; or a pharmaceutically acceptable salt thereof; with the proviso that a compound of formula II is not 2-(2-cyanopropan-2-yl)-N-(4-methyl-3-(1-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridazin-3-yl)phenyl)isonicotinamide or 2-(2-fluoropropan-2-yl)-N-(4-methyl-3-(1-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyridazin-3-yl)phenyl)isonicotinamide.

2. The compound of claim 1 of formula Ia:

in which:
L is selected from —NHC(O)— and —C(O)NH—;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from N and CH;
Y 4 is selected from N and CR 8 ; wherein R 8 is selected from H, hydroxy-ethoxy, 3-hydroxyoxetan-3-yl, 2,3-dihydroxypropoxy, hydroxy-ethyl-amino, 4-amino-4-methylpiperidin-1-yl, 2-oxooxazolidin-3-yl, methoxy and methyl;
Y 5 is selected from N and CR 1 ;
R 1 is selected from H, ethoxy, hydroxy-ethoxy, methoxy, (tetrahydro-2H-pyran-4-yl)oxy and pyrazolyl; wherein said pyrazolyl can be unsubstituted or substituted with 1 to 2 methyl groups;
R 2b is selected from H, methyl, halo, fluoro-methyl, hydroxy, difluoromethyl, formyl, methoxy and cyano;
R 15 is selected from —CF 3 , methoxy, —C(CH 3 ) 2 F, —CF 2 CH 2 F, —C(CH 3 ) 2 CN, —C(CH 3 )F 2 , —CHF 2 , —C(CH 3 ) 2 OH, t-butyl, 1-cyanocyclopropyl, 2-(trifluoromethyl)cyclopropyl, —C(F 2 )C 2 H 5 , methyl-sulfonyl, 4-ethylpiperazin-1-yl, —C(CH 3 ) 2 NH 2 and dimethyl-amino-methyl; 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:
L is selected from —NHC(O)— and —C(O)NH—;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from N and CH;
Y 4 is selected from N and CR 8 ; wherein R 8 is selected from H, hydroxy-ethoxy, 3-hydroxyoxetan-3-yl, 2,3-dihydroxypropoxy, hydroxy-ethyl-amino, 4-amino-4-methylpiperidin-1-yl, 2-oxooxazolidin-3-yl, methoxy and methyl;
Y 5 is selected from N and CR 1 ;
R 1 is selected from H, ethoxy, hydroxy-ethoxy, methoxy, (tetrahydro-2H-pyran-4-yl)oxy and pyrazolyl; wherein said pyrazolyl can be unsubstituted or substituted with 1 to 2 methyl groups;
R 2b is selected from H, methyl, halo, fluoro-methyl, hydroxy, difluoromethyl, formyl, methoxy and cyano;
R 15 is selected from —CF 3 , methoxy, —C(CH 3 ) 2 F, —CF 2 CH 2 F, —C(CH 3 ) 2 CN, —C(CH 3 )F 2 , —CHF 2 , —C(CH 3 ) 2 OH, t-butyl, 1-cyanocyclopropyl, 2-(trifluoromethyl)cyclopropyl, —C(F 2 )C 2 H 5 , methyl-sulfonyl, 4-ethylpiperazin-1-yl, —C(CH 3 ) 2 NH 2 and dimethyl-amino-methyl;
R 16 is selected from H, halo, hydroxy, dimethyl-amino, hydroxy-methyl, amino-methyl, —C(CH 3 ) 2 NH 2 and —CF 3 ; or a pharmaceutically acceptable salt thereof.

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

6. The compound of claim 1 of formula Ic:

in which:
L is selected from —NHC(O)— and —C(O)NH—;
Y 1 is selected from N and CH;
Y 2 is selected from N and CH;
Y 3 is selected from N and CH;
Y 4 is selected from N and CR 8 ; wherein R 8 is selected from H, hydroxy-ethoxy, 3-hydroxyoxetan-3-yl, hydroxy-ethyl-amine, methoxy and methyl;
Y 5 is selected from N and CR

Assignees

• Novartis Ag

Inventors

• Aversa Robert John
• Burger Matthew T
• Dillon Michael Patrick
• Dineen Jr Thomas A
• Lou Yan
• Nishiguchi Gisele A
• Ramurthy Savithri
• Rico Alice C
• Rauniyar Vivek
• Sendzik Martin
• Subramanian Sharadha
• Setti Lina Quattrocchio
• Taft Benjamin R
• Tanner Huw Rowland
• Wan Lifeng

Classifications

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title