Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1

Patent metadata

Field	Value
Publication number	US-9278981-B2
Application number	US-201314400987-A
Country	US
Kind code	B2
Filing date	May 9, 2013
Priority date	May 15, 2012
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

Abstract

The present invention relates to compounds of formula (I): in which Y, Y, R, R 2, R 3 and R 4 are defined in the Summary of the Invention; capable of inhibiting the activity of BCR-ABL1 and mutants thereof. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds in the treatment of cancers.

First claim

We claim:

1. A compound of formula (Ia):

in which:
R 4 is selected from the group consisting of —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from the group consisting of hydrogen, methyl, methoxy, cyano, trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
R 7 at each occurrence is independently selected from the group consisting of hydroxy, methyl, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano and amino-carbonyl; or two R 7 groups combine with the atom to which they are attached to form a ring selected from the group consisting of cyclopropyl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl; wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substituted with amino;
Y 1 is selected from the group consisting of N and CR 5 ; wherein R 5 is selected from the group consisting of hydrogen, methoxy and imidazolyl; wherein said imidazolyl is unsubstituted or substituted with methyl;
Y 2 is selected from the group consisting of CF 2 , O and S(O) 0-2 ; and
Y 3 is selected from the group consisting of hydrogen, halo, methyl, difluoromethyl and trifluoromethyl;
Y 4 is selected from the group consisting of CR 6 and N; or the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 of formula (Ib):

in which:
R 4 is selected from the group consisting of —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from the group consisting of hydrogen, methyl, methoxy, cyano, trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
R 7 at each occurrence is independently selected from the group consisting of hydroxy, methyl, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano and amino-carbonyl; or two R 7 groups combine with the atom to which they are attached to form a ring selected from the group consisting of cyclopropyl, pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl and 3-azabicyclo[3.1.0]hexan-3-yl; wherein said 3-azabicyclo[3.1.0]hexan-3-yl can be optionally substituted with amino;
Y 1 is selected from the group consisting of CH and N;
Y 2 is selected from the group consisting of CF 2 , O and S(O) 0-2 ;
Y 3 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or the pharmaceutically acceptable salts thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, selected from the group consisting of:

5. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. The compound of claim 1 of formula (Ic):

in which:
R 4 is selected from the group consisting of —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from the group consisting of hydrogen, methyl, methoxy, cyano, trifluoromethyl, methoxy-carbonyl, 2-hydroxypropan-2-yl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
R 7 at each occurrence is independently selected from the group consisting of hydroxy, methyl, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, cyano and amino-carbonyl; or two R 7 groups combine with the atom to which they are attached to form a ring selected from the group consisting of cyclopropyl and 3-azabicyclo[3.1.0]hexan-3-yl;
Y 1 is selected from the group consisting of CH and N;
Y 2 is selected from the group consisting of CF 2 , O and S(O) 0-2 ;
Y 3 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or the pharmaceutically acceptable salts thereof.

7. The compound of claim 1 , or the pharmaceutically acceptable salt thereof, selected from the group consisting of:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

9. The compound of claim 1 of formula (Id):

Assignees

• Furet Pascal
• Grotzfeld Robert Martin
• Jahnke Wolfgang
• Jones Darryl Brynley
• Manley Paul William
• Marzinzik Andreas
• Pelle Xavier Francois Andre
• Salem Bahaa
• Schoepfer Joseph
• Spieser Erich Alois
• Novartis Ag

Inventors

• Furet Pascal
• Grotzfeld Robert Martin
• Jahnke Wolfgang
• Jones Darryl Brynley
• Manley Paul William
• Marzinzik Andreas
• Pelle Xavier Francois Andre
• Salem Bahaa
• Schoepfer Joseph
• Spieser Erich Alois

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title