Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1

Patent metadata

Field	Value
Publication number	US-2016200705-A1
Application number	US-201615075620-A
Country	US
Kind code	A1
Filing date	Mar 21, 2016
Priority date	May 15, 2012
Publication date	Jul 14, 2016
Grant date	—

Abstract

The present invention relates to compounds of formula (I):

in which Y, Y 1 , R 1 , R 2 , R 3 and R 4 are defined in the Summary of the Invention; capable of inhibiting the tyrosine kinase enzymatic activity of the Abelson protein (ABL1), the Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1. 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 (Ic):

in which:
R 3 is selected from hydrogen and halo;
R 4 is selected from —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
R 7 at each occurrence is selected from hydroxy, methyl, halo, 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 cyclopropyl, azetidin-3-yl and 3-azabicyclo[3.1.0]hexan-3-yl;
Y 1 is selected from CH and N;
Y 2 is selected from CF 2 , O and S(O) 0-2 ;
Y 3 is selected from hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or
the pharmaceutically acceptable salts thereof.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:

3 . A compound of formula (Id):

in which:
R 3 is selected from hydrogen and halo;
R 4 is selected from —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl;
R 7 at each occurrence is selected from hydroxy, halo, 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 cyclopropyl, azetidin-3-yl and 3-azabicyclo[3.1.0]hexan-3-yl;
Y 1 is selected from CH and N;
Y 2 is selected from CF 2 , O and S(O) 0-2 ;
Y 3 is selected from hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or
the pharmaceutically acceptable salts thereof.

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

5 . A compound of formula (Ie):

in which:
R 3 is selected from hydrogen and halo;
R 4 is selected from —SF 5 and —Y 2 —CF 2 —Y 3 ;
R 6 at each occurrence is independently selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; each
R 7 is independently selected from fluoro, hydroxy, amino, methoxy and amino-methyl;
or both R 7 groups are hydrogen;
Y 1 is selected from CH and N;
Y 2 is selected from CF 2 , O and S(O) 0-2 ;
Y 3 is selected from hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or
the pharmaceutically acceptable salts thereof.

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

7 . A pharmaceutical composition comprising a compound of claim 1 , admixed with at least one pharmaceutically acceptable excipient selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.

8 . The pharmaceutical composition of claim 7 , further comprising an additional therapeutic agent selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent; wherein said anticancer compound is a BCR-ABL1 inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

9 . A method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 ; wherein the cancer is selected from lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, adenomas and carcinomas of the ovary, eye, liver, biliary tract, and nervous system.

10 . The method of claim 9 , further comprising administering to the subject an additional therapeutic agent selected from an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent; wherein said anticancer compound is a BCR-ABL1 inhibitor selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib.

Assignees

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

Inventors

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

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D401/04

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

• C07D417/10

  linked by a carbon chain containing aromatic rings · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title