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

Patent metadata

Field	Value
Publication number	US-9315489-B2
Application number	US-201314400990-A
Country	US
Kind code	B2
Filing date	May 9, 2013
Priority date	May 15, 2012
Publication date	Apr 19, 2016
Grant date	Apr 19, 2016

Abstract

The present invention relates to compounds of formula I: in which Y, Y 1 , Y 4 , Y 5 , Y 6 , R 1 , 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 (I):

in which:
Y at each occurrence is independently selected from N and CH;
Y 1 is CR 5 ; wherein R 5 is selected from hydrogen, methoxy and imidazolyl; wherein said imidazolyl is unsubstituted or substituted with methyl;
R 1 is pyridinyl unsubstituted or substituted with 1 to 3 R 6 groups;
R 2 is selected from hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, methoxy-carbonyl, 3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl-oxy and cyclobutyl; wherein said C 1-4 alkyl, C 1-4 alkoxy, cyclobutyl or tetrahydro-2H-pyran-4-yl of R 2 can be unsubstituted or substituted with 1 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, morpholino, piperazinyl and NR 5a R 5b ; wherein R 5a is selected from hydrogen and C 1-4 alkyl; and R 5b is selected from hydroxy-ethyl; wherein said piperazinyl substituent of R 2 can be unsubstituted or further substituted with C 1-4 alkyl;
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, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl, halo, amino, methyl-carbonyl, methoxy-carbonyl, cyclopropyl and pyrrolidinyl-methyl; wherein said C 1-4 alkyl or C 1-4 alkoxy of R 6 is unsubstituted or substituted with 1 to 3 groups independently selected from halo and hydroxy;
Y 2 is selected from CF 2 , O and S(O) 0-2 ; and
Y 3 is selected from hydrogen, halo, methyl, difluoromethyl and trifluoromethyl;
Y 4 is CR 2 ;
Y 5 and Y 6 are independently CR 5 ; wherein R 5 is selected from hydrogen and halo; or the pharmaceutically acceptable salts thereof; with the proviso that the compounds of formula I do not include 3-(2-aminoquinazolin-6-yl)-4-methyl-N-(4-(trifluoromethoxy)phenyl)-benzamide and 3-(2-aminoquinazolin-6-yl)-5-bromo-N-(4-(trifluoromethoxy)phenyl)-benzamide.

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

in which:
Y at each occurrence is independently selected from N and CH;
Y 1 is CR 5 ; wherein R 5 is selected from hydrogen, methoxy and imidazolyl; wherein said imidazolyl is unsubstituted or substituted with methyl;
R 1 is pyridinyl unsubstituted or substituted with a group selected from cyano, methyl, halo, hydroxy, hydroxy-ethyl, methyl-carbonyl, methoxy, hydroxy-ethoxy, amino, methoxy-carbonyl and pyrrolidinyl-methyl;
R 2 is selected from hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, methoxy-carbonyl, 3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl-oxy and cyclobutyl; wherein said C 1-4 alkyl, C 1-4 alkoxy, cyclobutyl or tetrahydro-2H-pyran-4-yl of R 2 can be unsubstituted or substituted with 1 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, morpholino, piperazinyl and NR 5a R 5b ; wherein R 5a is selected from hydrogen and C 1-4 alkyl; and R 5b is selected from hydroxy-ethyl; wherein said piperazinyl substituent of R 2 can be unsubstituted or further substituted with C 1-4 alkyl;
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, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl, halo, amino, methyl-carbonyl, methoxy-carbonyl, cyclopropyl and pyrrolidinyl-methyl; wherein said C 1-4 alkyl or C 1-4 alkoxy of R 6 is unsubstituted or substituted with 1 to 3 groups independently selected from halo and hydroxy;
Y 2 is selected from CF 2 , O and S(O) 0-2 ; and
Y 3 is selected from hydrogen, halo, methyl, difluoromethyl and trifluoromethyl;
Y 4 is CR 2 ;
Y 5 and Y 6 are independently CR 5 ; wherein R 5 is selected from hydrogen and halo; or the pharmaceutically acceptable salts thereof.

3. The compound of claim 2 in which: Y is CH; and R 2 is selected from hydrogen, halo and methyl.

4. The compound of claim 3 in which R 3 is hydrogen and R 4 is selected from trifluoro-methoxy, trifluoro-methyl-thio and chloro-difluoro-methoxy.

5. A compound selected from:

6. The compound of claim 2 in which: Y is CH; and R 2 is selected from hydroxy, C 1-4 alkoxy, methoxy-carbonyl, 3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl-oxy and cyclobutyl; wherein said C 1-4 alkoxy, cyclobutyl or tetrahydro-2H-pyran-4-yl of R 2 can be unsubstituted or substituted with 1 to 3 groups independently selected from halo, hydroxy, cyano, C 1-4 alkoxy, morpholino, piperazinyl and NR 5a R 5b ; wherein R 5a is selected from hydrogen and C 1-4 alkyl; and R 5b is selected from hydroxy-ethyl; wherein said piperazinyl substituent of R 2 can be unsubstituted or further substituted with C 1-4 alkyl.

7. The compound of claim 6 in which: R 2 is selected from methoxy, ethoxy, morpholino-ethoxy, hydroxy-ethoxy, pyrrolidinyl-ethoxy, hydroxy, methoxy-ethoxy, (hydroxy-ethyl)amino-ethoxy, (tetrahydro-2H-pyran-4-yl)oxy and piperazinyl-ethoxy; wherein said piperazinyl-ethoxy is unsubstituted or substituted with isobutyl.

8. The compound of claim 7 in which: R 3 is hydrogen and R 4 is selected from trifluoro-methoxy and chloro-difluoro-methoxy.

9. A compound selected from:

10. A pharmaceutical composition comprising a compound of claim 1 , admixed with at least one pharmaceutically acceptable excipient selected from 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.

11. The pharmaceutical composition of claim 10 , further comprising an additional therapeutic agent selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.

12. A method to treat chronic myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 .

13. The method of claim 12 , 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.

14. The method of claim 13 , wherein th

Assignees

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

Inventors

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

Classifications

• A61P43/00

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

• A61P31/12

  Antivirals · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title