Claims for Patent: 8,829,195

Summary for Patent: 8,829,195

Title:	Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
Abstract:	The present invention relates to compounds of formula (I): ##STR00001## in which Y, Y.sub.1, R.sub.1, R.sub.2, R.sub.3 and R.sub.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.
Inventor(s):	Dodd; Stephanie Kay (Ayer, MA), Furet; Pascal (Thann, FR), Grotzfeld; Robert Martin (Ettingen, CH), Jahnke; Wolfgang (Lorrach, DE), Jones; Darryl Brynley (Basel, CH), Manley; Paul William (Arlesheim, CH), Marzinzik; Andreas (Weil, DE), Pelle; Xavier Francois Andre (Kembs, FR), Salem; Bahaa (Basel, CH), Schoepfer; Joseph (Riehen, CH)
Assignee:	Novartis AG (Basel, CH)
Application Number:	13/892,769
Patent Claims:	1. The compound of formula (I): ##STR00125## in which: R.sub.1 is pyrazolyl; wherein said pyrazolyl is unsubstituted or substituted with 1 to 2 R.sub.6 groups; R.sub.2 is pyrrolidinyl; wherein said pyrrolidinyl is substituted with one R.sub.7 group; R.sub.3 is selected from hydrogen and halo; R.sub.4 is selected from --SF.sub.5 and --Y.sub.2--CF.sub.2--Y.sub.3; R.sub.6 at each occurrence is independently selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R.sub.7 is selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyloxy, carboxy, methoxy-carbonyl, phosphonooxy, cyano and amino-carbonyl; Y is selected from CH and N; Y.sub.1 is selected from CH and N; Y.sub.2 is selected from CF.sub.2, O and S(O).sub.0-2; and Y.sub.3 is selected from hydrogen, chloro, fluoro, methyl, difluoromethyl and trifluoromethyl; or the pharmaceutically acceptable salts thereof. 2. The compound of claim 1 of formula (Ib): ##STR00126## in which: R.sub.3 is selected from hydrogen and halo; R.sub.4 is selected from --SF.sub.5 and --Y.sub.2--CF.sub.2--Y.sub.3; R.sub.6 when linked to a nitrogen of the pyrazolyl ring is selected from hydrogen, methyl, hydroxy-ethyl, fluoro-ethyl, ethyl and cyclopropyl; and R.sub.6 when linked to a carbon atom of the pyrazolyl ring is selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R.sub.7 is selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyloxy, carboxy, methoxy-carbonyl, phosphonooxy, cyano and amino-carbonyl; Y.sub.1 is selected from CH and N; Y.sub.2 is selected from CF.sub.2, O and S(O).sub.0-2; Y.sub.3 is selected from hydrogen, fluoro, chloro, methyl, difluoromethyl and trifluoromethyl; or the pharmaceutically acceptable salts thereof. 3. The compound of claim 2 of formula (Ic): ##STR00127## in which: R.sub.3 is selected from hydrogen and halo; R.sub.4 is selected from --SF.sub.5 and --Y.sub.2--CF.sub.2--Y.sub.3; R.sub.6 when linked to a nitrogen of the pyrazolyl ring is selected from hydrogen, methyl, hydroxy-ethyl, fluoro-ethyl, ethyl and cyclopropyl; and R.sub.6 when linked to a carbon atom of the pyrazolyl ring is selected from hydrogen, hydroxy, methyl, methoxy, cyano, trifluoromethyl, hydroxy-methyl, halo, amino, fluoro-ethyl, ethyl and cyclopropyl; R.sub.7 is selected from hydroxy, methyl, halo, methoxy, hydroxy-methyl, amino, methyl-amino, amino-methyl, trifluoromethyl, 2-hydroxypropan-2-yl, methyl-carbonyl-amino, dimethyl-amino, 2-amino-3-methylbutanoyloxy, carboxy, methoxy-carbonyl, phosphonooxy, cyano and amino-carbonyl; Y.sub.1 is selected from CH and N; Y.sub.2 is selected from CF.sub.2, O and S(O).sub.0-2; Y.sub.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: ##STR00128## 5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, selected from: ##STR00129## ##STR00130## ##STR00131## ##STR00132## 6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, selected from: ##STR00133## ##STR00134## 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, that is: ##STR00135## 8. The compound of claim 1 that is (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(- 1H-pyrazol-5-yl)nicotinamide or a pharmaceutically acceptable salt thereof. 9. A method for treating a patient having a leukemia selected from chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) comprising administering to said patient a therapeutically effective amount of (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin- -1-yl)-5-(1H-pyrazol-5-yl)nicotinamide or a pharmaceutically acceptable salt thereof and optionally a sequential or simultaneous administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 10. The method of claim 9 comprising administering to said patient a therapeutically effective amount of (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(- 1H-pyrazol-5-yl)nicotinamide or a pharmaceutically acceptable salt thereof. 11. The method of claim 9 comprising a sequential administration of a therapeutically effective amount of a compound of (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(- 1H-pyrazol-5-yl)nicotinamide or a pharmaceutically acceptable salt thereof and a sequential administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 12. The method of claim 9 comprising administering to said patient a therapeutically effective amount of (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(- 1H-pyrazol-5-yl)nicotinamide or a pharmaceutically acceptable salt thereof and a simultaneous administration of a therapeutically effective amount of a compound selected from imatinib, nilotinib, dasatinib, bosutinib, ponatinib and bafetinib. 13. The method of claim 12 wherein (R)--N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(- 1H-pyrazol-5-yl)nicotinamide is dosed in the range of 90-130 mg/kg. 14. The method of claim 13 wherein nilotinib is dosed at 10-50 mg/kg. 15. The method of claim 14 wherein imatinib is dosed at 50-200 mg/kg. 16. A compound that is (S)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluorometho- xy)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof.