Granted Patent B2

US 8,829,195 · App. 13/892,769 · Granted Sep 9, 2014

Abstract

Claims (43)

1. The compound of formula (I):

in which:

R 1 is pyrazolyl; wherein said pyrazolyl is unsubstituted or substituted with 1 to 2 R 6 groups;

R 2 is pyrrolidinyl; wherein said pyrrolidinyl is substituted with one R 7 group;

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 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 1 is selected from CH and N;

Y 2 is selected from CF 2 , O and S(O) 0-2 ; and

Y 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):

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 when linked to a nitrogen of the pyrazolyl ring is selected from hydrogen, methyl, hydroxy-ethyl, fluoro-ethyl, ethyl and cyclopropyl; and R 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 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 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.

3. The compound of claim 2 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 when linked to a nitrogen of the pyrazolyl ring is selected from hydrogen, methyl, hydroxy-ethyl, fluoro-ethyl, ethyl and cyclopropyl; and R 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 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 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. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, selected from:

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

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, that is:

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-(trifluoromethoxy)phenyl)nicotinamide, or a pharmaceutically acceptable salt thereof.

Assignments (9)