[4,5′]Bipyrimidinyl-6,4′-diamine derivatives as protein kinase inhibitors
AssigneeNovartis AG
InventorsPamela A. Albaugh, Yun He, Songchun Jiang, Pingda Ren, Xia Wang, Xing Wang, Yongping Xie
Life of this patent
Estimating the term…
Abstract
The invention provides a novel class of compounds of the Formula I: in which the symbols have the meanings given in the description and claims, to pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of FGFR3 kinase.
Claims19
A compound of Formula I:
- in which:
- Z is N and Y is CH;
- R1 is C1-4alkoxy;
- R2 is selected from cyano, C1-4alkoxy, —C(O)NR7R8, —NR7C(O)R8, —NR7S(O)2R8, —S(O)2NR7R8, —NR7R8, —C(O)OR8, —OC(O)R8, —C(O)NR7OR8 and a saturated, unsaturated or partially saturated monocyclic ring containing 5 to 7 ring members selected from C, O, N and S;
- wherein R7 is selected from hydrogen and C1-4alkyl;
- and R8 is selected from hydrogen, C1-4alkyl and C3-12cycloalkyl,
- R3 is selected from hydrogen, halo, C1-4alkyl and C1-4alkoxy;
- R4a is selected from halo and C1-4alkyl;
- R4b is selected from hydrogen and C1-4alkyl;
- R5 is hydrogen and C1-4alkyl;
- R6 is selected from hydrogen, —X1R9 and X1NR10R11;
- wherein each X1 is independently selected from a bond and C1-4alkylene;
- R9 is selected from C6-10aryl, a monocyclic ring containing 5 to 7 ring members selected from C, O, N and S, and a bridged or fused bicyclic ring system containing 8 to 14 members selected from C, O, N and S;
- wherein said monocyclic and bridged or fused bicyclic rings of R9 can be saturated, unsaturated or partially unsaturated;
- R10 and R11 are independently selected from hydrogen and C1-4alkyl;
- wherein said aryl, monocyclic or bicyclic rings of R9 can be optionally substituted with a group selected from C1-4alkyl, —X2R12, and —OX2NR13R14;
- wherein each X2 is independently selected from a bond and C1-4alkylene;
- R13 and R14 are independently selected from hydrogen and C1-4alkyl;
- R12 is selected from a monocyclic ring containing 5 to 7 ring members selected from C, O, N and S optionally substituted with up to 3 groups selected from C1-4alkyl, —X3C(O)NR15R16, —X3OR16, —X3C(O)X3OR15, —X3C(O)R15 and —X3NR15R16;
- wherein said monocyclic ring of R12 can be saturated, unsaturated or partially unsaturated;
- wherein each X3 is independently selected from a bond and C1-4alkylene;
- each R15 and R16 is independently selected from hydrogen and C1-4alkyl;
- wherein any alkyl substituents of R9 can optionally substituted with up to 3 hydroxyl groups;
- or a pharmaceutically acceptable salt thereof.
A compound selected from the group consisting of 2,4-dichloro-5-methoxy-3-(6-(5-(morpholinomethyl)pyridin-2-ylamino)-4,5′-bipyrimidin-4′-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide, 2,4-dichloro-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-5-methoxy-3-(6-(5-(morpholinomethyl)pyridin-2-ylamino)-4,5′-bipyrimidin-4′-ylamino)benzamide, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-morpholin-4-ylmethyl-pyridin-2-yl) -amine, {6-[3-(2-chloro-3,5-dimethoxy-6-fluoro phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-morpholin-4-ylmethyl-pyridin-2-yl)-amine, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(4-morpholin-4-ylmethyl-pyridin-2-yl)-amine, {6-[3-(2-chloro-3,5-dimethoxy-6-fluoro phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(4-morpholin-4-ylmethyl-pyridin-2-yl)-amine, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(4-[2-(morpholin-4-yl)-ethyl]-pyridin-2-yl)-amine, {6-[3-(2-chloro-3,5-dimethoxy-6-fluorophenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(4-[2-(morpholin-4-yl)-ethyl]-pyridin-2-yl)-amine, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-[1-(2-hydroxyethyl)-piperazin-4-yl]-pyridin-2-yl)-amine, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-[1-(2-hydroxy-1-oxo-ethyl)-piperazin-4-yl]-pyridin-2-yl)-amine, {6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-[1-hydroxyethyl]-pyridin-2-yl)-amine, {6-[3-(2,6-Difluoro-3-methoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-amine, {6-[3-(2,6-Difluoro-3-methoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-N-(5-(morpholin-4-ylmethyl)-pyridin-2-yl)-amine, {6-[3-(2,6-Difluoro-3-methoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(4-(morpholin-4-ylmethyl)-pyridin-2-yl)-amine, 6-(3-(2,6-dichlorophenylamino)pyrazin-2-yl)pyrimidin-4-amine, 6-(3-(2,6-dichlorophenylamino)pyrazin-2-yl)-N-(5-(morpholinomethyl)pyridin-2-yl)pyrimidin-4-amine, 6-(3-(2,6-dichlorophenylamino)pyrazin-2-yl)-N-(5-(2-morpholinoethyl)pyridin-2-yl)pyrimidin-4-amine, 6-(3-(2,6-dichlorophenylamino)pyrazin-2-yl)-N-(4-(4-ethylpiperazin-1-yl)phenyl)pyrimidin-4-amine, and 6-(3-(2,6-dichlorophenylamino)pyrazin-2-yl)-N-(4-(2-(diethylamino)ethoxy)phenyl)pyrimidin-4-amine,
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.