Substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase BTK inhibitors

摘要

In one aspect, the invention relates to substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the BTK kinase; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of using the compounds and compositions to treat disorders associated with dysfunction of the BTK kinase. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

主权项

1. A compound having a structure represented by a formula: wherein R1 is halogen or NR8Ar1; or wherein R1 and R2 are optionally covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring;
wherein R8 is selected from hydrogen and C1-C6 alkyl;wherein Ar1 is phenyl substituted with 0-3 groups independently selected from cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO2R9, C1-C3 alkylamine, and C1-C3 dialkylamino or Ar1 is monocyclic heteroaryl substituted with 0-3 groups independently selected from halo, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 cyanoalkyl, SO2R9, C1-C3 alkylamine, and C1-C3 dialkylamino;wherein R9 is selected from hydrogen and C1-C6 alkyl; wherein R2 is hydrogen; or wherein R1 and R2 are optionally covalently bonded and, together with the intermediate carbons, comprise an optionally substituted fused five-membered or six-membered C2-C5 heterocyclic ring; wherein R3 is a structure represented by the formula: wherein R10 is selected from hydrogen and C1-C6 alkyl;wherein each of R11a and R11b is independently selected from hydrogen, halogen, and C1-C6 alkyl;wherein R12a is selected from hydrogen, halogen, and C1-C6 alkyl; andwherein R12b is selected from hydroxyl and a group having a structure represented by a formula: wherein z is an integer selected from 1, 2, and 3;wherein each occurrence of R90, when present, is independently selected from hydrogen, C1-C8 alkyl, and phenyl;wherein R13 is a five-membered or six-membered C3-C6 heterocycle substituted with 0-3 groups selected from halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyoxy, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; wherein each of R4a, R4b, R4c, and R4d is independently selected from hydrogen, halogen, and C1-C6 alkyl; wherein R5 is selected from hydrogen and C1-C6 alkyl; wherein R6 is selected from hydrogen and C1-C6 alkyl; and wherein each of R7a and R7b is independently selected from hydrogen and C1-C6 alkyl, or a pharmaceutically acceptable salt, solvate, or polymorph thereof.