NEK7 inhibitors
Compounds having activity as inhibitors of NEK7 are provided. The compounds have Structure (I): (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein A, X, Y, Z, R1, R2, R3, and n are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of the NLRP3 inflammasome are also provided.
1 . A compound having the following Structure (I):
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:
A is C 6 -C 10 arylene, C 3 -C 10 cycloalkylene, 3-10 membered heterocyclylene, or 5-6 membered heteroarylene;
X is N or CR 4 ;
Y is N or CH;
Z is N or CH;
R 1 is C 1 -C 6 alkyl, C 1 -C 6 alkynyl, C 1 -C 6 hydroxylalkyl, C 1 -C 6 carboxyalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 10 cycloalkyl, or 3-10 membered heterocyclyl;
R 2 is a 3-10 membered heterocyclyl, 3-10 membered heterocyclylalkyl, 3-10 membered heterocyclylalkenyl, 3-10 membered heterocyclylcarbonyl, 3-10 membered heterocyclyloxy, or 5-6 membered heteroaryl, or
R 2 joins with an occurrence of R 3 attached to a carbon adjacent to a carbon to which R 2 is attached to form a C 3 -C 8 cycloalkyl;
R 3 is, at each occurrence, independently halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C 3 -C 8 cycloalkyl;
R 4 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; and
n is 0, 1, 2, 3, or 4.
2 . The compound of claim 1 , wherein A is phenylene or pyridinylene.
3 . The compound of claim 1 , wherein A is C 3 -C 10 cycloalkylene or 3-10 membered heterocyclylene.
4 . The compound of claim 1 , wherein A is substituted with one or more substituents selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C 3 -C 8 cycloalkyl.
5 . The compound of claim 1 , wherein A is unsubstituted or substituted with one or more halo substituents.
6 . The compound of claim 1 , wherein X is N or X is CR 4 and R 4 is H or C 1 -C 6 alkyl.
7 . The compound of claim 1 , wherein R 1 has one of the following structures:
8 . The compound of claim 1 , wherein the compound has the following Structure (Ia):
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
9 . The compound of claim 1 , wherein Y is N.
10 . The compound of claim 1 , wherein Y is CH.
11 . The compound of claim 1 , wherein the compound has the following Structure (Ib):
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
12 . The compound of claim 1 , wherein R 2 is morpholino.
13 . The compound of claim 1 , wherein R 2 has one of the following structures:
14 . The compound of claim 1 , wherein R 3 is halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or C 3 -C 8 cycloalkyl.
15 . The compound of claim 14 , wherein R 3 is methyl, chloro, fluoro, cyano, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, or cyclopropyl.
16 . The compound of claim 1 , wherein the compound has the following Structure (Ic):
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, wherein:
R 3a is halo or 3-10 membered heterocyclyl; and
n1 is 1, 2, or 3.
17 . The compound of claim 1 , wherein Z is N.
18 . The compound of claim 1 , wherein Z is CH.
19 . A compound having one of the following structures:
or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
20 . The compound of claim 1 , wherein the compound is a modulator of the NLRP3 inflammasome or an inhibitor of NEK7.
21 . A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.
22 . A method of modulating NLRP3 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of claim 1 .
23 . A method of treating a disease or disorder, comprising administering a therapeutically effective amount of a compound of claim 1 to a subject in need thereof, wherein the disorder is selected from allergy, asthma, pancreatitis, multi-organ failure, platelet aggregation, transplantation, graft rejection, sperm motility, type II diabetes, atherosclerosis, Alzheimer's disease, fatty liver, asthma, psoriasis, obesity, acute and chronic tissue damage caused by infection, gout, arthritis, macular degeneration, enteritis, hepatitis, peritonitis, silicosis, UV-induced skin sunburn, contact hypersensitivity, sepsis, cancer, multiple sclerosis, Muckle-Wells syndrome, and combinations thereof.