ANALOGS FOR THE TREATMENT OF DISEASE
The disclosure provides TNIK and/or MAP4K4 kinases inhibitors for the treatment of disease. In one aspect, disclosed herein are kinase inhibitors having a structure of Formula (A), (A*), (I), (IIA), or (IIB). Further described herein are pharmaceutical composition comprising these compounds and methods of using these compounds. In one aspect, disclosed herein are methods of treating a disease or condition by administering the kinases inhibitors described herein.
1 - 29 . (canceled)
30 . A compound represented by Formula (IIA),
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from
substituted C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is substituted with one or more substituents selected from halogen, —OH, —CN, —NO 2 , —NH 2 , oxo, ═S, —C 1-10 haloalkyl, —O—C 1-10 alkyl, —O—C 1-6 alkyl-O—C(O)(O—C 1-10 alkyl), C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
optionally substituted 3 to 8-membered heterocycle, wherein the 3 to 8-membered heterocycle is optionally substituted with one or more substituents selected from halogen, —OH, —CN, —NO 2 , —NH 2 , oxo, ═S, —S(O 2 )NH 2 , —C 1-10 haloalkyl, —O—C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, 3- to 12-membered heterocycle, and optionally substituted C 1-10 alkyl, wherein the C 1-10 alkyl is optionally substituted with one or more substituents selected from hydroxy, halogen, oxo, —C 1-10 haloalkyl, —NH 2 , —CN, and —NO 2 ;
R 3 is optionally substituted C 3-10 carbocycle, which is optionally substituted with one or more substituents selected from halogen, —OH, —CN, —NO 2 , —NH 2 , oxo, ═S, C 1-6 alkyl, —C 1-10 haloalkyl, —O—C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle; and
R 4 is substituted C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is substituted with one or more halogen.
31 . The compound of claim 30 , wherein R 4 is substituted with two fluorine.
32 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein
R 4 is selected from
33 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 3 is substituted C 6 carbocycle, and wherein the C 6 carbocycle is substituted with one or more substituents selected from halogen and —C 1-10 haloalkyl.
34 . The compound of claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 1 is substituted C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is substituted with one or more substituents selected from halogen, —OH, —CN, —NO 2 , —NH 2 , oxo, ═S, —C 1-10 haloalkyl, —O—C 1-10 alkyl, —O—C 1-6 alkyl-O—C(O)(O—C 1-10 alkyl), C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3- to 12-membered heterocycle.
35 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted with one or more substituents selected from oxo, halogen, —O—C 1-10 alkyl, —C 1-10 haloalkyl, and —OH.
36 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted with one or more substituents selected from —OH, oxo, and —O—C 1-10 alkyl.
37 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
38 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
39 . The compound of claim 31 , or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted bicyclic heterocycle.
40 . The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein R 1 is an optionally substituted bridged bicyclic heterocycle.
41 . The compound of claim 39 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
42 . A method of treating a fibrotic disease or condition, comprising administering a compound of claim 30 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
43 . The method of claim 42 , wherein the fibrotic disease or condition is kidney fibrosis.
44 . The method of claim 42 , wherein the fibrotic disease or condition is associated with TNIK kinase.
45 . A pharmaceutical composition comprising (i) a compound of claim 30 or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable excipient.