US 2026/0294922 A1Published application

Inhibitors of JUN N-Terminal Kinases (JNK1, JNK2, and/or JNK3) and Mitogen-Activated Protein Kinases (MAPK8, MAPK9, and/or MAPK10) and Methods of Using Same

OwnerChandra Madasu, Stephen Palmer +11inventors

InventorsChandra Madasu, Stephen Palmer, Martin Matzuk, Diana Monsivais, Kurt Bohren, Zhi Tan, Jian-Yuan Li, Feng Li, Damian Young, Kiran Sharma, Murugesan Palaniappan, Srinivas Chamakuri, Ramakrishna Kommagani

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Abstract

The present disclosure relates, in part, to compounds of Formula (I) and (II), which selectively inhibit JUN N-Terminal Kinases (JNK1, JNK2, and/or JNK3; also known as MAPK8, MAPK9, and/or MAPK10), pharmaceutical compositions thereof, and methods of using the same for the treatment, prevention, and/or amelioration of one or more diseases and/or disorders in a subject. In certain embodiments, the inflammatory disease or disorder is endometriosis, arthritis, pulmonary fibrosis, cancer, type 1 and/or 2 diabetes, Alzheimer's disease, Parkinson's disease, or amyotrophic lateral sclerosis. In certain embodiments, the methods described herein further comprise detecting the disease and/or disorder in the subject with a suitable diagnostic method.

Claims32

Dependent claims

A compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof:

wherein:
R1a is selected from the group consisting of C1-C6 alkyl, phenyl, and C2-C10 heteroaryl, wherein the alkyl, phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of optionally substituted C1-C6 alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(═O)ORA, C(═O)N(RA)(RB), S(═O)2N(RA)(RB), S(═O)N(RA)(RB OC(═O)RA, and N(RA)C(═O)RB;
R1b is selected from the group consisting of H and optionally substituted C1-C6 alkyl, or
R1a and R1b can combine with the nitrogen atom to which they are bound form an optionally substituted C2-C8 heterocycloalkyl;
R2 is selected from the group consisting of optionally substituted C2-C9 heteroaryl and optionally substituted C6-C10 aryl;
L1 is selected from the group consisting of
R3a, R3b, R3c, and R3d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, CN, NO2, ORC, N(RC)(RD), C(═O)ORC, C(═O)N(RC)(RD), S(═O)2N(RC)(RD), S(═O)N(RC)(RD), OC(═O)RC, and N(RC)C(═O)RD;
and
Y is selected from the group consisting of optionally substituted C1-C3 alkylenyl and optionally substituted C3-C8 cycloalkylenyl;
RA, RB, RC, and RD, if present, are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heterocycloalkyl, optionally substituted C7-C12 aralkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C12 heteroaryl,
wherein RA and RB or RC and RD can combine with the nitrogen atom to which they are bound form an optionally substituted C2-C8 heterocycloalkyl,
wherein one or more of RA and RB can combine with L to form an optionally substituted C4-C8 heterocycloalkyl or C4-C6 heteroaryl.

9 more elements

A compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof:

wherein:
R4 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocycloalkyl, optionally substituted C7-C12 aralkyl, optionally substituted C3-C12 heteroaralkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C12 heteroaryl;
R5a, R5b, R5c, R5d, R5e, and R5 are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, halogen, ORE, and N(RE)(RF);
R6 is —(CH2)1-3C(═O)N(RG)(RH);
R7a is selected from the group consisting of H and C(═O)OR
R7b is H;
X is selected from the group consisting of ORJ and
G is selected from the group consisting of optionally substituted C1-C6 alkyl and —Z1—N(R7a)(R7b);
Z1 and Z2 are each independently-(optionally substituted C1-C6 alkylenyl)-;
R8 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;
R9a and R9b are each independently selected from the group consisting of H and optionally substituted C1-C6 alkyl;
R10a and R10b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, and optionally substituted C6-C10 aryl;
n is an integer selected from the group consisting of 1, 2, 3, 4, and 5;
and
RE, RF, RG, RH, RI, and RJ are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heterocycloalkyl, optionally substituted C7-C12 aralkyl, optionally substituted C6-C10 aryl, and optionally substituted C2-C12 heteroaryl.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 19/478,160Filed 24 Apr 2024
Priority: 24 Apr 2023
Published: 1 Oct 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/437
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring…
A61K 31/444
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine