US 2019/0315752 A1 · BICYCLIC UREA KINASE INHIBITORS AND USES THEREOF

Abstract

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
RA is substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, provided that the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted 3-pyrrolidinyl;
each instance of RA1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
each instance of Ra is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of Rb is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rb are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
k is 0, 1, 2, 3, or 4;
each instance of RB is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
m is 0, 1, 2, 3, 4, or 5;
RC is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RD is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RE is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RF is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
Ring A is substituted or unsubstituted phenyl;
substituted or unsubstituted, polycyclic aryl;
substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl;
or substituted or unsubstituted, polycyclic heteroaryl;
each instance of RG is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
n is 0, 1, 2, 3, or 4, as valency permits;
L is a bond or a substituted or unsubstituted C1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —S—, —NRb—, —N═, or ═N—;
and
RH is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted heterocyclyl, —OH, or —N(Rc)2, wherein each instance of Rc is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rc are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

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Bicyclic urea kinase inhibitors and uses thereof

Life of this patent

Bicyclic urea kinase inhibitors and uses thereof

Life of this patent

Abstract

Claims116