The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.

The present invention provides for a method for the treatment of a NLRP3-associated disease or condition in a subject, the method comprising the step of administering to said subject a medically active liquid in nebulized form by inhalation, wherein the medically active liquid comprises a NLRP3 inhibitor and wherein the medically active liquid is administered in nebulized form using an inhalation device.

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin. ##STR00001##

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin. ##STR00001##

The present invention relates to novel compounds that are autotaxin inhibitors, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in diseases and disorders mediated by autotaxin. ##STR00001##

A compound, or a pharmaceutically acceptable salt or ester thereof, according to formula I:
R.sup.20—(Z).sub.b—(Y).sub.c—(R.sup.21).sub.a—(X).sub.d—R.sup.22—R.sup.23
wherein R.sup.20 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O, S(═O), —S(═O)(═O)—, or NR.sup.10, wherein R.sup.10 is H or alkyl; R.sup.21 is alkanediyl, substituted alkanediyl, cycloalkanediyl, substituted cycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl, substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is —C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—; R.sup.22 includes at least one divalent amino radical; R.sup.23 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; a, b, c, and d independently are 0 or 1.

A compound, or a pharmaceutically acceptable salt or ester thereof, according to formula I:
R.sup.20—(Z).sub.b—(Y).sub.c—(R.sup.21).sub.a—(X).sub.d—R.sup.22—R.sup.23
wherein R.sup.20 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; Z is alkanediyl, substituted alkanediyl, cycloalkanediyl, or substituted cycloalkanediyl; Y is S, O, S(═O), —S(═O)(═O)—, or NR.sup.10, wherein R.sup.10 is H or alkyl; R.sup.21 is alkanediyl, substituted alkanediyl, cycloalkanediyl, substituted cycloalkanediyl, alkadienyl, substituted alkadienyl, cycloalkenediyl, substituted cycloalkenediyl, alkatrienyl, substituted alkatrienyl; X is —C(═O)—, —S(═O)(═O)—, or —N(H)C(═O)—; R.sup.22 includes at least one divalent amino radical; R.sup.23 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkoxy, aryloxy, a thio-containing group, or a seleno-containing group; a, b, c, and d independently are 0 or 1.

The present disclosure provides methods for treating patients with both EGFR- and RET-associated cancers with a combination of osimertinib and selpercatinib, in particular when treatment with the osimertinib leads to the development of fusions or mutations related to RET-associated cancers.

The present disclosure provides methods for treating patients with both EGFR- and RET-associated cancers with a combination of osimertinib and selpercatinib, in particular when treatment with the osimertinib leads to the development of fusions or mutations related to RET-associated cancers.

Provided herein are compositions comprising a RIPK2 inhibitor and methods of using the RIPK2 inhibitor for treating or preventing neurodegenerative diseases or disorders. Also provided herein are methods of screening or identifying therapeutic agents useful for treating or preventing neurodegenerative diseases or disorders.