Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors

Inventors

Fu, Jiping • Lou, Yan • HE, Yigang

Assignees

Nikang Therapeutics Inc

Abstract

The present disclosure provides certain fused tricyclic ring derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Core Innovation

The disclosure concerns compounds of formula (IIB) or pharmaceutically acceptable salts thereof, defined by a variable substituent framework including Z, R1, R2, R3, R4, R5, R6, L, R9, R10, and ring formation from R11 and R12 with the carbon atom to which they are attached. Z is defined either as -Y-M, where Y is a bond and M is selected from alkyl, haloalkyl, cycloalkyl, heterocyclyl, or heteroaryl substituted with -O(alk)ORa, or as named alternatives including methoxymethyloxy, methoxyethyloxy, methoxymethyl, cyclopropylmethyloxymethyl, oxetan-3-ylmethyloxymethyl, alkoxy, heterocyclyloxy, cycloalkylmethyloxymethyl, or heterocyclylmethyloxymethyl.

R1, R2, R3, and R4 are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, hydroxy, hydroxylalkyl, amino, and aminoalkyl. R5 and R6 are independently selected from the same general set, with one of R5 and R6 optionally being substituted heterocyclyl in some claim language.

L is bond, O, S, S(O), S(O)2, or CR7R8, where R7 and R8 are independently hydrogen or alkyl. R9 is hydrogen, alkyl, halo, hydroxy, amino, or haloalkyl, and R10 is hydrogen, alkyl, halo, hydroxy, hydroxyalkyl, —CD2OH, alkylsulfoxide, alkylsulfonyl, amino, aminoalkyl, aminosulfonyl, aminocarbonyl, carboxy, cyano, or alkoxycarbonyl. The disclosure also includes tautomers, geometric isomers, hydrates, isotopically labeled compounds, stereoisomers, racemic forms, and optically active forms.

Claims Coverage

The consolidated claim coverage includes two independent claims for compounds of formula (IIB) or pharmaceutically acceptable salts thereof. The inventive features center on five main feature groups: Z, R1-R6, L, R9/R10, and ring formation from R11 and R12.

The independent claims are directed to formula (IIB) compounds or pharmaceutically acceptable salts defined by an enumerated Z group, broadly selectable R1-R6 substituents, a linkage group L with sulfur oxidation-state options and a carbon-linkage option, defined R9 and R10 substituents, and ring formation from R11 and R12 with the attached carbon atom.

Stated Advantages

Documented Applications