Hexahydropyrrolo[3,4-c]pyrrole derivatives useful as LOX inhibitors

Inventors

Leung, Leo • North, Kiri • SMITHEN, Deborah • Aljarah, Mohammed • Brown, Michael • AYERS, Ben • Niculescu-Duvaz, Dan • Springer, Caroline

Assignees

Institute of Cancer Research Royal Cancer Hospital

Abstract

The disclosure relates to compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein X1 and X5 is each selected from CR1 or N; X2, X3 and X4 is each selected from CR1, CR2 or N, provided at least one of X2, X3 and X4 is CR2 and provided only one of X1, X2, X3, X4 and X5 can be N. R1, R2, R3, R4, R5, L1, L2 and L3 are as defined herein. Compounds according to Formula (I) are pharmacologically effective as lysyl oxidase (LOX) inhibitors and are believed to be useful in the treatment of, for instance, cancer.

Core Innovation

The invention relates to a compound having the structure of Formula (II-a), or a pharmaceutically acceptable salt thereof. The compound structure includes multiple variable groups and linkages defined by R1, R2, Y1, Y2, R2a-R2c, R3-R4, L1-L3, R5 and R6-R9, with broad substituent and optional modification options. The definition encompasses optional ring formation, optional oxidation of sulfur atoms in a heterocycloalkyl ring, and optional formation of 4- to 7-membered heterocycloalkyl under specified conditions.

R1 is selected from hydrogen, halo, cyano, hydroxy, and multiple alkyl, alkoxy, carbonyl, sulfonyl, and sulfonamido-bearing options, with optional substitution on any alkyl, alkenyl, alkynyl, or alkoxy within R1. R2 is defined through multiple structural alternatives involving Y1 and Y2 together with R2a or R2b/R2c, including O- and S-linkages, and corresponding substituent choices on Y1 and Y2. Y1 and Y2 are link elements that are a bond or alkylene, alkenylene, or alkynylene, each optionally substituted as specified.

Further, R2a and R2b/R2c include alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl, and heterocyclyl or heteroaryl groups, with optional substituents and heteroatom inclusion rules. Additional constraints describe when R2b and R2c together form a 3- to 7-membered heterocycloalkyl, optionally including an additional N or S atom, and when R1 and R2 together may form a 4- to 7-membered heterocycloalkyl including one heteroatom selected from O or S. The disclosure also imposes conditions such as -L1-L2-L3-R5 not being benzyl, benzyloxycarbonyl or tert-butyloxycarbonyl, and at least one of L1, L2 and L3 not being a bond for certain selections of R5.

Claims Coverage

The document includes one independent claim. This independent claim provides a comprehensive structure definition for Formula (II-a), including variable substituent selections and optional salt formation, and a total of one independent inventive feature.

The independent claim is directed to a compound corresponding to Formula (II-a) with extensive definitional flexibility across multiple substituent and linkage groups, while maintaining explicit structural constraints on optional ring formation and prohibited linker or terminus forms.

Stated Advantages

Documented Applications