Thiazole derivatives useful as mutant IDH1 inhibitors for treating cancer

Inventors

Boxer, Matthew Brian • Wang, Xiaodong • Brimacombe, Kyle Ryan • Davis, Mindy Irene Emily • Fang, Yuhong • Hall, Matthew • Jadhav, Ajit • Karavadhi, Surendra • Liu, Li • MARTINEZ, Natalia • McIver, Andrew Louis • Pragani, Rajan • Rohde, Jason Matthew • Simeonov, Anton • Zhao, Wei • Shen, Min

Assignees

University of North Carolina at Chapel Hill • US Department of Health and Human Services

Abstract

A compound of Formula II or a pharmaceutically acceptable salt thereof, wherein CyN is a cyclic amine group bound via a nitrogen atom; X is C or N; R1 and R2 are each independently a halogen, CN, CF3, CHF2, CH2F, a C1-C10alkyl group, a C1-C10alkoxy group, a di(C1-C5alkyl)amino; m and n are each independently 1, 2, or 3, and represents either a single bond or a double bond, wherein the racemic mixture of 3-(4-(4-chlorophenyl)thiazol-2-yl)-1-(2-ethyl-5-methoxyphenyl)-6-(2-methylprop-1-en-1-yl)-5-(piperazine-1-carbonyl)pyridin-2(1H)-one atropisomers is excluded.

Core Innovation

The present disclosure provides compounds of Formula II or pharmaceutically acceptable salts thereof, which are characterized by a cyclic amine group bound via a nitrogen atom (CyN), and variable moieties such as X, R1, and R2 with defined substituents and bonding patterns. The compounds exclude the racemic mixture of a specific atropisomer detailed in the specification. These compounds are designed as inhibitors of mutant isocitrate dehydrogenase 1 (IDH1) enzymes that have gained the ability to catalyze the NADPH-dependent reduction of α-ketoglutarate to R-2-hydroxyglutarate (2HG). Pharmaceutical compositions containing these compounds are also disclosed along with methods of use.

The background identifies mutated IDH1, particularly IDH1(R132H), as a common enzyme mutation in a variety of cancers such as glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. These mutations cause a gain-of-function, producing elevated 2HG, an oncometabolite that promotes hypermethylation of histones and inhibits cellular differentiation leading to cancer development. Targeting mutant IDH1 for inhibition addresses the problem of elevated 2HG in cancer cells, potentially reducing tumor progression. Mutant IDH1 inhibitors are expected to selectively affect mutant cancer cells with limited toxicity to normal cells.

This invention provides mutant IDH1 inhibitors that reduce 2HG levels and thus are useful therapeutics for treating cancers characterized by IDH1 mutations with neomorphic enzymatic activity. The methods include administering therapeutically effective amounts of Formula II compounds or salts to patients with cancers characterized by such mutations. The disclosure includes specific mutations like IDH1 R132H and R132C, and applies to a broad range of cancers including glioma, AML, sarcomas, lymphomas, lung cancer, cholangiocarcinoma, and colon cancer, as well as disorders such as Ollier disease and Maffucci syndrome.

Claims Coverage

This patent includes sixteen inventive features primarily covering compound compositions, specific stereoisomers, pharmaceutical formulations, and therapeutic methods targeting mutant IDH1-associated cancers.

The claims cover the novel compounds defined by Formula II, including specific atropisomeric forms, their pharmaceutical compositions, and methods of treating cancers and related diseases characterized by mutant IDH1 enzyme activity. The inventive features include structural definitions of the compounds, their stereochemical forms, therapeutic uses against specific mutations and cancer types, and methods of combination therapy.

Stated Advantages

Documented Applications