Crystalline forms of a KRas G12C inhibitor

Inventors

Andres, Patricia • Andrew, Samuel • Chen, Cheng Yi • GANCEDO, SUSANA DEL RIO • Gharbaoui, Tawfik • Nelson, Jennifer

Assignees

Mirati Therapeutics Inc

Abstract

The present invention relates to crystalline forms of a KRas G12C inhibitor and salt thereof. In particular, the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, pharmaceutical compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.

Core Innovation

The disclosure relates to crystalline forms of 2-[(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (MRTX849). The crystalline forms are characterized by X-ray powder diffraction (XRPD) with stated 2θ peak information, including peak lists for individual forms.

The disclosure further characterizes the solid-state forms using DSC, TGA, and DVS, and addresses hydrate/solvate status as well as hydrate versus hydrate/solvent-free characteristics. It also describes amorphous properties as an absence of XRPD peaks and a low glass transition, supporting differentiation between crystalline forms and amorphous material.

The disclosure includes pharmaceutical compositions comprising the crystalline forms of MRTX849 with pharmaceutically acceptable excipient/diluent components for KRas G12C-associated cancer, including lung cancer, and describes therapeutically effective amounts. It also provides high-level process approaches to obtain crystalline Forms A–E from amorphous material or other forms and addresses hydrate/solvent-free and mixed crystalline forms (A–E).

Claims Coverage

The claim coverage is anchored in XRPD-defined crystalline solid forms of MRTX849: Crystalline Form D is characterized by a peak at 2θ = 4.4 ± 0.2, and Crystalline Form E is characterized by at least one 2θ peak selected from 5.2 ± 0.2 and 10.2 ± 0.2. Dependent claims further restrict the XRPD peak sets, add hydrate status and residual organic solvent limits, and include pharmaceutical compositions with pharmaceutically acceptable excipients and/or diluents.

The claim coverage is centered on XRPD-defined crystalline forms of MRTX849, namely Crystalline Form D and Crystalline Form E. Dependent claims further specify additional XRPD peak criteria, hydrate status, residual organic solvent limits, and pharmaceutical compositions with pharmaceutically acceptable excipients and/or diluents.

Stated Advantages

Documented Applications