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WO2025019688A2 - Formes cristallines de sels d'adagrasib - Google Patents

Formes cristallines de sels d'adagrasib Download PDF

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Publication number
WO2025019688A2
WO2025019688A2 PCT/US2024/038570 US2024038570W WO2025019688A2 WO 2025019688 A2 WO2025019688 A2 WO 2025019688A2 US 2024038570 W US2024038570 W US 2024038570W WO 2025019688 A2 WO2025019688 A2 WO 2025019688A2
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Prior art keywords
crystalline form
fumarate
tosylate
ray powder
powder diffraction
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WO2025019688A3 (fr
Inventor
Patricia Andres
Samuel ANDREW
Susana Del Rio GANCEDO
Mengxing LIN
Yujie Li
Liyu WANG
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Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid

Definitions

  • the present invention relates to crystalline forms of salts of the KRas G12C inhibitor 2- [(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5/7- pyrido[3,4- ⁇ 7]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile (aka “adagrasib”), pharmaceutical compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.
  • KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP -bound active
  • cellular proliferation e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401.
  • KRas The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Santos et al., (1984) Science 223:661-664). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 -30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428).
  • Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation (e.g., see Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158/1078-0432.CCR-11-3265).
  • KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).
  • a covalent, irreversible inhibitor of KRas G12C is 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2- [[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, also known as adagrasib and as MRTX849.
  • Process development for pharmaceutical compositions plays an important role for solid pharmaceutical compounds in balancing the desired pharmacological properties of the therapeutic agent. For example, identifying an appropriate crystalline forms and salt forms of the solid therapeutic agent can beneficially influence the dissolution rate, solubility, bioavailability, manufacturing, packaging and/or storage shelf life of the pharmaceutical composition.
  • crystalline forms may be pressed into tablets for oral delivery as opposed to the need to use a capsule or spray-dry form for amorphous compounds.
  • the crystalline form is fumarate crystalline Form 1.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern (“XRPD”) comprising at least one characteristic peak at °20 values selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • XRPD X-ray powder diffraction pattern
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising peaks at °20 values of 8.1 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising peaks at °20 values of 8.1 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.0 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.3 ⁇ 0.2, 18.6 ⁇ 0.2, 19.5 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.1 ⁇ 0.2, 25.9 ⁇ 0.2, 26.3 ⁇ 0.2, 26.7 ⁇ 0.2, 29.2 ⁇ 0.2, and 31.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 1.
  • fumarate crystalline Form 1 is characterized by having an endothermic peak onset at about 165°C as measured by differential scanning calorimetry (“DSC”). In another embodiment, fumarate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 2. [0016] In another embodiment, fumarate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 8.1 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 is characterized by having about 0.3% weight loss until the onset of degradation at about 170°C as estimated by thermogravimetric analysis (“TGA”). In another embodiment, fumarate crystalline Form 1 has a TGA profile substantially as shown in FIG. 2.
  • fumarate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8. l ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 is characterized by having an observed water intake of about 0.6% upon increasing relative humidity (RH) from 0% RH to 80 % RH, as measured by dynamic vapor sorption (“DVS”).
  • RH relative humidity
  • DVS dynamic vapor sorption
  • fumarate crystalline Form 1 has a DVS isotherm substantially as shown in FIG. 3.
  • fumarate crystalline Form 1 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 8.H0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.
  • fumarate crystalline Form 1 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated fumarate crystalline Form 2.
  • fumarate crystalline Form 2 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • fumarate crystalline Form 2 has an XRPD pattern comprising peaks at °20 values of 4.1 ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 has an XRPD pattern comprising peaks at °26 values of 4.1 ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 12.5 ⁇ 0.2, 14.2 ⁇ 0.2, 15.3 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 22.4 ⁇ 0.2, 24.7 ⁇ 0.2, and 26.4 ⁇ 0.2 .
  • fumarate crystalline Form 2 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 6.
  • fumarate crystalline Form 2 is characterized by having an endothermic peak onset at about 187°C as measured by DSC. In another embodiment, fumarate crystalline Form 2 has a DSC thermogram substantially as shown in FIG. 7.
  • fumarate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 is characterized by negligible weight loss until the onset of degradation at about 190°C as measured by TGA. In another embodiment, fumarate crystalline Form 2 has a TGA profde substantially as shown in FIG. 7.
  • fumarate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 is characterized by having an observed water intake of about 0.9% upon increasing RH from 0% RH to 80 % RH, as measured by DVS.
  • fumarate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 8.
  • fumarate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 is substantially free of residual organic solvents.
  • Tn one embodiment, the crystalline form is designated tosylate crystalline Form 1 .
  • tosylate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • tosylate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, I7.4 ⁇ 0.2, 18.0 ⁇ 0.2 and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2, 23.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • tosylate crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 11.
  • tosylate crystalline Form 1 is characterized by having an endothermic peak onset at about 131°C as measured by DSC. In another embodiment, tosylate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 12.
  • tosylate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • Tn one embodiment, tosylate crystalline Form 1 is characterized by about 0.3% weight loss until about 150°C as measured by TGA.
  • tosylate crystalline Form 1 has a TGA profile substantially as shown in FIG. 12.
  • tosylate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 7.6 ⁇ 0.2, 10.H0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • tosylate crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated tosylate crystalline Form 2.
  • tosylate crystalline Form 2 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • tosylate crystalline Form 2 has an XRPD pattern comprising peaks at °29 values of 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 21.9 ⁇ 0.2.
  • tosylate crystalline Form 2 has an X-ray powder diffraction pattern comprising two or more peaks at °29 at 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 14. [0058] Tn one embodiment, tosylate crystalline Form 2 is characterized by having an endothermic peak onset at about 148 °C, as measured by DSC. In another embodiment, tosylate crystalline Form 2 has a DSC thermogram substantially as shown in FIG. 15.
  • tosylate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 1 1.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.8 ⁇ 0.2, and 22.0 ⁇ 0.2.
  • tosylate crystalline Form 2 is characterized by about 0.3% weight loss until about 100°C as measured by TGA. In another embodiment, tosylate crystalline Form 2 has a TGA profile substantially as shown in FIG. 15.
  • tosylate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 21.9 ⁇ 0.2.
  • tosylate crystalline Form 2 is characterized by having an observed water intake of about 1.3% upon increasing RH from 0% RH to 80 % RH, as measured by DVS.
  • tosylate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 17.
  • tosylate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 21.9 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2 .
  • tosylate crystalline Form 2 is substantially free of residual organic solvents.
  • the crystalline form is designated naphthalene 1,5 -di sulfonate (NPD) crystalline Form 1.
  • NPD crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °29 values selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • NPD crystalline Form 1 has an XRPD pattern comprising peaks at °29 values of 8.8 ⁇ 0.2, 12.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has an XRPD pattern comprising two or more peaks at °29 at 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 24.
  • NPD crystalline Form 1 is characterized by having an exothermic peak onset at about 177°C, as measured by DSC. In another embodiment, NPD crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 25.
  • NPD crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 8.8 ⁇ 0.2, 12.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 is characterized by about 0.6% weight loss until about 150°C as measured by TGA. In another embodiment, NPD crystalline Form 1 has a TGA profde substantially as shown in FIG. 25.
  • NPD crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.8 ⁇ 0.2, 12.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated orotate crystalline Form 1.
  • the crystalline form is designated glycolate crystalline Form 1.
  • the crystalline form is designated phosphate crystalline Form
  • the crystalline form is designated besylate crystalline Form 1.
  • the crystalline form is designated tartrate crystalline Form 1.
  • the crystalline form is designated tartrate crystalline Form 2.
  • the crystalline form is designated tartrate crystalline Form 3.
  • the crystalline form is designated ketoglutarate crystalline
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2 and 19.9 ⁇ 0.2, 21.3 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising peaks at °29 values of 4.3 ⁇ 0.2, 9.2 ⁇ 0.2, 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2, 17.0 ⁇ 0.2, 17.2 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 21.3 ⁇ 0.2, 22.4 ⁇ 0.2.
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising two or more peaks at °29 at 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2 and 19.9 ⁇ 0.2, 21.3 ⁇ 0.2.
  • ketoglutarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 18. In one embodiment, ketoglutarate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 19.
  • ketoglutarate crystalline Form 1 has a TGA profile substantially as shown in FIG. 19.
  • the crystalline form is designated oxalate crystalline Form 1.
  • oxalate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 12.9 ⁇ 0.2, 17.8 ⁇ 0.2, 19.6 ⁇ 0.2, and 22.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • oxalate crystalline Form 1 has an XRPD pattern comprising peaks at °29 values of 9.0 ⁇ 0.2, 19.8 ⁇ 0.2, 12.9 ⁇ 9.2, 13.8 ⁇ 0.2, 15.0 ⁇ 0.2, 16.3 ⁇ 0.2, 16.6 ⁇ 0.2, 17.8 ⁇ 9.2, 18.0 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, 20.9 ⁇ 9.2, 22.4 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • oxalate crystalline Form 1 has an XRPD pattern comprising two or more peaks at °29 at 12.9 ⁇ 0.2, 17.8 ⁇ 0.2, 19.6 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • oxalate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 21.
  • oxalate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 23.
  • oxalate crystalline Form 1 has a TGA profile substantially as shown in FIG. 23.
  • the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.
  • compositions for use in the methods comprising a therapeutically effective amount of at least one of the following salts: fumarate crystalline Form 1, fumarate crystalline Form 2, tosylate crystalline Form 1, tosylate crystalline Form 2, ketoglutarate crystalline Form 1, oxalate crystalline Form 1, naphthalene 1,5 -di sulfonic acid (NPD) crystalline Form 1, orotate crystalline Form 1, glycolate crystalline Form 1, phosphate crystalline Form 1, besylate crystalline Form 1, tartrate crystalline Form 1, tartrate crystalline Form 2, and tartrate crystalline Form 3 of the KRas G12C inhibitor 2- [(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-l-(
  • the crystalline form is fumarate crystalline Form 1. In another embodiment, the crystalline form is fumarate crystalline Form 2. In one embodiment, the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1. In one embodiment, the crystalline form is NPD crystalline Form 1. In another embodiment, the crystalline form is orotate crystalline Form 2. In one embodiment, the crystalline form is glycolate crystalline Form 1. In another embodiment, the crystalline form is phosphate crystalline Form 2. In one embodiment, the crystalline form is besylate crystalline Form 1.
  • the crystalline form is tartrate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 2. In one embodiment, the crystalline form is tartrate crystalline Form 3. In one embodiment, the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • the pharmaceutical compositions of the present invention contain 95% of fumarate crystalline Form 1 of2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of fumarate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of fumarate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of fumarate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of fumarate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of fumarate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of fumarate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of fumarate crystalline Form 2 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl] acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of fumarate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain at least 90% of fumarate crystalline Form 2. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of fumarate crystalline Form 2. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of fumarate crystalline Form 2. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of fumarate crystalline Form 2. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of fumarate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain 95% of tosylate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl] acetonitrile or salts thereof
  • the pharmaceutical compositions of the present invention contain at least 95% of tosylate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of tosylate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of tosylate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of tosylate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of tosylate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of tosylate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of tosylate crystalline Form 2 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)- l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of tosylate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain at least 90% of tosylate crystalline Form 2. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of tosylate crystalline Form 2. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of tosylate crystalline Form 2. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of tosylate crystalline Form 2. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of tosylate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain 95% of ketoglutarate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof
  • the pharmaceutical compositions of the present invention contain at least 95% of ketoglutarate crystalline Form 1 .
  • the pharmaceutical compositions of the present invention contain at least 90% of ketoglutarate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of ketoglutarate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of ketoglutarate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of ketoglutarate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of ketoglutarate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of oxalate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of oxalate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of oxalate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of oxalate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of oxalate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of oxalate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of oxalate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% ofNPD crystalline Form 1 of2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% ofNPD crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of NPD crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 80% ofNPD crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% ofNPD crystalline Form 1 . In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of NPD crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of NPD crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of orotate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l -(2 -fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of orotate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of orotate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of orotate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of orotate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of orotate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of orotate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of glycolate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of glycolate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of glycolate crystalline Form 1 . In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of glycolate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of glycolate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of glycolate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of glycolate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of phosphate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of phosphate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of phosphate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of phosphate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of phosphate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of phosphate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of phosphate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% ofbesylate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% ofbesylate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of besylate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% ofbesylate crystalline Form 1. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% ofbesylate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of besylate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% ofbesylate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of tartrate crystalline Form 1 of 2-[(2S)-4-[7-(8-chl oro-1 -naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l -(2 -fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of tartrate crystalline Form 1 . Tn other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of tartrate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of tartrate crystalline Form 1. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of tartrate crystalline Form 1.
  • the pharmaceutical compositions of the present invention contain 95% of tartrate crystalline Form 2 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain at least 80% of tartrate crystalline Form 2. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of tartrate crystalline Form 2. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of tartrate crystalline Form 2. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of tartrate crystalline Form 2.
  • the pharmaceutical compositions of the present invention contain 95% of tartrate crystalline Form 3 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile or salts thereof.
  • the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 3.
  • the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 3.
  • the pharmaceutical compositions of the present invention contain at least 80% of tartrate crystalline Form 3. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of tartrate crystalline Form 3. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of tartrate crystalline Form 3. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of tartrate crystalline Form 3. [00116] Tn one aspect of the invention, provided herein are methods for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with a therapeutically effective amount of a crystalline form of the present invention, alone or in combination with one or more pharmaceutically acceptable excipients and/or diluents.
  • the crystalline form is fumarate crystalline Form 1. In another embodiment, the crystalline form is fumarate crystalline Form 2. In one embodiment, the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1. In one embodiment, the crystalline form is NPD crystalline Form 1. In another embodiment, the crystalline form is orotate crystalline Form 1. In one embodiment, the crystalline form is glycolate crystalline Form 1. In another embodiment, the crystalline form is phosphate crystalline Form 1. In one embodiment, the crystalline form is besylate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 2. In one embodiment, the crystalline form is tartrate crystalline Form 3.
  • the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a salt crystalline form of KRAS G12C inhibitor of the present invention.
  • the cancer is a KRas G12C-associated cancer.
  • the KRas G12C-associated cancer is lung cancer.
  • the crystalline form is fumarate crystalline Form 1. In another embodiment, the crystalline form is fumarate crystalline Form 2. In one embodiment, the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1. In one embodiment, the crystalline form is NPD crystalline Form 1 . In another embodiment, the crystalline form is orotate crystalline Form 1. In one embodiment, the crystalline form is glycolate crystalline Form 1. In another embodiment, the crystalline form is phosphate crystalline Form 1. In one embodiment, the crystalline form is besylate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 2. In one embodiment, the crystalline form is tartrate crystalline Form 3.
  • the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • a KRas G12C mutation e.g., a KRas G12C-associated cancer
  • a regulatory agency-approved e.g., FDA-approved, assay or kit
  • the crystalline form is fumarate crystalline Form 1. In another embodiment, the crystalline form is fumarate crystalline Form 2. In one embodiment, the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1. In one embodiment, the crystalline form is NPD crystalline Form 1. In another embodiment, the crystalline form is orotate crystalline Form 1. In one embodiment, the crystalline form is glycolate crystalline Form 1. In another embodiment, the crystalline form is phosphate crystalline Form 1. In one embodiment, the crystalline form is besylate crystalline Form 1.
  • the crystalline form is tartrate crystalline Form 1 . In one embodiment, the crystalline form is tartrate crystalline Form 2. In one embodiment, the crystalline form is tartrate crystalline Form 3. [00123] In one embodiment, the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • the subject is an adult patient. In one embodiment, the subject is a pediatric patient.
  • the patient before treatment with the compositions or methods of the invention, was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinumbased chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
  • the process describes the preparation of fumarate crystalline Form 1. In one embodiment, the process describes the preparation of fumarate crystalline Form 2. In one embodiment, the process describes the preparation of tosylate crystalline Form 1. In one embodiment, the process describes the preparation of tosylate crystalline Form 2. In one embodiment, the process describes the preparation of ketoglutarate crystalline Form 1. In one embodiment, the process describes the preparation of oxalate crystalline Form 1. In one embodiment, the process describes the preparation of NPD crystalline Form 1. In one embodiment, the process describes the preparation of glycolate crystalline Form 2.
  • the process describes the preparation of phosphate crystalline Form 1 . In one embodiment, the process describes the preparation of besylate crystalline Form 1. In one embodiment, the process describes the preparation of tartrate crystalline Form 1. In one embodiment, the process describes the preparation of tartrate crystalline Form 2. In one embodiment, the process describes the preparation of tartrate crystalline Form 3.
  • FIG. 1 illustrates X-ray powder diffraction (XRPD) pattern of fumarate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, prepared according to Example 1.
  • XRPD X-ray powder diffraction
  • FIG. 2 illustrates a combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) profile of fumarate crystalline Form 1 prepared according to Example 1.
  • FIG. 3 illustrates a dynamic vapor sorption (DVS) isotherm profile of fumarate crystalline Form 1 prepared according to Example 1.
  • FIG. 4 illustrates a 'H-NMR profile of fumarate crystalline Form 1 prepared according to Example 1 .
  • FIG. 5 illustrates an XRPD pattern of fumarate crystalline Form 1 prepared according to Example 1 before and after DVS evaluation.
  • FIG. 6 illustrates an XRPD pattern of fumarate crystalline Form 2 prepared according to Example 1 before and after DVS evaluation.
  • FIG. 7 illustrates a combined DSC and TGA profile of fumarate crystalline Form 2 prepared according to Example 2.
  • FIG. 8 illustrates a DVS isotherm profile of fumarate crystalline Form 2 prepared according to Example 2.
  • FIG. 9 illustrates a 'H-NMR profile of fumarate crystalline Form 2 prepared according to Example 2.
  • FIG. 10 illustrates an XRPD pattern of fumarate crystalline Form 2 prepared according to Example 2 before and after DVS evaluation.
  • FIG. 11 illustrates an XRPD pattern of tosylate crystalline Form 1 prepared according to Example 3.
  • FIG. 12 illustrates a combined DSC and TGA profile of tosylate crystalline Form 1 prepared according to Example 3.
  • FIG. 13 illustrates a 'H-NMR profile of tosylate crystalline Form 1 prepared according to Example 3.
  • FIG. 14 illustrates an XRPD pattern of tosylate crystalline Form 2 prepared according to Example 4.
  • FIG. 15 illustrates a combined DSC and TGA profile of tosylate crystalline Form 2 prepared according to Example 4.
  • FIG. 16 illustrates a 'H-NMR profile of tosylate crystalline Form 2 prepared according to Example 4.
  • FIG. 17 illustrates a DVS profile of tosylate crystalline Form 2 prepared according to Example 4.
  • FIG. 18 illustrates an XRPD pattern of ketoglutarate crystalline Form 1 prepared according to Example 5.
  • FIG. 19 illustrates a DSC profile and TGA profile of ketoglutarate crystalline Form 1 prepared according to Example 5.
  • FIG. 20 illustrates a 'H-NMR profile of ketoglutarate crystalline Form 1 prepared according to Example 5.
  • FIG. 21 illustrates an XRPD pattern of oxalate crystalline Form 1 prepared according to Example 6.
  • FIG. 22 illustrates a J H-NMR profile of oxalate crystalline Form 1 prepared according to Example 6.
  • FIG. 23 illustrates a DSC profile and TGA profile of oxalate crystalline Form 1 prepared according to Example 6.
  • FIG. 24 illustrates an XRPD pattern of naphthalene 1,5-disulfonate (NPD) crystalline Form 1 prepared according to Example 7.
  • FIG. 25 illustrates a DSC profile and TGA profile of NPD crystalline Form 1 prepared according to Example 7
  • FIG. 26 illustrates a 'H-NMR profile of NPD crystalline Form 1 prepared according to Example 7.
  • FIG. 27 illustrates an XRPD pattern of orotate crystalline Form 1 prepared according to Example 8.
  • FIG. 28 illustrates an XRPD pattern of glycolate crystalline Form 1 prepared according to Example 9.
  • FIG. 29 illustrates an XRPD pattern of phosphate crystalline Form 1 prepared according to Example 10.
  • FIG. 30 illustrates an XRPD pattern of besylate crystalline Form 1 prepared according to Example 11.
  • FIG. 31 illustrates an XRPD pattern of tartrate crystalline Form 1 prepared according to Example 12.
  • FIG. 32 illustrates an XRPD pattern of tartrate crystalline Form 2 prepared according to Example 13.
  • FIG. 33 illustrates XRPD patterns of tartrate crystalline Form 3 prepared according to Example 14.
  • FIG. 34 illustrates an XRPD pattern of tartrate crystalline Form 3 prepared according to Example 14.
  • the present invention relates to crystalline forms of pharmaceutically acceptable salts of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl] acetonitrile.
  • the present invention relates to fumarate crystalline Form 1, fumarate crystalline Form 2, tosylate crystalline Form 1, tosylate crystalline Form 2, ketoglutarate crystalline Form 1, oxalate crystalline Form 1, naphthalene 1,5-disulfonic acid (NPD) crystalline Form 1, orotate crystalline Form 1, glycolate crystalline Form 1, phosphate crystalline Form 1, besylate crystalline Form 1, tartrate crystalline Form 1, tartrate crystalline Form 2, and tartrate crystalline Form 3 of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-l- naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, pharmaceutical compositions comprising the crystalline forms
  • KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
  • the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.
  • KRas G12C inhibitor refers to the KRas G12C inhibitor of the present invention: 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl] acetonitrile and a novel salt thereof as described herein.
  • This compound is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
  • the KRas G12C inhibitor of the present invention interacts with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C.
  • solvate refers to a crystalline form of the KRas G12C inhibitor which contains solvent.
  • hydrate refers to a solvate wherein the solvent comprises water.
  • residual organic solvents refers to organic volatile chemicals used or produced during the crystallization/manufacturing processes that are not completely removed during the manufacturing technique.
  • the term “substantially free of residual organic solvents” means that the manufactured pharmaceutical preparation, e.g., a pharmaceutical preparation comprising a crystalline form of a slat of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile, contains less than 1.0% by weight of residual organic solvents, contains less than 0.5% by weight of residual organic solvents, contains less than 0.4% by weight of residual organic solvents, contains less than 0.3% by weight of residual organic solvents, contains less than 0.2% by weight of residual organic solvents, or contains less than 0.1% by weight of residual organic solvents.
  • the manufactured pharmaceutical preparation e.g., a pharmaceutical preparation
  • KRas G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
  • a non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
  • the term “subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
  • the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency- approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency- approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a KRas G12C gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
  • an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR). As is well-known in the art, the assays are typically performed, e.
  • a sample e.g., a biological sample or a
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • regulatory agency is the U.S. Food and Drug Administration (FDA).
  • a "therapeutically effective amount" of a crystalline form of a salt of 2- [(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
  • the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter. For example, about 0.5 mg, 0.75 mg or 1.0 mg means about 0.5 mg, about 0.75 mg or about 1.0 mg. Likewise, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.
  • the term “about” when used in reference to XRPD peak positions refers to the inherent variability of peaks depending on the calibration of the instrument, processes used to prepare the crystalline forms of the present invention, age of the crystalline forms and the type of instrument used in the analysis.
  • the variability of the instrumentation used for XRPD analysis was about ⁇ 0.2 °20.
  • Crystalline forms may be analyzed using any suitable analytical method or assay procedure including, but not limited to, X-Ray Powder Diffraction, NMR, differential scanning calorimetry, thermo-gravimetric analysis, and gravimetric vapor sorption to assure formation of the preferred crystalline form of the KRas G12C inhibitor.
  • the crystalline form is typically produced in an amount of greater that 50% by weight isolated yield, greater that 60% by weight isolated yield, greater that 70% by weight isolated yield, greater that 80% by weight isolated yield, greater that 90% by weight isolated yield or greater that 95% by weight isolated yield.
  • the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.
  • X-Ray Powder Diffraction analysis was conducted with an X-ray diffractometer (Bruker D8 advance). The system was equipped with LynxEye detector. Samples were scanned from 3 to 4O°20, at a step size 0.02°29. The tube voltage and current were 40 KV and 40 mA, respectively.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric analysis
  • Vapor Sorption isotherms were obtained using a Surface Measurement System (SMS) DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software.
  • SMS Surface Measurement System
  • Solution proton NMR spectra were acquired using a Bruker Advance 300 MHz NMR spectrometer according to the manufacturer’s instructions. Samples were prepared by dissolving about 5-10 mg of sample in DMSO-d6 or CD3OD containing TMS.
  • the crystalline form is fumarate crystalline Form 1.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern (“XRPD”) comprising at least one characteristic peak at °29 values selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • XRPD X-ray powder diffraction pattern
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising peaks at °29 values of 8.1 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising peaks at °29 values of 8.1 ⁇ 0.2, 10.4 ⁇ 0.2, 12.0 ⁇ 0.2, 13.0 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.3 ⁇ 0.2, 18.6 ⁇ 0.2, 19.5 ⁇ 0.2, 20.2 ⁇ 0.2, 21 ,0 ⁇ 0.2, 22.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 24.1 ⁇ 0.2, 25.9 ⁇ 0.2, 26.7 ⁇ 0.2, 29.2 ⁇ 0.2, and 31.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 1.
  • fumarate crystalline Form 1 is characterized by having an endothermic peak onset at about 165°C as measured by differential scanning calorimetry (“DSC”). In another embodiment, fumarate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 2.
  • fumarate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 is characterized by having about 0.3% weight loss until the onset of degradation at about 170°C as estimated by thermogravimetric analysis (“TGA”). In another embodiment, fumarate crystalline Form 1 has a TGA profile substantially as shown in FIG. 2.
  • fumarate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 has both: I) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8. l ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.2.
  • fumarate crystalline Form 1 is characterized by having an observed water intake of about 0.6% upon increasing relative humidity (RH) from 0% RH to 80 % RH, as measured by dynamic vapor sorption (“DVS”).
  • fumarate crystalline Form 1 has a DVS isotherm substantially as shown in FIG. 3.
  • fumarate crystalline Form 1 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 14.3 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.3 ⁇ 0.2, 18.6 ⁇ 0.2, 21.0 ⁇ 0.2, 22.8 ⁇ 0.2, 23.5 ⁇ 0.2, 26.7 ⁇ 0.2, and 29.2 ⁇ 0.
  • fumarate crystalline Form 1 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.1 ⁇ 0.2, 17.3 ⁇ 0.2, 21.0 ⁇ 0.2 and 22.8 ⁇ 0.2.
  • fumarate crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated fumarate crystalline Form 2.
  • fumarate crystalline Form 2 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • fumarate crystalline Form 2 has an XRPD pattern comprising peaks at °20 values of 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 has an XRPD pattern comprising peaks at °20 values of 4.1 ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 12.5 ⁇ 0.2, 14.2 ⁇ 0.2, 15.3 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 22.4 ⁇ 0.2, 24.7 ⁇ 0.2, and 26.4 ⁇ 0.2 .
  • fumarate crystalline Form 2 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 6.
  • fumarate crystalline Form 2 is characterized by having an endothermic peak onset at about 187°C as measured by DSC. In another embodiment, fumarate crystalline Form 2 has a DSC thermogram substantially as shown in FIG. 7.
  • fumarate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4.1 ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 is characterized by negligible weight loss until the onset of degradation at about 190°C as measured by TGA. In another embodiment, fumarate crystalline Form 2 has a TGA profile substantially as shown in FIG. 7.
  • fumarate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11 ,3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 is characterized by having an observed water intake of about 0.9% upon increasing RH from 0% RH to 80 % RH, as measured by DVS.
  • fumarate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 8.
  • fumarate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4. l ⁇ 0.2, 8.3 ⁇ 0.2, 8.8 ⁇ 0.2, 11.3 ⁇ 0.2, 14.2 ⁇ 0.2, 17.7 ⁇ 0.2, 22.4 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • fumarate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2Q selected from 4.1 ⁇ 0.2, 8.8 ⁇ 0.2, 17.7 ⁇ 0.2 and 22.4 ⁇ 0.2.
  • fumarate crystalline Form 2 is substantially free of residual organic solvents.
  • the crystalline form is designated tosylate crystalline Form 1.
  • tosylate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °29 values selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • tosylate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2 and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2, 23.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • tosylate crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 11.
  • tosylate crystalline Form 1 is characterized by having an endothermic peak onset at about 131°C as measured by DSC.
  • tosylate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 12.
  • tosylate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • tosylate crystalline Form 1 is characterized by about 0.3% weight loss until about 150°C as measured by TGA. In another embodiment, tosylate crystalline Form 1 has a TGA profile substantially as shown in FIG. 12.
  • tosylate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2Q selected from 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 18.0 ⁇ 0.2, and 20.3 ⁇ 0.2.
  • tosylate crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 7.6 ⁇ 0.2, 10.1 ⁇ 0.2, 13.0 ⁇ 0.2, 13.8 ⁇ 0.2, 15.4 ⁇ 0.2, 17.4 ⁇ 0.2, 18.0 ⁇ 0.2, 20.3 ⁇ 0.2, 22.9 ⁇ 0.2 and 24.8 ⁇ 0.2.
  • tosylate crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated tosylate crystalline Form 2.
  • tosylate crystalline Form 2 has an XRPD pattern comprising at least one characteristic peak at °29 values selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • tosylate crystalline Form 2 has an XRPD pattern comprising peaks at °20 values of 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.0 ⁇ 0.2, 16.8 ⁇ 0.2, 17.5 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 22.0 ⁇ 0.2.
  • tosylate crystalline Form 2 has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 14.
  • tosylate crystalline Form 2 is characterized by having an endothermic peak onset at about 148°C, as measured by DSC.
  • tosylate crystalline Form 2 has a DSC thermogram substantially as shown in FIG. 15.
  • tosylate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.0 ⁇ 0.2, 16.8 ⁇ 0.2, 17.5 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 22.0 ⁇ 0.2.
  • tosylate crystalline Form 2 is characterized by about 0.3% weight loss until about 100°C as measured by TGA. In another embodiment, tosylate crystalline Form 2 has a TGA profile substantially as shown in FIG. 15.
  • tosylate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.0 ⁇ 0.2, 16.8 ⁇ 0.2, 17.5 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 22.0 ⁇ 0.2.
  • Tn one embodiment, tosylate crystalline Form 2 is characterized by having an observed water intake of about 1.3% upon increasing RH from 0% RH to 80 % RH, as measured by DVS.
  • tosylate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 17.
  • tosylate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 5.6 ⁇ 0.2, 7.9 ⁇ 0.2, 11.2 ⁇ 0.2, 12.4 ⁇ 0.2, 13.4 ⁇ 0.2, 16.0 ⁇ 0.2, 16.8 ⁇ 0.2, 17.5 ⁇ 0.2, 17.8 ⁇ 0.2, 18.5 ⁇ 0.2, 21.4 ⁇ 0.2, and 22.0 ⁇ 0.2.
  • tosylate crystalline Form 2 has both: 1) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 11.2 ⁇ 0.2, 13.4 ⁇ 0.2, 16.8 ⁇ 0.2, and 17.8 ⁇ 0.2 .
  • tosylate crystalline Form 2 is substantially free of residual organic solvents.
  • the crystalline form is designated naphthalene 1,5 -di sulfonate (NPD) crystalline Form 1.
  • NPD crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °29 values selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • NPD crystalline Form 1 has an XRPD pattern comprising peaks at °29 values of 8.8 ⁇ 9.2, 12.8 ⁇ 0.2, 13.7 ⁇ 9.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.9 ⁇ 0.2, 19.7 ⁇ 9.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has an XRPD pattern comprising two or more peaks at °20 at 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 24. [00256] Tn one embodiment, NPD crystalline Form 1 is characterized by having an exothermic peak onset at about 177°C, as measured by DSC. In another embodiment, NPD crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 25.
  • NPD crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °26 selected from 8.8 ⁇ 0.2, 12.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 is characterized by about 0.6% weight loss until about 150°C as measured by TGA. In another embodiment, NPD crystalline Form 1 has a TGA profile substantially as shown in FIG. 25.
  • NPD crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 8.8 ⁇ 0.2, 12.8 ⁇ 0.2, 13.7 ⁇ 0.2, 15.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.5 ⁇ 0.2, 19.0 ⁇ 0.2, 19.7 ⁇ 0.2, 20.7 ⁇ 0.2, 22.3 ⁇ 0.2 and 22.7 ⁇ 0.2.
  • NPD crystalline Form 1 is substantially free of residual organic solvents.
  • the crystalline form is designated orotate crystalline Form 1.
  • the crystalline form is designated glycolate crystalline Form 1.
  • the crystalline form is designated phosphate crystalline Form 1.
  • the crystalline form is designated besylate crystalline Form 1.
  • the crystalline form is designated tartrate crystalline Form 1 .
  • the crystalline form is designated tartrate crystalline Form 2.
  • the crystalline form is designated tartrate crystalline Form 3.
  • the crystalline form is designated ketoglutarate crystalline
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °29 values selected from 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2, 19.9 ⁇ 0.2, and 21.3 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of4.3 ⁇ 0.2, 9.2 ⁇ 0.2, 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2, 17.0 ⁇ 0.2, 17.2 ⁇ 0.2, 18.6 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9, 21.3 ⁇ 0.2, and 23.0 ⁇ 0.2.
  • ketoglutarate crystalline Form 1 has an XRPD pattern comprising two or more peaks at °20 at 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.9 ⁇ 0.2, 19.9 ⁇ 0.2, and 21.3 ⁇ 0.2.
  • ketoglutarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 18. In one embodiment, ketoglutarate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 19.
  • ketoglutarate crystalline Form 1 has a TGA profde substantially as shown in FIG. 19.
  • the crystalline form is designated oxalate crystalline Form 1.
  • oxalate crystalline Form 1 has an XRPD pattern comprising at least one characteristic peak at °20 values selected from 12.9 ⁇ 0.2, 17.8 ⁇ 0.2, 19.6 ⁇ 0.2, and 22.8 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.
  • oxalate crystalline Form 1 has an XRPD pattern comprising peaks at °20 values of 9.0 ⁇ 0.2, 10.8 ⁇ 0.2, 12.9 ⁇ 0.2, 13.8 ⁇ 0.2, 15.0 ⁇ 0.2, 16.3 ⁇ 0.2, 16.6 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, 20.9 ⁇ 0.2, 22.4 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • oxalate crystalline Form 1 has an XRPD pattern comprising two or more peaks at °20 at 12.9 ⁇ 0.2, 17.8 ⁇ 0.2, 19.6 ⁇ 0.2, and 22.8 ⁇ 0.2.
  • oxalate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 21.
  • oxalate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 23.
  • oxalate crystalline Form 1 has a TGA profile substantially as shown in FIG. 23.
  • the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.
  • fumarate crystalline Form 1 is obtained by the process comprising the steps: dissolving free base in an organic solvent; adding fumaric acid; cooling the resulting mixture to room temperature; filtering and drying under vacuum or under ambient environment.
  • the organic solvent comprises one or more of methanol, heptane, acetone, acetonitrile (ACN) and isopropyl alcohol (IP A).
  • fumarate crystalline Form 2 is obtained by the process comprising cooling and crystallization in IPA.
  • the process may comprise the steps: dissolving free base in IPA; adding fumaric acid at 50 °C, stirring for 16 hours, cooling the resulting mixture to room temperature; filtering and drying under vacuum or under ambient environment.
  • tosylate crystalline Form 1 is obtained by dissolving free base in IPA at about at 50 °C; adding p-toluenesulfonic acid; cooling the resulting mixture to room temperature; filtering and drying under vacuum or under ambient environment.
  • tosylate crystalline Form 2 is obtained by dissolving free base Form 2 in acetone; adding p-toluenesulfonic acid; cooling the resulting mixture to room temperature; filtering and drying under vacuum or under ambient environment.
  • NPD crystalline Form 1 is obtained by dissolving free base Form 1 in IPA; adding Naphthalene 1,5-disulfonic acid; cooling the resulting mixture to room temperature; filtering and drying under vacuum or under ambient environment
  • ketoglutarate crystalline Form 1 is obtained by dissolving free base Form 2 in MEK (methyl ethyl ketone); adding a-ketoglutaric acid; cooling the resulting mixture to room temperature; filtering and drying under vacuum.
  • MEK methyl ethyl ketone
  • oxalate crystalline Form 1 is obtained by dissolving free base Form 2 in THF; adding oxalic acid; cooling the resulting mixture to room temperature; filtering and drying.
  • the organic solvent is heptane.
  • the organic solvent is isopropanol.
  • the obtained solids are analyzed by X-ray powder diffraction to confirm a specific Form.
  • the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.
  • the crystalline forms may be formulated into pharmaceutical compositions.
  • the invention provides pharmaceutical compositions comprising crystalline forms of the salts of the KRas G12C inhibitor according to the invention and a pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein.
  • the crystalline forms of the salts of the KRas G12C inhibitor may be formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • the crystalline forms of the salts of the KRas G12C inhibitor are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
  • the crystalline form is fumarate crystalline Form 1. In another embodiment, the crystalline form is fumarate crystalline Form 2. In one embodiment, the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In another embodiment, the crystalline form is NPD crystalline Form 1. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1.
  • the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to about 300 mg/kg, from about 0.1 to about 100 mg/kg per day, from about 0.5 to about 50 mg/kg per day, or from about 1 to about 25 mg/kg per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the pharmaceutical compositions of the present invention contain at least 95% of a crystalline form. In other embodiments, the pharmaceutical compositions of the present invention contain at least 90% of a crystalline form. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of a crystalline form. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of a crystalline form. In one embodiment, the pharmaceutical compositions of the present invention contain at least 60% of a crystalline form. In another embodiment, the pharmaceutical compositions of the present invention contain at least 50% of a crystalline form.
  • compositions comprising the crystalline forms of the KRas G12C inhibitor or salt thereof may be used in the methods of use described herein.
  • compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, colorectal, pancreas, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • a method for treating cancer in a subject in need thereof comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a crystalline form of a salt of the KRas G12C inhibitor, alone or in combination with or pharmaceutically acceptable excipients and/or diluents.
  • a KRas G12C mutation e.g., a KRas G12C-associated cancer
  • the crystalline form is fumarate crystalline Form 1.
  • the crystalline form is fumarate crystalline Form 2.
  • the crystalline form is tosylate crystalline Form 1. In another embodiment, the crystalline form is tosylate crystalline Form 2. In one embodiment, the crystalline form is ketoglutarate crystalline Form 1. In one embodiment, the crystalline form is oxalate crystalline Form 1. In one embodiment, the crystalline form is NPD crystalline Form 1. In another embodiment, the crystalline form is orotate crystalline Form 1. In one embodiment, the crystalline form is glycolate crystalline Form 1. In another embodiment, the crystalline form is phosphate crystalline Form 1. In one embodiment, the crystalline form is besylate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 1. In one embodiment, the crystalline form is tartrate crystalline Form 2. In one embodiment, the crystalline form is tartrate crystalline Form 3.
  • the crystalline form is a mixture of fumarate crystalline Form 1 and fumarate crystalline Form 2. In another embodiment, the crystalline form is a mixture of tosylate crystalline Form 1 with tosylate crystalline Form 2. In another embodiment, the crystalline form is a mixture of any of the described crystalline forms with the amorphous form.
  • a crystalline form of the KRas G12C inhibitor is administered as a capsule during the period of time.
  • a tablet or capsule comprises about 10 mg to about 1500 mg, for instance about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 0 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg and about 1500 mg.
  • the method comprises oral administration of a crystalline form once or twice a day on a daily basis (during a period of time), e.g., in an amount of about about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg and about 1500 mg.
  • Oral administration of a crystalline form of the KRas G12C inhibitor occurs , for example, once a day on a daily basis (during a period of time).
  • the KRAS inhibitor is orally administered once daily.
  • the crystalline form of the KRAS G12C inhibitor is orally administered twice daily.
  • the methods provided herein can result in a 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 95%, 2% to
  • time of survival means the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing the time of survival in a mammal having a cancer are described herein.
  • any of the methods described herein can result in an increase (e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5%
  • This Example illustrates the preparation of fumarate crystalline Form 1 of 2-[(2S)-4- [7-(8-chloro-l-naphthyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4- d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.
  • Fumarate Form 1 was obtained from MeOH/heptane, acetone, ACN and IPA. Certain amount of free base Form 2 was dissolved in the selected solvent. Then, 1.1 eq. neat fumaric acid was added. After precipitation, the solids were filtered and dried under ambient environment overnight. The detailed information and results are provided in Table 1. The characterization results of fumarate Form 1 are summarized in Table 2.
  • A07942-003A8 was characterized by XRPD, DSC, TGA, PLM and 'H-NMR.
  • Fumarate Form 1 is composed of irregular crystals with modest crystallinity.
  • Figure 1 shows the XRPD pattern of fumarate Form 1.
  • TGA/DSC thermogram (FIG. 2) of fumarate Form 1 exhibited an endothermic peak at approximately 171 °C (peak maximum), likely attributable to the melting event. 0.3 % of weight loss was observed by TGA from room temperature to 120 °C.
  • FIG. 3 illustrates the DVS profile of fumarate Form 1.
  • 'H-NMR result (FIG. 4) indicates the stoichiometry of fumarate Form 1 is 1/1. 0.8 % of heptane was observed based on 'H-NMR profile.
  • the fumarate Form l is a likely anhydrate. Approximately 0.6 % of water uptake was observed upon increasing relative humidity from 0% to 80% RH. As shown in FIG. 5, the XRPD pattern of fumarate Form 1 remained unchanged after DVS study.
  • Fumarate Form 2 can be obtained by cooling crystallization in IPA. 400 mg of free base Form 2 was dissolved into 10.2 mL of IPA at 50 °C. Then, 1.1 eq. of neat fumaric acid was added.
  • A07942-021S1 was characterized by XRPD, DSC, TGA, PLM and ‘H-NMR.
  • Fumarate Form 2 is composed of irregular crystals with high crystallinity. No residual solvent was detected by 'H-NMR as shown in FIG. 9. TGA/DSC thermogram (FIG. 7) of fumarate Form 2 exhibited an endotherm at approximately 190 °C (peak maximum), likely attributable to melting. Negligible mass loss was found in TGA trace. The stoichiometry (acid/base) of the fumarate Form 2 is 1/1 as determined by 'H-NMR. Therefore, fumarate Form 2 is an anhydrate. As shown in FIG. 10, XRPD remained the same after DVS evaluation.
  • Fumarate Form 2 adsorbed approximately 0.9% of moisture at 80% RH.
  • Tosylate crystalline Form 2 shows small needle-like particles with agglomerates.
  • tosylate crystalline Form 2 is an anhydrate.
  • the acid/base ratio is 1/1 based on NMR result ( Figure 16).
  • DVS profiles of tosylate Form 2 are presented in FIG. 17. It is clear that the tosylate Form 2 is totally dehydrated after being equilibrated under 0 % RH, and then readily adsorbed water upon increasing of RH. When RH is increased to 80 %, the mass of adsorbed water reached approximately 1.3 %. All the characterization results are given in Table 8.
  • XRPD pattern of ketoglutarate crystalline Form 1 is illustrated in FIG. 18. It was found that it had equant particles with some agglomeration. The endothermic peak observed in the DSC curve (FIG. 19) at 119/129 °C (onset/peak maximum) is likely attributable to the melting event. 0.18 % of weight loss was observed before the melting process in the TGA trace. 0.6 % of MEK was detected by ’H-NMR as shown in FIG. 20. The acid/base ratio determined by NMR is 1.14/1 (—1/1). All the characterization results are summarized in Table 10.
  • Oxalate crystalline Form 1 has been obtained in acetone/heptane, ACN/MTBE, acetone/water, and THF solvent systems.
  • Oxalate Form 1 (Lot# A07942-010A11) [00329] Freebase ( ⁇ 50 mg) was dissolved in 0.5 mb of THF at RT. Then 1.1 eq. (8 mg) of oxalic acid was dissolved and stirred at 50 °C for 3 days. After fdtration and dried at 50 °C for 16 h, solids were obtained.
  • Oxalate Form 1 is composed of irregular crystals with modest crystallinity.
  • FIG. 21 shows the XRPD pattern.
  • the DSC thermogram (FIG. 23) of oxalate Form 1 exhibited four broad endothermic peaks at approximately 79, 141, 187, and 198°C (peak maxima). 0.9% of continuous weight loss was observed from RT to 120 °C by TGA. No residual organic solvent was observed by 'H-NMR as shown in FIG 22, suggesting that oxalate Form 1 is an anhydrous form or potential channel hydrate.
  • NBD naphthalene 1,5-disulfonate
  • Phosphate Form 1 was consistently crystallized from acetone or acetone/heptane at RT.
  • Freebase Form 2 was dissolved into acetone at RT.
  • 1.1 eq. H3PO4/MeOH solution (IM) was charged in. The solution was stirred at RT for 16 hours followed by filtration and drying at 50 C for 16 hours under vacuum to get the resulted solids.
  • the experimental details are listed in Table 17.
  • the characterization results of phosphate Form I are given in Table 18.
  • A07942-021S2 was characterized by XRPD, DSC, TGA, PLM and 'H-NMR.
  • the XRPD pattern of phosphate Form 1 is illustrated in FIG. 29.
  • Phosphate Form 1 exhibited irregular shape with agglomeration. From the DSC data, the phosphate Form 1 showed three endothermic peaks at 65.3, 129.3, and 153.7 °C, relating to dehydration (first two peaks) and melting events. The TGA result indicated that phosphate Form 1 went through two steps of dehydration at RT-120 °C and 120-180 °C. 2.8 % of weight loss was observed in total at 180°C. No residual solvent was detected by 'H-NMR. The stoichiometry of phosphate Form 1 was determined by IC as 1/1. Phosphate Form 1 is identified as a hydrate. When RH increases to 80 %, the mass of adsorbed water is 7.1%.
  • Besylate Form 1 was generated from IPA. Certain amount of freebase was dissolved into 28 V IPA at RT or 50 °C. 1.1 eq. benzene sulfonic acid/MeOH solution (IM) was charged in. The solution was cooling from 50 °C to RT followed by slurry at RT for 5 hours. The resulted solids were generated after filtration and vacuum drying at 50 °C for 2 days. The detailed information is given in Table 18. The characterization results ofbesylate Form 1 are summarized in Table 19.
  • A07942-015A3 was characterized by XRPD, DSC, TGA, PLM and ’H-NMR.
  • the XRPD pattern of besylate Form 1 is illustrated in FIG. 30.
  • Besylate Form 1 is composed of irregular crystals with modest crystallinity.
  • DSC thermogram of besylate Form 1 exhibited an endotherm at 181.3 °C, likely attributable to a melting event. 0.9% and 2.2% of weight losses were observed by TGA at RT-120 °C and 120-200 °C, respectively.
  • the stoichiometry (acid/base) of the besylate Form 1 is 1/1 as determined by H-NMR. Water uptake of besylate Form 1 at 80 % RH is 3.39%.
  • the XRPD pattern remained unchanged after DVS study.
  • A07942-005A9 was characterized by XRPD, DSC, TGA, PLM and ’H-NMR.
  • the XRPD pattern of tartrate Form 1 is illustrated in FIG. 31.
  • Tartrate Form 1 is composed of irregular crystals with modest crystallinity. 7.5% of acetone was observed by 1 H- NMR. DSC thermogram of tartrate Form 1 exhibited a broad endotherm with a peak maximum at 120 °C, representing desolvation of acetone (4.5% of weight loss observed by TGA). The stoichiometry (acid/base) of tartrate Form 1 determined by 'H-NMR is 1/1. Data for tartrate Form 1 are consistent with an acetone solvate.
  • MRTX849 50 mg was weighed into an HPLC vial and 0.25 mL ethanol was added at 50 °C. 1.1 eq. of L-tartaric acid (IM in THF) was added at 50 °C. After 5 minutes stirring a suspension began to form and the sample was seeded with previously isolated crystalline ethanol-solvated tartrate Form 3 material from Preparation 1. An aliquot was taken and dried by evaporation before analysis by XRPD which matched the crystalline tartrate formed previously. The sample was filtered under vacuum and analyzed again by XRPD showing MRTX849 tartrate Form 3.
  • IM in THF L-tartaric acid
  • Peak list associated with scale up from Preparation 3 is below in Table 25. The four most intense peaks are: 13.0; 18.2; 22.6; and 23.7.

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Abstract

La présente invention concerne des formes cristallines de sels de l'inhibiteur de KRas G12C 2-[(2b)-4-[7-(8-chloro-1-naphtyl)-2-[[ (25)-1-méthylpyrrolidin-2-yl]méthoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-énoyl)pipérazin-2-yl]acétonitrile, des compositions pharmaceutiques comprenant les formes cristallines, des procédés de préparation des formes cristallines et leurs procédés d'utilisation.
PCT/US2024/038570 2023-07-20 2024-07-18 Formes cristallines de sels d'adagrasib Pending WO2025019688A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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EP3710439B1 (fr) * 2017-11-15 2023-02-15 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
US10647715B2 (en) * 2017-11-15 2020-05-12 Mirati Therapeutics, Inc. KRas G12C inhibitors
AU2020356455A1 (en) * 2019-09-24 2022-04-14 Mirati Therapeutics, Inc. Combination therapies
JP2023540809A (ja) * 2020-09-11 2023-09-26 ミラティ セラピューティクス， インコーポレイテッド Ｋｒａｓ ｇ１２ｃ阻害剤の結晶形態

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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