Crystalline forms of salts of adagrasib

Abstract

The present invention relates to crystalline forms of salts of the KRas G12C inhibitor 2-[(2b)-4- [7-(8-chloro-1-naphthyl)-2-[[(25)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H -pyrido [3,4- d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, pharmaceutical compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.

Description

CRYSTALLINE FORMS OF SALTS OF ADAGRASIBFIELD OF THE INVENTION

[0001] 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.BACKGROUND OF THE INVENTION

[0002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP-bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors regulating a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0003] 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).

[0004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor hasdemonstrated sufficient safety and / or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).

[0005] Recently, irreversible, covalent inhibitors that target KRas G12C have been described (e.g., see Ostrem et al., (2013) Nature 503:548-551). For instance, commonly-owned and assigned U.S. Provisional Application Serial Number 62 / 586,775 discloses potent, orally bioavailable compounds that irreversibly bind to KRas G12C for treating KRas G12C-mediated cancers.

[0006] 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. An amorphous form of this compound was described in International Patent Application PCT / US2018 / 061060 filed November 14, 2018, published as WO2019 / 099524A1 on May 23, 2019 at Example 478, and in Fell et al., (2020) J.Med. Chem. 63, 6679-6693. Crystalline forms of this compound were described in International Patent Application PCT / US2021 / 049940 filed September 10, 2021, published as WO 2022 / 056307 Al on March 17, 2022.

[0007] 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. In addition, 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.

[0008] For all the foregoing reasons, there is a need to produce a solid, crystalline salt form or salt forms of the compound 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, that would ideally provide enhanced dissolution rate, solubility, bioavailability, manufacturing improvements and / or storage shelf life of the pharmaceutical composition. The present invention advantageously addresses one or more of those needs.SUMMARY OF THE INVENTION

[0009] In one aspect of the invention, provided herein are crystalline forms of salts of the KRas G12C inhibitor 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l-methylpyrrolidin-2-yl]methoxy]- 6,8-dihydro-577-pyrido[3,4-<7]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile.

[0010] In one embodiment, the crystalline form is fumarate crystalline Form 1. In one embodiment, 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.

[0011] In one embodiment, 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.

[0012] In another embodiment, 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.

[0013] In another embodiment, 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.

[0014] In other embodiments, fumarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 1.

[0015] In one embodiment, 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.

[0017] 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 °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.

[0018] In one embodiment, 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.

[0019] In another embodiment, 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. In another embodiment, 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.

[0020] In one embodiment, 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”).

[0021] In another embodiment, fumarate crystalline Form 1 has a DVS isotherm substantially as shown in FIG. 3.

[0022] In another embodiment, 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.

[0023] In another embodiment, 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.

[0024] In one embodiment, fumarate crystalline Form 1 is substantially free of residual organic solvents.

[0025] In one embodiment, the crystalline form is designated fumarate crystalline Form 2.

[0026] In one embodiment, 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.

[0027] In one embodiment, 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.

[0028] In another embodiment, 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 .

[0029] In another embodiment, 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.

[0030] In other embodiments, fumarate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 6.

[0031] In one embodiment, 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.

[0032] In another embodiment, 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.

[0033] In another embodiment, 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.

[0034] In one embodiment, 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.

[0035] In another embodiment, 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. In another embodiment, 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.

[0036] In one embodiment, 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.

[0037] In another embodiment, fumarate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 8.

[0038] In another embodiment, 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.

[0039] In another embodiment, 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.

[0040] In one embodiment, fumarate crystalline Form 2 is substantially free of residual organic solvents.

[0041] Tn one embodiment, the crystalline form is designated tosylate crystalline Form 1 .

[0042] In one embodiment, 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.

[0043] In one embodiment, 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.

[0044] In another embodiment, 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.

[0045] In another embodiment, 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.

[0046] In other embodiments, tosylate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 11.

[0047] In one embodiment, 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.

[0048] In another embodiment, 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.

[0049] In another embodiment, 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.

[0050] Tn one embodiment, 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.

[0051] In another embodiment, 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. In another embodiment, 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.

[0052] In one embodiment, tosylate crystalline Form 1 is substantially free of residual organic solvents.

[0053] In one embodiment, the crystalline form is designated tosylate crystalline Form 2.

[0054] In one embodiment, 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.

[0055] In one embodiment, 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.

[0056] In another embodiment, 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.

[0057] In other embodiments, 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.

[0059] In another embodiment, 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.

[0060] In another embodiment, 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.

[0061] In one embodiment, 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.

[0062] In another embodiment, 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. In another embodiment, 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.

[0063] In 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.

[0064] In another embodiment, tosylate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 17.

[0065] In another embodiment, 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.

[0066] In another embodiment, 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 .

[0067] In one embodiment, tosylate crystalline Form 2 is substantially free of residual organic solvents.

[0068] In another embodiment, the crystalline form is designated naphthalene 1,5 -di sulfonate (NPD) crystalline Form 1.

[0069] In one embodiment, 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.

[0070] In one embodiment, 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.

[0071] In another embodiment, 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.

[0072] In other embodiments, NPD crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 24.

[0073] In 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.

[0074] In another embodiment, 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.

[0075] In another embodiment, NPD crystalline Form 1 has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at leastone 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.

[0076] In one embodiment, 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.

[0077] In another embodiment, 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. In another embodiment, 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.

[0078] In one embodiment, NPD crystalline Form 1 is substantially free of residual organic solvents.

[0079] In another embodiment, the crystalline form is designated orotate crystalline Form 1.

[0080] In another embodiment, the crystalline form is designated glycolate crystalline Form 1.

[0081] In another embodiment, the crystalline form is designated phosphate crystalline Form1.

[0082] In another embodiment, the crystalline form is designated besylate crystalline Form 1.

[0083] In another embodiment, the crystalline form is designated tartrate crystalline Form 1.

[0084] In another embodiment, the crystalline form is designated tartrate crystalline Form 2.

[0085] In another embodiment, the crystalline form is designated tartrate crystalline Form 3.

[0086] In another embodiment, the crystalline form is designated ketoglutarate crystallineForm 1.

[0087] Tn one embodiment, 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.

[0088] In one embodiment, 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.

[0089] In another embodiment, 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.

[0090] In other embodiments, 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.

[0091] In another embodiment, ketoglutarate crystalline Form 1 has a TGA profile substantially as shown in FIG. 19.

[0092] In another embodiment, the crystalline form is designated oxalate crystalline Form 1.

[0093] In one embodiment, 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.

[0094] In one embodiment, 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.

[0095] In another embodiment, 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.

[0096] In other embodiments, oxalate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 21.

[0097] In one embodiment, oxalate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 23.

[0098] In another embodiment, oxalate crystalline Form 1 has a TGA profile substantially as shown in FIG. 23.

[0099] In one embodiment, the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.

[0100] In another aspect of the invention, pharmaceutical compositions are provided 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-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, and / or a pharmaceutically acceptable excipient.

[0101] In one embodiment, 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. 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 tartratecrystalline 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.

[0102] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of fumarate crystalline Form 1. In one embodiment, 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.

[0103] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of fumarate crystalline Form 2. In one embodiment, 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, thepharmaceutical compositions of the present invention contain at least 50% of fumarate crystalline Form 2.

[0104] In one embodiment, 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 In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of tosylate crystalline Form 1. In one embodiment, 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.

[0105] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of tosylate crystalline Form 2. In one embodiment, 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.

[0106] In one embodiment, 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 In one embodiment, the pharmaceuticalcompositions of the present invention contain at least 95% of ketoglutarate crystalline Form 1 . In one embodiment, 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.

[0107] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of oxalate crystalline Form 1. In one embodiment, 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.

[0108] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% ofNPD crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 90% of NPD crystalline Form 1. In another embodiment, 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 crystallineForm 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.

[0109] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of orotate crystalline Form 1. In one embodiment, 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.

[0110] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of glycolate crystalline Form 1. In one embodiment, 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.

[0111] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of phosphate crystalline Form 1. In one embodiment, 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.

[0112] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% ofbesylate crystalline Form 1. In one embodiment, 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.

[0113] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 1. In one embodiment, the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 1. In another embodiment, the pharmaceutical compositions of thepresent 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.

[0114] Tn one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 2. In one embodiment, the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 2. In another embodiment, 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.

[0115] In one embodiment, 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. In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of tartrate crystalline Form 3. In one embodiment, the pharmaceutical compositions of the present invention contain at least 90% of tartrate crystalline Form 3. In another embodiment, 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.

[0116] 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. In one embodiment, 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.

[0117] 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.

[0118] In one aspect of the invention, provided herein are methods of 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. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.

[0119] In one embodiment, 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 oneembodiment, 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.

[0120] 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.

[0121] Also provided herein are methods for treating cancer in a subject in need thereof, the method 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 salt crystalline form of KRAS G12C inhibitor of the present invention, alone or in combination with one or more pharmaceutically acceptable excipients and / or diluent.

[0122] In one embodiment, 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.

[0123] 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.

[0124] In one embodiment, the subject is an adult patient. In one embodiment, the subject is a pediatric patient.

[0125] In some embodiments of any of the methods described herein, before treatment with the compositions or methods of the invention, the patient 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).

[0126] In another aspect of the invention, provided herein are process for the preparation of salt crystalline forms of the KRas G12C inhibitor. In one embodiment, 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. In one embodiment, 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 thepreparation of tartrate crystalline Form 2. In one embodiment, the process describes the preparation of tartrate crystalline Form 3.BRIEF DESCRIPTION OF THE FIGURES

[0127] 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.

[0128] FIG. 2 illustrates a combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) profile of fumarate crystalline Form 1 prepared according to Example 1.

[0129] FIG. 3 illustrates a dynamic vapor sorption (DVS) isotherm profile of fumarate crystalline Form 1 prepared according to Example 1.

[0130] FIG. 4 illustrates a 'H-NMR profile of fumarate crystalline Form 1 prepared according to Example 1 .

[0131] FIG. 5 illustrates an XRPD pattern of fumarate crystalline Form 1 prepared according to Example 1 before and after DVS evaluation.

[0132] FIG. 6 illustrates an XRPD pattern of fumarate crystalline Form 2 prepared according to Example 1 before and after DVS evaluation.

[0133] FIG. 7 illustrates a combined DSC and TGA profile of fumarate crystalline Form 2 prepared according to Example 2.

[0134] FIG. 8 illustrates a DVS isotherm profile of fumarate crystalline Form 2 prepared according to Example 2.

[0135] FIG. 9 illustrates a 'H-NMR profile of fumarate crystalline Form 2 prepared according to Example 2.

[0136] FIG. 10 illustrates an XRPD pattern of fumarate crystalline Form 2 prepared according to Example 2 before and after DVS evaluation.

[0137] FIG. 11 illustrates an XRPD pattern of tosylate crystalline Form 1 prepared according to Example 3.

[0138] FIG. 12 illustrates a combined DSC and TGA profile of tosylate crystalline Form 1 prepared according to Example 3.

[0139] FIG. 13 illustrates a 'H-NMR profile of tosylate crystalline Form 1 prepared according to Example 3.

[0140] FIG. 14 illustrates an XRPD pattern of tosylate crystalline Form 2 prepared according to Example 4.

[0141] FIG. 15 illustrates a combined DSC and TGA profile of tosylate crystalline Form 2 prepared according to Example 4.

[0142] FIG. 16 illustrates a 'H-NMR profile of tosylate crystalline Form 2 prepared according to Example 4.

[0143] FIG. 17 illustrates a DVS profile of tosylate crystalline Form 2 prepared according to Example 4.

[0144] FIG. 18 illustrates an XRPD pattern of ketoglutarate crystalline Form 1 prepared according to Example 5.

[0145] FIG. 19 illustrates a DSC profile and TGA profile of ketoglutarate crystalline Form 1 prepared according to Example 5.

[0146] FIG. 20 illustrates a 'H-NMR profile of ketoglutarate crystalline Form 1 prepared according to Example 5.

[0147] FIG. 21 illustrates an XRPD pattern of oxalate crystalline Form 1 prepared according to Example 6.

[0148] FIG. 22 illustrates aJH-NMR profile of oxalate crystalline Form 1 prepared according to Example 6.

[0149] FIG. 23 illustrates a DSC profile and TGA profile of oxalate crystalline Form 1 prepared according to Example 6.

[0150] FIG. 24 illustrates an XRPD pattern of naphthalene 1,5-disulfonate (NPD) crystalline Form 1 prepared according to Example 7.

[0151] FIG. 25 illustrates a DSC profile and TGA profile of NPD crystalline Form 1 prepared according to Example 7

[0152] FIG. 26 illustrates a 'H-NMR profile of NPD crystalline Form 1 prepared according to Example 7.

[0153] FIG. 27 illustrates an XRPD pattern of orotate crystalline Form 1 prepared according to Example 8.

[0154] FIG. 28 illustrates an XRPD pattern of glycolate crystalline Form 1 prepared according to Example 9.

[0155] FIG. 29 illustrates an XRPD pattern of phosphate crystalline Form 1 prepared according to Example 10.

[0156] FIG. 30 illustrates an XRPD pattern of besylate crystalline Form 1 prepared according to Example 11.

[0157] FIG. 31 illustrates an XRPD pattern of tartrate crystalline Form 1 prepared according to Example 12.

[0158] FIG. 32 illustrates an XRPD pattern of tartrate crystalline Form 2 prepared according to Example 13.

[0159] FIG. 33 illustrates XRPD patterns of tartrate crystalline Form 3 prepared according to Example 14.

[0160] FIG. 34 illustrates an XRPD pattern of tartrate crystalline Form 3 prepared according to Example 14.DETAILED DESCRIPTION OF THE INVENTION

[0161] 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. In particular, 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, processes for preparing the crystalline forms and methods of use thereof.

[0162] In particular, multiple salts included in this application have demonstrated advantages over the crystalline form of the free base currently used in development, referred to as Form B in WO 2022 / 056307 in terms of hygroscopicity and physical stability above 65%RH, thus presenting a potential for substantial manufacturing, storing and handling improvements.DEFINITIONS

[0163] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.

[0164] As used herein, “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.

[0165] As used herein, a “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.

[0166] As used herein, the term "solvate" refers to a crystalline form of the KRas G12C inhibitor which contains solvent.

[0167] As used herein, the term "hydrate" refers to a solvate wherein the solvent comprises water.

[0168] As used herein, the term “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.

[0169] As used herein, 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.

[0170] A "KRas G12C-associated disease or disorder" as used herein 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.

[0171] As used herein, 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. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, 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). In some embodiments, 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). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, 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).

[0172] 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.

[0173] In some embodiments of any of the methods or uses described herein, 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 moresymptoms 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.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.

[0174] The term “regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0175] As used herein, 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.

[0176] As used herein, 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.

[0177] As used 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.

[0178] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a crystalline form of a salt of the KRAS inhibitor detailed herein, or the length of treatment time described herein) 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 alisting 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.

[0179] As used herein, 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.GENERAL METHODS AND INSTRUMENTATION

[0180] The general methods outlined below were used in the exemplified Examples, unless otherwise noted.

[0181] 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.

[0182] In one embodiment, the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.I. X-Ray Powder Diffraction (XRPD)

[0183] 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.II. Differential Scanning Calorimetry (DSC)

[0184] DSC was performed using a Discovery DSC 250 (TA Instruments, US). The sample was placed into an aluminum pin-hole hermetic pan and the weight was accurately recorded. The sample was heated at a rate of 10 °C / min from 25 °C to the final temperature. Routine variations on the above techniques could be implemented by a skilled practitioner.III. Thermo-Gravimetric Analysis (TGA)

[0185] Thermogravimetric analysis (TGA) was carried out on a Discovery TGA 55 (TA Instruments, US). The sample was placed into an open tared aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated at a rate of 10 °C / min from ambient temperature to the final temperature.IV. Dynamic Vapor Sorption (DYS)

[0186] Vapor Sorption isotherms were obtained using a Surface Measurement System (SMS) DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software.Samples were placed into a tarred sample chamber and automatically weighed. Samples were dried at 40°C until the dm / dt was less than 0.002% and cooled to 25 °C. Sorption and desorption data were collected over a range of 0% - 90% relative humidity (RH) at 10% RH increments. The equilibrium criterion used for analysis was less than 0.002% weight change with a maximum equilibration time of 60 min.V. Nuclear Magnetic Resonance

[0187] 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.KRAS G12C INHIBITOR

[0188] In one aspect of the invention, provided herein are 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]pyrimi din-4- yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, also known as adagrasib and as MRTX849.

[0189] As noted above, methods for manufacturing the KRas G12C inhibitor disclosed herein are known. For example, International Patent Application PCT / US2018 / 061060 fded November 14, 2018, published as WO2019 / 099524A1 on May 23, 2019, and the related US application publication number US2019014444 describes suitable intermediates and general reaction schemes for preparing KRas G12C inhibitors, and also provides a detailed synthetic route for the preparation of amorphous 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 in Example 478.

[0190] Pharmaceutically acceptable salts of adagrasib are also known and are described, for example, in WO 2022 / 056307.

[0191] Methods for preparing crystalline forms of pharmaceutically acceptable salts 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 are provided herein.CRYSTALLINE FORMS OF SALTS OF THE KRAS G12C INHIBITOR

[0192] Exemplary methods for preparing crystalline forms of salts of adagrasib are described in Examples 1-14, respectively.

[0193] In one embodiment, the crystalline form is fumarate crystalline Form 1. In one embodiment, 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.

[0194] In one embodiment, 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.

[0195] In another embodiment, 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.

[0196] In another embodiment, 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.

[0197] In other embodiments, fumarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 1.

[0198] In one embodiment, 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.

[0199] 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 °20 selected from 8.1±0.2, 17.3±0.2, 21.0±0.2 and 22.8 ±0.2.

[0200] 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 °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.

[0201] In one embodiment, 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.

[0202] In another embodiment, 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. In another embodiment, 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.

[0203] In one embodiment, 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”).

[0204] In another embodiment, fumarate crystalline Form 1 has a DVS isotherm substantially as shown in FIG. 3.

[0205] In another embodiment, 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.

[0206] In another embodiment, 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.

[0207] In one embodiment, fumarate crystalline Form 1 is substantially free of residual organic solvents.

[0208] In one embodiment, the crystalline form is designated fumarate crystalline Form 2.

[0209] In one embodiment, 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.

[0210] In one embodiment, 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.

[0211] In another embodiment, 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 .

[0212] Tn another embodiment, 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.

[0213] In other embodiments, fumarate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 6.

[0214] In one embodiment, 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.

[0215] In another embodiment, 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.

[0216] In another embodiment, 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.

[0217] In one embodiment, 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.

[0218] In another embodiment, 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. In another embodiment, 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.

[0219] In one embodiment, 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.

[0220] In another embodiment, fumarate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 8.

[0221] In another embodiment, 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.

[0222] In another embodiment, 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.

[0223] In one embodiment, fumarate crystalline Form 2 is substantially free of residual organic solvents.

[0224] In one embodiment, the crystalline form is designated tosylate crystalline Form 1.

[0225] In one embodiment, 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.

[0226] In one embodiment, 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.

[0227] In another embodiment, 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.

[0228] In another embodiment, 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.

[0229] In other embodiments, tosylate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 11.

[0230] Tn one embodiment, 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.

[0231] In another embodiment, 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.

[0232] In another embodiment, 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.

[0233] In one embodiment, 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.

[0234] In another embodiment, 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. In another embodiment, 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.

[0235] In one embodiment, tosylate crystalline Form 1 is substantially free of residual organic solvents.

[0236] In one embodiment, the crystalline form is designated tosylate crystalline Form 2.

[0237] In one embodiment, 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.

[0238] In one embodiment, 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.

[0239] In another embodiment, 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.

[0240] In other embodiments, tosylate crystalline Form 2 has an XRPD pattern substantially as shown in FIG. 14.

[0241] In 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.

[0242] In another embodiment, 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.

[0243] In another embodiment, 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.

[0244] In one embodiment, 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.

[0245] In another embodiment, 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. In another embodiment, 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.

[0246] 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.

[0247] In another embodiment, tosylate crystalline Form 2 has a DVS isotherm substantially as shown in FIG. 17.

[0248] In another embodiment, 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.

[0249] In another embodiment, 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 .

[0250] In one embodiment, tosylate crystalline Form 2 is substantially free of residual organic solvents.

[0251] In another embodiment, the crystalline form is designated naphthalene 1,5 -di sulfonate (NPD) crystalline Form 1.

[0252] In one embodiment, 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.

[0253] In one embodiment, 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.

[0254] In another embodiment, 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.

[0255] In other embodiments, NPD crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 24.

[0256] 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.

[0257] In another embodiment, 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.

[0258] In another embodiment, 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.

[0259] In one embodiment, 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.

[0260] In another embodiment, 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. In another embodiment, 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.

[0261] In one embodiment, NPD crystalline Form 1 is substantially free of residual organic solvents.

[0262] In another embodiment, the crystalline form is designated orotate crystalline Form 1.

[0263] In another embodiment, the crystalline form is designated glycolate crystalline Form 1.

[0264] In another embodiment, the crystalline form is designated phosphate crystalline Form 1.

[0265] In another embodiment, the crystalline form is designated besylate crystalline Form 1.

[0266] Tn another embodiment, the crystalline form is designated tartrate crystalline Form 1 .

[0267] In another embodiment, the crystalline form is designated tartrate crystalline Form 2.

[0268] In another embodiment, the crystalline form is designated tartrate crystalline Form 3.

[0269] In another embodiment, the crystalline form is designated ketoglutarate crystallineForm 1.

[0270] In one embodiment, 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.

[0271] In one embodiment, 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.

[0272] In another embodiment, 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.

[0273] In other embodiments, 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.

[0274] In another embodiment, ketoglutarate crystalline Form 1 has a TGA profde substantially as shown in FIG. 19.

[0275] In another embodiment, the crystalline form is designated oxalate crystalline Form 1.

[0276] In one embodiment, 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 someembodiments two characteristic peaks are present. In some embodiments three characteristic peaks are present. In some embodiments four characteristic peaks are present.

[0277] In one embodiment, 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.

[0278] In another embodiment, 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.

[0279] In other embodiments, oxalate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 21.

[0280] In one embodiment, oxalate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 23.

[0281] In another embodiment, oxalate crystalline Form 1 has a TGA profile substantially as shown in FIG. 23.

[0282] In one embodiment, the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.PROCESSES FOR PREPARING CRYSTALLINE FORMS OF THE SALTS OF ADAGRASIB

[0283] In one embodiment, 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.

[0284] In a preferred embodiment, the organic solvent comprises one or more of methanol, heptane, acetone, acetonitrile (ACN) and isopropyl alcohol (IP A).

[0285] In another embodiment, fumarate crystalline Form 2 is obtained by the process comprising cooling and crystallization in IPA. Thus, the process may comprise the steps: dissolving free base in IPA; adding fumaric acid at 50 °C, stirring for 16 hours, cooling theresulting mixture to room temperature; filtering and drying under vacuum or under ambient environment.

[0286] In another embodiment, 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.

[0287] In another embodiment, 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.

[0288] In another embodiment, 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

[0289] In another embodiment, 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.

[0290] In another embodiment, 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.

[0291] In one embodiment, the organic solvent is heptane.

[0292] In one embodiment, the organic solvent is isopropanol.

[0293] In some embodiments the obtained solids are analyzed by X-ray powder diffraction to confirm a specific Form.

[0294] In one embodiment, the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.

[0295] The crystalline forms may be formulated into pharmaceutical compositions.PHARMACEUTICAL COMPOSITIONS

[0296] Tn another aspect, 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. In certain embodiments, 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.

[0297] In one embodiment, 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.

[0298] 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.

[0299] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions may contain, in addition to the inhibitor, 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.

[0300] 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 causingserious toxic effects in the patient treated. In one embodiment, 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.

[0301] In one embodiment, 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.

[0302] The pharmaceutical compositions comprising the crystalline forms of the KRas G12C inhibitor or salt thereof may be used in the methods of use described herein.METHODS OF USE

[0303] The 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. More specifically, 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, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.

[0304] Also provided herein is a method for treating cancer in a subject in need thereof, the method 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. In one embodiment, 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.

[0305] 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.

[0306] In one embodiment, a crystalline form of the KRas G12C inhibitor is administered as a capsule during the period of time. In embodiments of the invention, 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.

[0307] In one embodiment, 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). In one embodiment, the KRAS inhibitor is orally administered once daily. In one embodiment, the crystalline form of the KRAS G12C inhibitor is orally administered twice daily.

[0308] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound of the combination or the combination to treat or prevent a given disorder.

[0309] One skilled in the art will further recognize that human clinical trials including first-in- human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

[0310] In some embodiments, 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 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65%, 6% to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 85%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to 90%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%, 55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%) reduction in the volume of one or more solid tumors in a patient following treatment with the combination therapy for a period of time between 1 day and 2 years (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months,between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 week and 16 months, between 1 week and 14 months, between 1 week and 12 months, between 1 week and 10 months, between 1 week and 9 months, between 1 week and 8 months, between 1 week and 7 months, between 1 week and 6 months, between 1 week and 5 months, between 1 week and 4 months, between 1 week and 3 months, between 1 week and 2 months, between 1 week and 1 month, between 2 weeks and 2 years, between 2 weeks and 22 months, between 2 weeks and 20 months, between 2 weeks and 18 months, between 2 weeks and 16 months, between 2 weeks and 14 months, between 2 weeks and 12 months, between 2 weeks and 10 months, between 2 weeks and 9 months, between 2 weeks and 8 months, between 2 weeks and 7 months, between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 1 month and 20 months, between 1 month and 18 months, between 1 month and 16 months, between 1 month and 14 months, between 1 month and 12 months, between 1 month and 10 months, between 1 month and 9 months, between 1 month and 8 months, between 1 month and 7 months, between 1 month and 6 months, between 1 month and 6 months, between 1 month and 5 months, between 1 month and 4 months, between 1 month and 3 months, between 1 month and 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between 2 months and 14 months, between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months, or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months, between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 6 months and 22 months, between 6 months and 20 months, between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months, or between 6 months and 8 months) (e.g., as compared to the size of the one or more solid tumors in the patient prior to treatment).

[0311] The phrase “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.

[0312] In some embodiments, 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% to 320%, 5% to 300%, 5% to 280%, 5% to 260%, 5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%, 5% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380%, 10% to 360%, 10% to 340%, 10% to 320%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%, 10% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 100%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 400%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%, 20% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% to 180%, 20% to 160%, 20% to 140%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 400%, 30% to 380%, 30% to 360%, 30% to 340%, 30% to 320%, 30% to 300%, 30% to 280%, 30% to 260%, 30% to 240%, 30% to 220%, 30% to 200%, 30% to 180%, 30% to 160%, 30% to 140%, 30% to 120%, 30% to 100%, 30% to 90%, 30% to%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 400%, 40% to 380%, 40% to0%, 40% to 340%, 40% to 320%, 40% to 300%, 40% to 280%, 40% to 260%, 40% to 240%,% to 220%, 40% to 200%, 40% to 180%, 40% to 160%, 40% to 140%, 40% to 120%, 40% to0%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 400%, 50% to0%, 50% to 360%, 50% to 340%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to 260%,% to 240%, 50% to 220%, 50% to 200%, 50% to 180%, 50% to 160%, 50% to 140%, 50% to0%, 50% to 120%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% 400%, 60% to 380%, 60% to 360%, 60% to 340%, 60% to 320%, 60% to 300%, 60% to0%, 60% to 260%, 60% to 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to 160%,% to 140%, 60% to 120%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% to0%, 70% to 380%, 70% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to 280%,% to 260%, 70% to 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 160%, 70% to0%, 70% to 120%, to 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%, 80% to0%, 80% to 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to 240%,% to 220%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%, 80% to0%, 80% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to 320%,% to 300%, 90% to 280%, 90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%, 90% to0%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% to0%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% to0%, 100% to 240%, 100% to 220%, 100% to 200%, 100% to 180%, 100% to 160%, 100% to0%, 100% to 120%, 120% to 400%, 120% to 380%, 120% to 360%, 120% to 340%, 120% to0%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% to0%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% to0%, 140% to 340%, 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% to0%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160%, 160% to 400%, 160% to0%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% to0%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, 180% to 400%, 180% to0%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% to0%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380%, 200% to0%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to0%, 200% to 220%, 220% to 400%, 220% to 380%, 220% to 360%, 220% to 340%, 220% to320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%, 240% to 260%, 260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, 260% to 300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%) in the time of survival of the patient (e.g., as compared to a patient having a similar cancer and administered a different treatment or not receiving a treatment).

[0313] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.EXAMPLE 1Preparation 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

[0314] 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.

[0315] 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.Table 1* A07942-003A8 was characterized by XRPD, DSC, TGA, PLM and 'H-NMR.Table 2

[0316] 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.

[0317] 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.EXAMPLE 2Preparation 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

[0318] 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. The solution was allowed to slurry at 50 °C for 16 h followed by cooling to RT and holding for 3 hours. The solids were collected after filtration and drying at 50 °C for 48 hours. The experimental details are given in Table 3. The characterization results of fumarate Form 2 are summarized in Table 4.Table 3* A07942-021S1 was characterized by XRPD, DSC, TGA, PLM and ‘H-NMR.Table 4

[0319] 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.EXAMPLE 3Preparation 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

[0320] About 40 mg of free base was dissolved into 1 mL of IPA and heated up to 50 °C to dissolve the free base. 1.1 eq. p-toluenesulfonic acid was added into the solution at 50 °C. Then, the solution was naturally cooled to RT and stirred for 3 days. The solids were collected after filtration and drying at RT overnight. The experimental details are given in Table 5.Table 5

[0321] XRPD (FIG. 11) results show the tosylate crystalline Form 1 has acceptable crystallinity. The DSC / TGA curves are presented in FIG. 12. The endothermic peak around 131 / 143°C (onset / peak maximum) in the DSC curve is assumed to be attributable to the melting event of tosylate crystalline Form 1, and no obvious weight loss was observed by TG thermogram prior to melting. Therefore, data for tosylate crystalline Form 1 are consistent with an anhydrate, designated as tosylate Form 1. The acid / base ratio is calculated as 1 / 1 based on NMR result (FIG. 13). The characterization results are summarized in Table 6.Table 6*Thc molar ratio of free base to p-tolucncsulfonic acid is 1:1.EXAMPLE 4Preparation 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

[0322] About 40 mg of free base Form 2 was dissolved into 0.4 mL of acetone. 1.1 eq. of the p-toluenesulfonic acid was dissolved into the solution. The obtained solution was stirred for 1day, tosylate crystalline Form 2 was obtained. XRPD pattern is given in FIG. 14. The detailed experimental information is presented in Table 7.Table 7*Lot# A07942-050B2 was characterized by XRPD, DSC. TG, PLM and ’H-NMR.

[0323] Tosylate crystalline Form 2 shows small needle-like particles with agglomerates. One endothermic peak found in the DSC curve at 148 / 156 °C (onset / peak maximum), is likely due to melting and no weight loss was observed in TG thermogram before melting (FIG. 15).Therefore, 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.Table 8*The molar ratio of free base to p-toluenesulfonic acid is 1:1.EXAMPLE 5Preparation of ketoglutarate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2- [l(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido|3,4-dJpyrimidin-4-ylJ-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0324] About 60 mg of free base was dissolved into 600 pL of MEK at 60 °C. 1.1 eq. a- ketoglutaric acid was added into the solution. Then, the solution was naturally cooled to RT andstirred for 7 days. The solids were collected after filtration and drying under vacuum at 50°C for 4 hours. The experimental parameters and results are shown in Table 9.Table 9*Lot# A07942-069K1 was characterized by XRPD, DSC, TGA, PLM and 'H-NMR.

[0325] 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.Table 10*The molar ratio of free base to a-ketoglutaric acid is 1:1.EXAMPLE 6Preparation 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

[0326] Oxalate crystalline Form 1 has been obtained in acetone / heptane, ACN / MTBE, acetone / water, and THF solvent systems.

[0327] A sample was made with THF using the following procedure:

[0328] Oxalate Form 1 (Lot# A07942-010A11)

[0329] 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.EXAMPLE 7Preparation of naphthalene 1,5-disulfonate (NPD) 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

[0330] About 40 mg of free base was dissolved into 1 mL of IPA at 50 °C. 0.5 eq.Naphthalene 1,5-disulfonic acid was added into the solution. Then, the solution was naturally cooled to RT and stirred for 18 days. The solids were collected after fdtration and drying under vacuum overnight. The experimental parameters and results are shown in Table 11.Table 11*Lot# A07942-058E1 was characterized by XRPD, DSC, TG, PLM and ’H-NMR.

[0331] XRPD pattern of NPD salt Form 1 is presented in FIG. 24. The DSC / TG curves are presented in FIG. 25. 0.6 % of weight loss was observed within the temperature range from RT to 150 °C in TGA curve, which is associated with water, as no residual solvent was detected by 'H-NMR (FIG. 26). The exothermic peak around 177 / 188 °C (onset / peak maximum) in the DSC curve is assumed to be due to decomposition based on the absence of subsequent endothermic event and the observation that the white powder converted to brown stick solids after heating up to 210 °C. A melting event did not occur before the decomposition. The acid / base ratio determined by 'H-NMR is 0.48 / 1 (-0.5 / 1). The characterization results are shown in Table 12.Table 12*The molar ratio of free base to naphthalene 1,5 -disulfonic acid is 2: 1.EXAMPLE 8Preparation of orotate 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

[0332] About 40 mg of free base was dissolved into 320 pL of IPA / MTBE (60 / 40) at 60 °C.0.5 eq. orotic acid was added into the solution. Then, the solution was naturally cooled to RT and stirred for 7 days. The solids were collected after filtration and drying under vacuum at 50 °C for 4 hours. The experimental parameters and results are shown in Table 13Table 13*Lot# A07942-064B5 was characterized by XRPD, DSC, TG, PLM and ’H-NMR.

[0333] The XRPD pattern of orotate is shown in FIG. 27. The endothermic peak observed from the DSC curve at 132 / 136 °C (onset / peak maximum) is likely attributable to a melting event. 0.8% of weight loss was observed during the melting process, and 1.0 % of IPA as well as 0.2 % of MTBE were detected by 'H-NMR. The acid / base ratio determined by NMR is 0.35 / 1 (-0.5 / 1). Based on pKa considerations, orotate Form 1 is expected to be an orotic acid cocrystal of the mono-orotate salt of MRTX849. All the characterization results are summarized in Table 14.Table 14*The molar ratio of free base to orotic acid is 0.5:1.EXAMPLE 9Preparation of glycolate 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

[0334] About 40 mg of free base was dissolved into 1 mL (25 V) of IP A at 50 °C. 1.1 eq. glycolic acid was added into the solution. Then, the solution was naturally cooled to RT and stirred overnight. Since no solids appeared, 1 mL of MTBE was added as antisolvent. After stirring at RT for 4 weeks, the solids were filtered and dried under vacuum at 40 °C overnight. The detailed preparation information and results are given in Table 15.Table 15*Lot# A07942-052C12 was characterized by XRPD. DSC, TG, PLM and 'H-NMR

[0335] XRPD pattern of glycolate is presented in FIG. 28. Glycolate Form 1 exhibits needlelike morphology. 2.3 % of weight loss was observed before the endpoint of melting. 1.8 % of IPA was detected by 'H-NMR. The sharp endothermic peak at 131 / 135 °C is likely due to the melting event of glycolate Form 1. The acid / base ratio determined by NMR is 1.33 / 1. The characterization data is shown in Table 16.Table 16EXAMPLE 10Preparation of phosphate Form 1 of2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxyJ-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0336] 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.Table 17* A07942-021S2 was characterized by XRPD, DSC, TGA, PLM and 'H-NMR.Table 18

[0337] 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 ofdehydration 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%.EXAMPLE 11Preparation of besylate 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

[0338] 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.Table 19* A07942-015A3 was characterized by XRPD, DSC, TGA, PLM and ’H-NMR.Table 20

[0339] 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.EXAMPLE 12Preparation of tartrate 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

[0340] About 20 mg free base Form 2 was added into 13 V acetone. 1.1 eq. of the neat L- tartaric acid was added into the solution and stirred at RT overnight. 0.3 V heptane was charged in and stirred overnight. The solids were fdtered and vacuum dried at 50 °C for 3 hours. The detailed preparation information and results are given in Table 21. The characterization results of tartrate Form 1 are summarized in Table 22.Table 21* A07942-005A9 was characterized by XRPD, DSC, TGA, PLM and ’H-NMR.Table 22

[0341] 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 by1H-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.EXAMPLE 13Preparation of tartrate 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

[0342] About 25 mg freebase Form 2 was added into 28 V IPA at 50 °C. 1.1 eq. neat L- tartaric acid was added into the solution and stirred at RT for 1 day. The resulted solids were generated after filtration and vacuum drying at 50 °C for 3 h. The detailed information is shown in Table 23. The characterization results of tartrate Form 2 are summarized in Table 24.Table 23* A07942-015A8 was characterized by XRPD. DSC. TGA. PLM and 'H-NMR.Table 24

[0343] The XRPD pattern of tartrate Form 2 is illustrated in FIG. 32. Tartrate Form 2 is irregular crystals with low crystallinity. DSC thermogram showed two endothermic events at 116.1 and 172.3 °C, attributable to desolvation and melting. 5.5 % of weight loss observed from RT to 135 °C is related to 5.2% of IPA detected by 'H-NMR. The acid / base ratio is around 1 / 1 based on 'H-NMR profile. Data for tartrate Form 2 are consistent with an IPA solvate.EXAMPLE 14Preparation of tartrate Form 3 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxyJ-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile

[0344] Preparation 1 : Non-seeded preparation from EtOH

[0345] 50 mg MRTX849 was weighed into an HPLC vial and 0.5 mL ethanol was added at 80 °C. 1.1 eq. of L-tartaric acid (IM in THF) was added to the sample. The sample was cooled to 5 °C, following which it was placed to mature at 25 / 80 °C in 4-hour cycles for 24 hours. The resulting crystalline solids were isolated by filtration under vacuum.

[0346] Preparation 2: Seeded preparation

[0347] 50 mg MRTX849 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.

[0348] Preparation 3 (seeded scale up)

[0349] 500 mg MRTX849 was weighed into a 4 ml vial and 2 mL ethanol was added at 50 °C. 1.1 eq. of L-tartaric acid (IM in THF) was added at 50 °C. The sample was then immediately seeded with the crystalline material prepared according to Preparation 2. A suspension began to form and the sample was left for 30 mins. The sample was then isolated by filtration under vacuum and analyzed by XRPD.

[0350] 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.Table 25While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

WE CLAIM:

1. A fumarate crystalline form of 2-[(2 )-4-[7-(8-chloro-l-naphthyl)-2-[[(2A')- l - methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 7-pyrido[3,4-tZ]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

2. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 1 having 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.

3. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 1 having an X-ray powder diffraction pattern comprising two or more peaks at °20 at 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.

4. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 1 having an X-ray powder diffraction pattern comprising peaks at °20 at 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.

5. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 1 having an XRPD pattern substantially as shown in FIG. 1.

6. The fumarate crystalline form according to claim 2, wherein Form 1 is characterized by having an endothermic peak with an onset at about 165°C by differential scanning calorimetry.

7. The fumarate crystalline form according to claim 2, wherein Form 1 has a DSC thermogram substantially as shown in FIG. 2.

8. The fumarate crystalline form according to claim 3, wherein Form 1 has a DSC thermogram substantially as shown in FIG. 2.

9. The fumarate crystalline form according to claim 3, wherein Form 1 has a thermogravimetric analysis (“TGA”) profile substantially as shown in FIG. 2.

10. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 1 and which has about 0.3% weight loss until the onset of degradation at about 170°C as estimated by TGA.

11. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 1 having dynamic vapor sorption (“DVS”) isotherm substantially as shown in FIG. 3.

12. The fumarate crystalline form of any one of claims 10-11, wherein Form 1 has an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 8. l±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.

13. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 1 which has water intake of about 0.6% upon increasing relative humidity (RH) from 0% RH to 80 % RH, as measured by DVS.

14. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 having 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.

15. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 having 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.

16. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 having an X-ray powder diffraction pattern comprising peaks at °29 at 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.

17. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 having an XRPD pattern substantially as shown in FIG. 6.

18. The fumarate crystalline form according to claim 14, wherein Form 2 is characterized by having an endothermic peak with an onset at about 187°C by differential scanning calorimetry.

19. The fumarate crystalline form according to claim 14, wherein Form 2 has a DSC thermogram substantially as shown in FIG. 7.

20. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 which has a DSC thermogram substantially as shown in FIG. 7.

21. The fumarate crystalline form according to claim 1, wherein the fumarate crystalline form is Form 2 which has a thermogravimetric analysis (“TGA”) profde substantially as shown in FIG. 7.

22. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 2 and which has negligible weight loss until the onset of degradation at about 190°C as measured by TGA.

23. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 2 having dynamic vapor sorption (“DVS”) isotherm substantially as shown in FIG. 8.

24. The fumarate crystalline form of any one of claims 22-23, wherein Form 2 has an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 4. l±0.2, 8.8±0.2, 17.7±0.2 and 22.4 ±0.2.

25. The fumarate crystalline form of claim 1, wherein the fumarate crystalline form is Form 2 which has water intake of about 0.9% upon increasing relative humidity (RH) from 0% RH to 80 % RH, as measured by DVS.

26. A tosylate crystalline form of 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-577-pyrido[3,4-£7]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

27. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 having 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.

28. The tosylate crystalline form according to claim 27, wherein the fumarate 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.

29. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 having an X-ray powder diffraction pattern comprising two or more 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, 16.0±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.

30. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 having an XRPD pattern substantially as shown in FIG. 14.

31. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 and wherein Form 2 is characterized by having an endothermic peak with an onset of 148°C as measured by differential scanning calorimetry.

32. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 and wherein Form 2 has a DSC thermogram substantially as shown in FIG. 15.

33. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 2 which has a thermogravimetric analysis (“TGA”) profile substantially as shown in FIG. 15.

34. The tosylate crystalline form of claim 26, wherein the tosylate crystalline form is Form 2 and which has about 0.3% weight loss until about 100°C as measured by TGA.

35. The tosylate crystalline form of claim 26, wherein the tosylate crystalline form is Form 2 having dynamic vapor sorption (“DVS”) isotherm substantially as shown in FIG. 17.

36. The tosylate crystalline form of any one of claims 34-35, wherein Form 2 has an X-ray powder diffraction pattern comprising at least one peak at °20 selected 11.2±0.2, 13.4±0.2, 16.8±0.2, and 17.8±0.2.

37. The tosylate crystalline form of claim 26, wherein the tosylate crystalline form is Form 2 which has water intake of about 1.3% upon increasing relative humidity (RH) from 0% RH to 80 % RH, as measured by DVS.

38. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 having an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 13.8±0.2, 15.4±0.2, 18.0±0.2, and 20.3±0.2.

39. The tosylate crystalline form according to claim 38, wherein the tosylate crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °26 at 13.8±0.2, 15.4±0.2, 18.0±0.2, and 20.3±0.2.

40. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 having an X-ray powder diffraction pattern comprising two or more 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.

41. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 having an XRPD pattern substantially as shown in FIG. 11.

42. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 and wherein Form 1 is characterized by having an endothermic peak with an onset of 131°C as measured by differential scanning calorimetry.

43. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 and wherein Form 1 has a DSC thermogram substantially as shown in FIG. 12.

44. The tosylate crystalline form according to claim 26, wherein the tosylate crystalline form is Form 1 which has a thermogravimetric analysis (“TGA”) profile substantially as shown in FIG. 12.

45. The tosylate crystalline form of claim 26, wherein the tosylate crystalline form is Form 1 and which has about 0.3% weight loss until about 150°C as measured by TGA.

46. The tosylate crystalline form of any one of claims 42-45, wherein Form 1 has an X-ray powder diffraction pattern comprising at least one peak at °29 selected from 13.8±0.2, 15.4±0.2, 18.0±0.2, and 20.3±0.2.

47. A naphthalene 1,5-disulfonic acid (NPD) crystalline Form 1 of 2-[(25)-4-[7-(8-chloro-l- naphthyl)-2-[[(25)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / f-pyrido[3,4- < ]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

48. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline form has 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.

49. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 has an X-ray powder diffraction pattern comprising two or more peaks at °29 at 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.

50. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 24.

51. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 is characterized by having an exothermic peak with an onset of 177 °C as measured by differential scanning calorimetry.

52. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 25.

53. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 has a thermogravimetric analysis (“TGA”) profile substantially as shown in FIG. 25.

54. The NPD crystalline Form 1 according to claim 47, wherein the NPD crystalline Form 1 has about 0.6% weight loss until about 150°C as measured by TGA.

55. A ketoglutarate crystalline Form 1 of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-l - methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / -pyrido[3,4-t / ]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

56. The ketoglutarate crystalline Form 1 according to claim 55, wherein the ketoglutarate crystalline form has an X-ray powder diffraction pattern comprising at least one peak at °20 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.

57. The ketoglutarate crystalline Form 1 according to claim 55, wherein the ketoglutarate crystalline Form 1 has an X-ray powder diffraction 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.

58. The ketoglutarate crystalline Form 1 according to claim 55, wherein the ketoglutarate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 18.

59. The ketoglutarate crystalline Form 1 according to claim 55, wherein the ketoglutarate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 19.

60. The ketoglutarate crystalline Form 1 according to claim 55, wherein the ketoglutarate crystalline Form 1 has a thermogravimetric analysis (“TGA”) profile substantially as shown in FIG. 19.

61. An oxalate crystalline Form 1 of 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(21S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5 / / -pyrido[3,4-< / ]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.

62. The oxalate crystalline Form 1 according to claim 61, wherein the oxalate crystalline form has an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 12.9±0.2, 17.8±0.2, 19.6±0.2, and 22.8±0.2.

63. The oxalate crystalline Form 1 according to claim 61, wherein the oxalate crystalline Form 1 has an X-ray powder diffraction 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.

64. The oxalate crystalline Form 1 according to claim 61, wherein the oxalate crystalline Form 1 has an XRPD pattern substantially as shown in FIG. 21.

65. The oxalate crystalline Form 1 according to claim 61, wherein the oxalate crystalline Form 1 has a DSC thermogram substantially as shown in FIG. 23.

66. The oxalate crystalline Form 1 according to claim 61, wherein the oxalate crystalline Form 1 has a thermogravimetric analysis (“TGA”) profde substantially as shown in FIG. 23.

67. The crystalline form according to any one of claims 1-66, wherein the crystalline form is substantially free of residual organic solvents.

68. The crystalline form according to any one of claims 1-67, wherein the crystalline form is a hydrate.

69. The crystalline form according to any one of claims 1-67, wherein the crystalline form is anhydrous.

70. A pharmaceutical composition, comprising a therapeutically effective amount of a crystalline form of a salt of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-577-pyrido[3,4-t ]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile according to any one of claims 1-69.

71. The pharmaceutical compositions according to claim 70, further comprising at least one pharmaceutically acceptable excipient and / or diluent.

72. A method 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 according to any one of claims 1-69, alone or in combination with one or more pharmaceutically acceptable excipient and / or diluent.

73. A method for treating cancer in a subject in need thereof comprising administering to the subject with a therapeutically effective amount of a crystalline form according to any oneof claims 1 -69, alone or in combination with one or more pharmaceutically acceptable excipient and / or diluent.

74. The method according to claim 73, wherein the therapeutically effective amount of the crystalline form of the KRas G12C inhibitor is between about 0.01 to 100 mg / kg per day.

75. The method according to claim 73, wherein the therapeutically effective amount of the crystalline form of the KRas G12C inhibitor is between about 0.1 to 50 mg / kg per day.

76. The method of claim 73, wherein the cancer is selected from the group consisting of 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, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial ' carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

77. The method according to claim 73, wherein the cancer is a KRas G12C-associated cancer.

78. The method according to claim 73, wherein the cancer is non-small cell lung cancer.

79. The method according to claim 73, wherein the subject is an adult patient.

80. The method according to claim 73, wherein the subject is a pediatric patient.

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