WO2022056307A1 - Crystalline forms of a kras g12c inhibitor - Google Patents

Crystalline forms of a kras g12c inhibitor Download PDF

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Publication number
WO2022056307A1
WO2022056307A1 PCT/US2021/049940 US2021049940W WO2022056307A1 WO 2022056307 A1 WO2022056307 A1 WO 2022056307A1 US 2021049940 W US2021049940 W US 2021049940W WO 2022056307 A1 WO2022056307 A1 WO 2022056307A1
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Prior art keywords
crystalline form
ray powder
powder diffraction
crystalline
diffraction pattern
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English (en)
French (fr)
Inventor
Patricia Andres
Samuel ANDREW
Cheng Yi Chen
Susana Del Rio Gancedo
Tawfik Gharbaoui
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Mirati Therapeutics Inc
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Mirati Therapeutics Inc
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Priority to KR1020237012251A priority Critical patent/KR20230137286A/ko
Priority to MX2023002942A priority patent/MX2023002942A/es
Priority to BR112023004569A priority patent/BR112023004569A2/pt
Priority to US18/025,817 priority patent/US12286431B2/en
Priority to JP2023516126A priority patent/JP2023540809A/ja
Priority to AU2021340716A priority patent/AU2021340716A1/en
Priority to IL301236A priority patent/IL301236A/en
Priority to CN202180062631.4A priority patent/CN116601151A/zh
Priority to EP21867707.8A priority patent/EP4210833A4/en
Application filed by Mirati Therapeutics Inc filed Critical Mirati Therapeutics Inc
Priority to CA3190944A priority patent/CA3190944A1/en
Publication of WO2022056307A1 publication Critical patent/WO2022056307A1/en
Anticipated expiration legal-status Critical
Priority to CONC2023/0004141A priority patent/CO2023004141A2/es
Priority to ZA2023/04180A priority patent/ZA202304180B/en
Priority to US18/782,879 priority patent/US12281113B2/en
Priority to US19/088,148 priority patent/US20250282778A1/en
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to crystalline forms of a KRas G12C inhibitor.
  • the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-
  • compositions comprising the crystalline forms, processes for preparing the crystalline forms and methods of use thereof.
  • KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
  • GDP-bound inactive
  • GTP-bound active
  • cellular proliferation e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13 :394-401 ).
  • 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-1 1-3265).
  • KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).
  • a covalent, irreversible inhibitor of KRas G12C is 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2- [[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro ⁇ 5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2- fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile, also known as MRTX849.
  • Process development for pharmaceutical compositions plays an important role for solid pharmaceutical compounds in balancing the desired pharmacological properties of the therapeutic agent, For example, identifying an appropriate crystalline forms and salt forms of the solid therapeutic agent can beneficially influence the dissolution rate, solubility, bioavailability, manufacturing, packaging and/or storage shelf life of the pharmaceutical composition.
  • crystalline forms may be pressed into tablets for oral delivery as opposed to the need to use a capsule or spray-dry form for amorphous compounds.
  • KRas G12C inhibitor in particular 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-yr]acetonitrile, that provides 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.
  • the crystalline form is designated crystalline Form A
  • crystalline Form A has an X-ray powder diffraction pattern (“XRPD”) comprising at least one characteristic peak at °20 values selected from 8.6 ⁇ 0.2, 14.6 ⁇ 0.2. 16.9 ⁇ 0.2 and 18.3 ⁇ 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.
  • XRPD X-ray powder diffraction pattern
  • crystalline Form A has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • crystalline Form A has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 7.1 ⁇ 0.2, 8.6 ⁇ 0.2. 11.7 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0,2, i 6.0 ; 0.2, 16.9 ⁇ 0.2.
  • crystalline Form A has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A has an XRPD pattern substantially as shown in FIG. 1 A or ' FIG I B.
  • crystalline Form A is characterized by having an endothermic peak onset at about 107°C with a heat of fusion of 46 J/g as measured by differential scanning calorimetry' (“DSC”).
  • crystalline Form A has a DSC thermogram substantially as shown in FIG. 2.
  • crystalline Form A is characterized by having an endothermic peak onset at about 1 19°C with a heat of fusion of 58 J/g as measured by differential scanning calorimetry (“DSC”).
  • crystalline Form A has a DSC thermogram substantially as shown in FIG. 11.
  • Form A 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 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • Form A has both: I) one or more DSC characteristics described above: and 2) an X-ray powder diffraction pattern comprising at least one peak at °20 selected from 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 183 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • crystalline Form A is characterized by having negligible weight loss until the onset of degradation at about 200°C as measured by thermogravimetric analysis (“TGA”). In another embodiment, crystalline Form A has a TGA profile substantially as shown in FIG. 3.
  • Form A 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 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2,
  • Form A 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 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A is characterized by having an observed weight gain from about 0.1 % at 40 % RH to 0.6 % at 90 % RH, fully lost upon desorption to 0 % RH, Cycles repeat show little to no hysteresis, as measured by dynamic vapor sorption (“DVS”).
  • DVD dynamic vapor sorption
  • crystalline Form A has a DVS isotherm substantially as shown in FIG. 4.
  • Form A has both: 1) one or more D VS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2 ⁇ selected from 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9+0.2 and 25.5 ⁇ 0.2.
  • Form A 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 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A is substantially free of residual organic solvents.
  • the crystalline form is designated crystalline Form B.
  • crystalline Form B has an X-ray powder diffraction pattern comprising at least one characteristic peak at °20 values selected from 16.7 ⁇ 0.2, 17.5 ⁇ 0.2 and 18.8 ⁇ 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.
  • crystalline Form B has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19,9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 9.1 ⁇ 0.2. 11.2 ⁇ 0.2, 11.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.3 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.4 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 20.4 ⁇ 0.2, 21 ,4 ⁇ 0.2, 21.8 ⁇ 0.2, 22.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.4 ⁇ 0.2, 23.7 ⁇ 0.2, 24.0 ⁇ 0.2, 24.3 ⁇ 0.2, 24.7 ⁇ 0.2, 25.1 ⁇ 0.2, 25.6 ⁇ 0,2, 25.8 ⁇ 0.2, 26.3 ⁇ 0.2, 26.7 ⁇ 0.2, 27.3 ⁇ 0.2, 27.6 ⁇ 0.2, 28.6 ⁇ 0.2, 29.4 ⁇ 0.2, 29.7 ⁇ 0.2 and 30.0 ⁇
  • crystalline Form B has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17,9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19,9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B has XRPD pattern substantially as shown in FIG. 5 A or in FIG. 5B.
  • crystalline Form B as measured by DSC as shown in FIG, 12 is characterized by having an endothermic peak onset at about 122°C and a heat of fusion of 61 J/g.
  • crystalline Form B as measured by DSC is characterized by having an endothermic peak onset at about 109°C with a heat of fusion of 49 J/g. In one embodiment, crystalline Form B has a DSC thermogram substantially as shown in FIG. 6.
  • Form B has both: 1) one or more DSC characteristics described abo ve; and 2) an X-ray po wder diffraction pattern comprising at least one peak at °2 ⁇ selected from 5.8 ⁇ 0.2, 13,3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18,1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23,7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B as measured by TGA is characterized by having a 0.6 % weight loss from 25 to 150 °C with no further events until degradation onset at • -200 °C.
  • crystalline Form B has a TGA profile substantially as shown in FIG. 7.
  • crystalline Form B as measured by DVS as shown in FIG. 8 is characterized by having a weight gain from about 0.6 % at 60 % RH to 2.9 % at 70 % RH, further increasing to 2.5 % at 90 % RH. Following a weight loss to 2.2% from 90% RH to 70% RH, a rapid weight loss is observed from 70 to 50 % RH with a weight change from 2.2 % to 0.4 %. Constant gentle decrease in weight to 0 % from 50 to 0 % RH is observed. Cycles repeat showing little hysteresis.
  • Form B 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 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.71-0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B is substantially free of residual organic solvents.
  • the crystalline form is designated crystalline Form C.
  • crystalline Form C has an X-ray powder diffraction pattern comprising at least one characteristic peak at "20 value selected from 16.4 ⁇ 0.2 and 19.7 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present.
  • crystalline Form C has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C has an X-ray powder diffraction pattern comprising peaks at "20 values of 5.7 ⁇ 0.2, 9.0 ⁇ 0.2, 11.0 ⁇ 0.2, 11.3 ⁇ 0.2, 12.3 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.1 ⁇ 0.2, 15.5 ⁇ 0.2, 15.8 ⁇ 0.2, 16.4 ⁇ 0.2, 17.1 ⁇ 0.2, 17.3 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 18.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19,3 ⁇ 0.2, 19.7 ⁇ 0.2, 21.1 ⁇ 0.2, 21.5 ⁇ 0.2, 21.8 ⁇ 0.2, 22.1 ⁇ 0.2, 22.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.2 ⁇ 0.2, 23.6 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2, 24.7 ⁇ 0.2, 25.2 ⁇ 0.2, 26.3 ⁇ 0.2, 26.7 ⁇ 0.2, 27.2+0.2, 28.1 ⁇ 0.2, 29.0 ⁇ 0.2, 29,4 ⁇ 0.2 and 29.8 ⁇ 0.2.
  • crystalline Form C has an X-ray powder diffraction pattern comprising two or more peaks at °20 values at 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7+0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C has XRPD pattern substantially as shown in FIG. 9. [00461 In one embodiment, crystalline Form C as measured by DSC is characterized by having a small endothermic peak onset about 58°C and a strong endothermic peak onset at about
  • crystalline Form C has a DSC thermogram substantially as shown in FIG. 10.
  • Form C 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 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C as measured by TGA is characterized by having a stepwise loss of mass of about 1.2% from about 45"C to about 86 C C until the onset of degradation at about 260°C.
  • crystalline Form C has a TGA profile substantially as shown in FIG. 10.
  • Form C has both: 1 ) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak al °29 selected from 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C is a hydrate.
  • the crystalline form is designated crystalline Form I).
  • crystalline Form D has an X-ray powder diffraction pattern comprising at least one characteristic peak.
  • crystalline Form D has an X-ray powder diffraction pattern comprising a characteristic peak at a °2 ⁇ value of 4.4 ⁇ 0.2.
  • crystalline Form D has an X-ray powder diffraction pattern comprising peaks at "20 values of 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D has an X-ray powder diffraction patient comprising peaks at °20 values of 4.4 ⁇ 0.2, 8.9 ⁇ 0.2, 10.0 ⁇ 0.2, 11.2 ⁇ 0.2, 12.3 ⁇ 0.2, 12.7 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 14.3 ⁇ 0.2, 15.2 ⁇ 0.2, 16.1 ⁇ 0.2, 16.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7-10.2, 18.0 ⁇ 0.2, 18.6 ⁇ 0.2, 19.2 ⁇ 0.2, 20.1 ⁇ 0.2, 20.9 ⁇ 0.2, 21.2 ⁇ 0.2, 21.8 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 24.7 ⁇ 0.2, 25.2 ⁇ 0.2, 26.1 ⁇ 0.2, 26.3 ⁇ 0.2, 27.2 ⁇ 0.2, 27.6 ⁇ 0.2, 27.9 ⁇ 0.2, 28.3 ⁇ 0.2, 29.0 ⁇ 0.2 and 29.2 ⁇ 0.2.
  • crystalline Form D has an X-ray powder diffraction pattern comprising two or more peaks at °20 value at 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20,9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D has XRPD patern substantially as shown in FIG. 13.
  • crystalline Form D is characterized by having an endothermic peak with a maximum at about 84°C and another endothermic peak with a maximum at about 110°C by differentia! scanning calorimetry.
  • crystalline Form D has a DSC thermogram substantially as shown in FIG. 14.
  • crystalline Form D has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2 ⁇ selected from 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2.
  • crystalline Form D as measured by TGA is characterized by having a stepwise loss of mass of about 4.3% from about 45°C to about 1 16°C until the onset of degradation at about 260°C.
  • crystalline Form D has a TGA profile substantially as shown in FIG. 14.
  • crystalline Form D is a hydrate
  • crystalline Form D has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2 ⁇ selected from 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • the crystalline form is designated crystalline Form E.
  • crystalline Form E has an X-ray powder diffraction pattern comprising at least one characteristic peak.
  • crystalline Form E has an X-ray powder diffraction pattern comprising at least one characteristic peak at. °20 values selected from 5.2 ⁇ 0.2 and 10.2 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present.
  • crystalline Form E has an X-ray powder diffraction pattern comprising peaks at °2 ⁇ values of 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2, 21.9 ⁇ 0.2.
  • crystalline Form E has an X-ray powder diffraction pattern comprising peaks at °2 ⁇ values of 5.2 ⁇ 0.2, 9.2 ⁇ 0.2, 10.2 ⁇ 0.2, 1 1.2 ⁇ 0.2, 11.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 15,4 ⁇ 0.2, 16.4 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0+0.2, 19.4 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2, 21.0 ⁇ 0.2, 21.3 ⁇ 0.2, 21.9 ⁇ 0.2, 22.4 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 23.8 ⁇ 0.2, 24.2 ⁇ 0.2, 25.7 ⁇ 0.2, 26.8 ⁇ 0.2, 27.2 ⁇ 0.2, 27.4 ⁇ 0.2, 27.9 ⁇ 0.2, 28.6 ⁇ 0.2 and 29.0 ⁇ 0.2.
  • crystalline Form E has an X-ray powder diffraction pattern comprising two or more peaks at °20 value at 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 1 1 .8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.9 ⁇ 0.2.
  • crystalline Form E has an XRPD pattern substantially as shown in FIG. 15.
  • crystalline Form E as measured by DSC is characterized by having an endothermic peak onset at about 99°C and a heat of fusion of 47 J/g.
  • crystalline Form E has a DSC thermogram substantially as shown in FIG. 16.
  • crystalline Form E has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction patern comprising at least one peak at °20 selected from 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11.8 ⁇ 0.2, 13.5 ⁇ 0.2. 14.3 ⁇ 0.2, 16.9 ⁇ 0.2,
  • crystalline Form E as measured by TGA is characterized by having negligible loss of mass for crystalline Form E up to about 94°C through the onset of degradation at about 240°C.
  • crystalline Form E has a TGA profile substantially as shown in FIG. 17.
  • crystalline Form E 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 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3.-10.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5+0.2 and 21.9 ⁇ 0.2.
  • crystalline Form E as measured by DVS is characterized by having a gradual weight gain of 1.2% between 5% to 95% RH. During desorption, the weight gained was lost with some hysteresis.
  • crystalline Form E has a DVS isotherm substantially as shown in FIG. 18.
  • crystalline Form E 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 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 1 1.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21 .9 ⁇ 0.2.
  • crystalline Form E is substantially free of residual organic solvents.
  • Amorphous 2-[(2S)-4-[7-(8-chloro- 1 -naphthy I)-2-[[(2S)- 1 -methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile free base has an XRPD pattern substantially as shown in FIG. 19, and a modulated
  • a mixture of crystalline Forms A and B have an XRPD pattern substantially as shown in the bottom trace of FIG. 21.
  • the crystalline forms of the present invention are at least 40%, 50%, 60%, 70%, 80%, 90% or 95% crystalline.
  • compositions for use in the methods comprising a therapeutically effective amount of a crystalline form of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chloro-l-naphthyl) ⁇ 2-[[(2S)-l-methylpyrrolidin-2-yl]methoxj']- 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl] ⁇ l"(2-fluoroprop-2-enoyl)piperazin-2- yljacetonitrile, or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable excipient.
  • the crystalline form is Form A. In another embodiment, the crystalline form is Form B. In one embodiment, the crystalline form is Form C. In another embodiment, the crystalline form is Form D. In one embodiment, the crystalline form is Form E. In one embodiment, the crystalline form is a mixture of any two or more of Forms A - E. In another embodiment, the crystalline form is a mixture of any two or more of Forms A - E with the amorphous form.
  • the pharmaceutical compositions of the present invention contain 95% of a crystalline form of 2-[(2S) ⁇ 4-[7-(8-chloro-1 -naphthyl)-2-[[(2S)-1 -methylpyiTolidin-2- yl]methoxy]-6,8-dihydro-5H”pyrido[3,4-d]pyrimidin-4-yi]-l-(2-fiuoroprop-2-enoyl)piperazin-2- yljacetonitrile or salts thereof, In one embodiment, the pharmaceutical compositions of the present invention contain at least 95% of a crystalline form.
  • 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. In one embodiment, the crystalline form is Form A. In another embodiment, the crystalline form is Form B. In one embodiment, the crystalline form is Form C. In another embodiment, the crystalline form is Form D, In one embodiment, the crystalline form is Form E. In one embodiment, the crystalline form is a mixture of any two or more of Forms A - E. In another embodiment, the crystalline form is a mixture of any two or more of Forms A - E with the amorphous form.
  • crystalline form is Form A.
  • the crystalline form is Form B.
  • the crystalline form is Form C.
  • the crystalline form Is Form D.
  • the crystalline form is Form E.
  • the crystalline form is a mixture of any two or more of Forms A - E.
  • the crystalline form is a mixture of any two or more of Forms A - E with the amorphous form.
  • the cancer is a KRas G12C-associated cancer.
  • the KRas G12C-associated cancer is lung cancer.
  • the crystalline form is Form A.
  • the crystalline form is Form B.
  • the crystalline form is Form C.
  • the crystalline form is Form D.
  • the crystalline form is Form E.
  • the crystalline form is a mixture of any two or more of Forms A - E.
  • the crystalline form is a mixture of any two or more of Forms A - E with the amorphous form.
  • a KRas G12C mutation e.g., a KRas G12C-associated cancer
  • the crystalline form is Form A.
  • the crystalline form is Form B.
  • the crystalline form is Form C.
  • the crystalline form is Form D. In one embodiment, the crystalline form is Form E. In one embodiment, the crystalline form is a mixture of any two or more of Forms A - E. In another embodiment, the crystalline form is a mixture of any two or more of Forms A - E with the amorphous form.
  • the subject is an adult patient. In one embodiment, the subject is a pediatric patient.
  • the patient before treatment with the compositions or methods of the invention, was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful: and/or the patient has been treated with a platinumbased chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful: and/or the patient was treated with one or more other therapeutic agent(s).
  • process for the preparation of crystalline forms of the KRas G12C inhibitor describes the preparation of crystalline Form A. In one embodiment, the process describes the preparation of crystalline Form B, In one embodiment, the process describes the preparation of crystalline Form C. In one embodiment, the process describes the preparation of crystalline Form D. In one embodiment, the process describes the preparation of crystalline Form E.
  • FIG. 1 A and FIG. IB illustrate X-ray powder diffraction (XRPD) patterns of crystalline Form A free base 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]-1-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile, according to Examples 1A and IB respectively.
  • XRPD X-ray powder diffraction
  • FIG. 2 illustrates a differential scanning calorimetry (DSC) profile of crystalline Form A prepared according to Example 1A.
  • FIG. 3 illustrates a combined thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) profile of crystalline Form A prepared according to Example 1 A.
  • FIG. 4 illustrates a dynamic vapor sorption (DVS) isotherm profile of crystalline Form A prepared according to Example 1.
  • FIG. 5 A illustrates an XRPD pattern of crystalline Form B made according to Example 2D.
  • FIG. 5B illustrates an additional XRPD pattern of crystalline Form B.
  • FIG. 6 illustrates a DSC profile of crystalline Form B prepared according to Example 2B.
  • FIG. 7 illustrates a combined DSC and TGA profile of crystalline Form B prepared according to Example 2B.
  • FIG. 8 illustrates a DVS isotherm profile of crystalline Form B prepared according to Example 2B.
  • FIG. 9 illustrates an XRPD pattern of crystalline Form C prepared according to Example 3.
  • FIG. 10 illustrates a combined DSC and TGA profile of crystalline Form C prepared according to Example 3.
  • FIG. 11 illustrates a differential scanning calorimetry (DSC) profile of crystalline Form A prepared according to Example IB.
  • FIG. 12 illustrates a DSC profile of crystalline Form B prepared according to Example 2C.
  • FIG. 13 illustrates an XRPD pattern of crystalline Form D prepared according to Example 4.
  • FIG. 14 illustrates a DSC profile and TGA profile of crystalline .Form D prepared according to Example 4.
  • FIG. 15 illustrates an XRPD pattern of crystalline Form E prepared according to Example 5.
  • FIG . 16 illustrates a DSC profile of crystalline Form E prepared according to Example
  • FIG. 17 illustrates a TGA profile of crystalline Form E prepared according to Example 5.
  • FIG. 18 illustrates a DVS isotherm profile of crystalline Form E.
  • FIG. 19 illustrates an X-ray powder diffraction (XRPD) pattern of amorphous free base 2 ⁇ [(2S)-4-[7-(8-chloro-1-naphthyl)-2-[[(2S)"l-methylpyrrolidin-2-yI]methoxy]-6 , 8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile.
  • XRPD X-ray powder diffraction
  • FIG. 20 illustrates a modulated DSC profile of amorphous free base 2-[(2S)-4-[7 ⁇ (8- chloro-lmaphthyl) ⁇ 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, according to Comparative Example 3.
  • FIG. 21 illustrates a XRPD pattern of a mixture of crystalline Form A and Form B, compared to a XRPD pattern of amorphous free base 2-[(2S)-4-[7-(8-chloro-l-naphfnyl)-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 Comparative Example 4,
  • FIG. 22 illustrates a DSC profile of crystalline Form B prepared according to Example 2D.
  • FIG. 23 is a FEM image of crystals 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]acetonitriIe grown from isopropanol-heptane at 40°C.
  • a plate-like crystal was used for structure determination of Form B, and a small needle-like crystal was used for structure determination of Form A.
  • FIG. 24 is an overlay of simulated XRPD paterns of Form A (bottom), Form B simulated (b), and bulk of the starting material (c), showing the bulk was a mixture of Form A and Form B2.
  • FIG. 25 depicts the unit cell shape and structure of content in the crystal structure of 2- [(2S)-4-[7-(8-chlorO-l-naphthyl)-2-[[(2S)-l-methyIpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-y]]-l-(2 ⁇ fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Form A containing two molecules (top), and in Form B containing four molecules (bottom).
  • FIG. 26 is a PLM image of crystals of 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)- 1 - methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile grown from isopropanol-water. The structure was determined to be Form C.
  • FIG. 27 depicts the unit cell shape and structure of content in the crystal structure 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]- 1 -(2-fluoroprop-2-enoy
  • Fig. 28 displays an XRPD pattern of crystalline Form B prepared according to Example 2F.
  • the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-
  • the present invention relates to crystalline forms of the KRas G12C inhibitor 2-[(2S)-4-[7-(8-chIoro-l- naphthyd )-2-[[(2S)-I-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.
  • 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.
  • KRas G12C inhibitor refers to the KRas G12C inhibitor of the present invention: 2-[(2S)-4-[7-(8-chloro- 1 -naphthyi)-2-[[(2S) ⁇ l -methyipyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]"l-(2-fluoroprop-2-en.oyl)piperazin-2- yl]aceionitrile 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.
  • Form A or “crystalline Form A” when used alone refers to 2-[(2S)"4-[7-(8-chloro-l-naphtltyl)-2-[[(2S)-i-methylpyrrolidin-2-yI]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitri1e Form A.
  • Form B or “crystalline Form B” when used alone refers to
  • Form C or “crystalline Form C” when used alone refers to
  • Form D or “crystalline Form D” when used alone refers to 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-yr]acetonitrile Form D.
  • Form E or “crystalline Form E” when used alone refers to 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 Form E.
  • solvate refers to a crystalline form of the KRas G12C inhibitor which contains solvent.
  • hydrate refers io a solvate wherein the solvent comprises water.
  • solvents refers to organic volatile chemicals used or produced during the crystallization/manufacturing processes that are not completely removed during the manufacturing technique.
  • the term “substantially free of residua) organic solvents” means that the manufactured pharmaceutical preparation, e.g., a pharmaceutical preparation comprising a crystalline form 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 jacetonitrile or a crystalline form of a salt thereof, 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 solvent
  • KRas G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
  • a non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
  • the term “subject,” “individual,” or “patient,” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the patient is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented,
  • the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency- approved, e.g., FDA-approved, assay or kit).
  • the subject can be a subject whose tumors have a K Ras G12C mutation (e.g., where the tumor is identified as such using a regulatory agency- approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a KRas G12C gene-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a KRas GT2C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment.
  • the term “pediatric’’ can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
  • an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis.
  • a sample e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample
  • a patient e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated
  • Northern blotting and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR).
  • 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.
  • regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
  • regulatory agency is the U.S. Food and Drug Administration (FDA).
  • a "therapeutically effective amount" of a crystalline form of 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-enoy l)piperazin-2-yl]acetonitrile or salt thereof is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
  • treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
  • amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administra tion of the composition.
  • the term "about” when used to modify a numerically defined parameter means that the parameter may vary' by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter. For example, about 0.5 mg, 0.75 mg or 1 .0 mg means about 0.5 mg, about 0.75 mg or about 1 .0 mg. Likewise, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.
  • the term “about” when used in reference to XRPD peak positions refers to the inherent variability of peaks depending on the calibration of the instrument, processes used to prepare the crystalline forms of the present invention, age of the crystalline forms and the type of instrument used in the analysis.
  • the variability of the instrumentation used for XRPD analysis was about ⁇ - 0,2 °2 ⁇ .
  • Crystalline forms may be analyzed using any suitable analytical method or assay procedure including, but not limited to, X-Ray Powder Diffraction, NMR, differential scanning calorimetry, thermo-gravimetric analysis, and gravimetric vapor sorption to assure formation of the preferred crystalline form of the KRas G12C inhibitor.
  • the crystalline form is typically produced in an amount of greater that 50% by weight isolated yield, greater that 60% by weight isolated yield, greater that 70% by weight isolated yield, greater that 80% by weight isolated yield, greater that 90% by weight, isolated yield or greater that 95% by weight isolated yield.
  • the crystalline forms of the present invention are at least 40%, 50%. 60%, 70%, 80%, 90% or 95% crystalline.
  • PANalytical X’Pert Pro MPD diffractometer using an incident beam of Cu Ka radiation produced in a long fine focused source and a nickel, and in accordance with the manufacturer’s instructions.
  • the diffractometer was configured using the symmetric Bragg- Brentano geometry.
  • a silicon specimen (NIST SRM 640e) was analyzed to verity the observed position of the Si 111 peak is consistent with NIST-certified position
  • a specimen of the sample was prepared as a thin, circular layer center on a silicon zero-background substrate.
  • Anti-scatter slits (SS) were used to minimize the background generated by air.
  • Seller slits for the incident and diffracted beams to minimize broadening from axial divergence.
  • Diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the sample.
  • the software used for data collection and analysis was Data
  • DSC Differential Scanning Calorimetry
  • each sample was placed in a hermetically sealed aluminium DSC pan, the sample was weighed and the lid was pierced, and inserted into the DSC cell.
  • a second aluminum DSC pan of the same weight was configured as the sample pan for the reference side of the cell, and the lid was pierced. Data were collected from 25°C to 350°C at 10°C/min.
  • DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to 300°C. A purge of dry nitrogen at 50 ml/min was maintained over the sample. Modulated temperature DSC was carried out using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every' 60 seconds (period). The instrument control software was Advantage for Q Series and Thermal Advantage and the data were analysed using Universal Analysis.
  • DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5 - 3 mg of each sample, in a pin-holed aluminium pan, was heated at 10 °C/min from 25 °C to -300 °C. A purge of dry' nitrogen at 50 ml/min was maintained over the sample.
  • the instrument control software was TRIOS and the data were analysed using TRIOS or Universal Analysis.
  • TGA analysis or combined DSC/TGA analysis was performed using a Mettler-Toledo TGA/DSC3 ⁇ analyzer according to the manufacturer’s instructions. The temperature and enthalpy were adjusted using indium, tin and zinc, and verified using indium. The balance was verified using calcium oxalate. Typically, each sample was loaded into an open aluminium DSC pan, the pan was hermetically sealed, the lid was pierced, the pan was inserted into the TGA furnace and heated at 10 °C/min from ambient temperature to 350 °C under a nitrogen purge.
  • Vapor Sorption isotherms were obtained using a Surface Measurement System (SMS) DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software.
  • SMS Surface Measurement System
  • Solution NMR spectra were acquired using an Avance 600 MHz NMR spectrometer according to the manufacturer’s instructions. Sample were prepare by solving about 5-10 mg of sample in DMSO d6 ⁇ containing TMS.
  • KRAS G12C IN HIBITOR In one aspect of the invention, provided herein are crystalline forms of the KRAS G12C inhibitor 2-[(2S)-4-[7-(8-chloro-l-naphthyl)-2-[[(2S)-1-methyIpyrroIidin-2-yl]methoxy]-
  • FIG. 19 As shown in FIG. 19, the XRPD pattern of the amorphous free base lacks any characteristic peaks.
  • the DSC thermogram shows a glass transition temperature of ⁇ 70°C, which is a relatively low glass transition temperature and therefore known to be associated with processability difficulties and increased physical and chemical instability due to greater molecular mobility within the solid.
  • the crystalline form is designated crystalline Form A.
  • crystalline Form A has an X-ray powder diffraction pattern (“XRPD”) comprising at least one characteristic peak at °20 values selected from 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9+0.2 and 18.3
  • ⁇ 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.
  • crystalline Form A has an X-ray powder diffraction pattern comprising peaks at °20 values of 5, 8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18,1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4+0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • crystalline Form A has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 7.1 ⁇ 0.2, 8.6 ⁇ 0.2, 11.7+0.2, 12.3 ⁇ 0.2, 13,0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 17.2 ⁇ 0.2, 17.6 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 19.4 ⁇ 0.2, 19.7 ⁇ 0.2, 20.4 ⁇ 0.2, 20.7 ⁇ 0.2, 21.2 ⁇ 0.2, 21 ,4 ⁇ 0.2, 21.8 ⁇ 0.2, 22.7 ⁇ 0.2, 23.0 ⁇ 0.2, 23.5 ⁇ 0.2, 23.9 ⁇ 0.2, 24.7 ⁇ 0.2, 25.5 ⁇ 0.2, 26.2 ⁇ 0.2, 26.4 ⁇ 0.2, 27.2 ⁇ 0.2, 28.0 ⁇ 0.2, 28.2 ⁇ 0.2 and 29.6 ⁇ 0.2.
  • crystalline Form A has an X-ray powder diffraction pattern comprising two or more peaks at °2 ⁇ at 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A has an XRPD pattern substantially as shown in FIG. 1.
  • crystalline Form A is characterized by having an endothermic peak onset at about 107°C with a heat effusion of 46 J/g as measured by differential scanning calorimetry (“DSC”). In another embodiment, crystalline Form A has a DSC thermogram substantially as shown in FIG. 2. In one embodiment, crystalline Form A is characterized by having an endothermic peak onset at about 119°C with a heat of fusion of 58 J/g as measured by differential scanning calorimetry (“DSC”). In another embodiment, crystalline Form A has a
  • Form A has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2G selected from 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16,9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • Form A has both: 1) one or more DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2G selected from 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2,
  • crystalline Form A is characterized by having negligible weight loss until degradation starting at about 200°C as measured by thermogravimetric analysis (“TGA”). In another embodiment, crystalline Form A has a TGA profile substantially as shown in FIG. 3.
  • Form A has both: I) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2 ⁇ selected from 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • Form A has both: 1) one or more TGA characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2 ⁇ selected from 8.6 ⁇ 0.2, 14.6 ⁇ 0.2. 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A is characterized by having an observed weight gain from 0.4% from 5% to 90% RH and as RH declined during desorption, the observed weight gain was lost as measured by dynamic vapor sorption (“DVS”).
  • crystalline Form A has a DVS isotherm substantially as shown in FIG. 4.
  • Form A has both: 1 ) one or more DVS characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2G selected from 5.8 ⁇ 0.2, 8.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 14.2 ⁇ 0.2, 14.6 ⁇ 0.2, 16.0 ⁇ 0.2, 16.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.3 ⁇ 0.2, 20.4 ⁇ 0.2, 21.2 ⁇ 0.2, 23.9 ⁇ 0.2 and 25.5 ⁇ 0.2.
  • Form A 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 8.6 ⁇ 0.2, 14.6 ⁇ 0.2, 16.9 ⁇ 0.2 and 18.3 ⁇ 0.2.
  • crystalline Form A is substantially free of residual organic solvents.
  • the crystalline form is designated crystalline Form B.
  • crystalline Form B has an X-ray powder diffraction pattern comprising at least one characteristic peak at °20 values selected from 16.7 ⁇ 0,2, 17.5 ⁇ 0.2 and 18.8 ⁇ 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.
  • crystalline Form B has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0,2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystal Line Form B has an X-ray powder diffraction pattern comprising peaks at °2 ⁇ values of 5.8 ⁇ 0.2, 9.1 ⁇ 0.2, 1 1.2 ⁇ 0, 2, 11.6 ⁇ 0.2, 12.3 ⁇ 0.2, 13.0 ⁇ 0.2, 13.3 ⁇ 0.2, 13.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 14.5 ⁇ 0.2, 15.3 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.4+0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.4 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5+0.2, 19.9 ⁇ 0.2, 20.4 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 22.6 ⁇ 0.2, 23.1 ⁇ 0.2, 23.4 ⁇ 0.2, 23.7+0.2, 24.0 ⁇ 0.2, 24.3 ⁇ 0.2, 24.7 ⁇ 0.2, 25.1 ⁇ 0.2, 25.6 ⁇ 0.2, 25.8 ⁇ 0.2, 26.3 ⁇ 0.2, 26.7 ⁇ 0.2, 27.3 ⁇ 0.2, 27.6 ⁇ 0.2, 28.6 ⁇ 0.2, 29.4 ⁇ 0.2, 29.7 ⁇ 0.2 and 30.0 ⁇
  • crystalline Form B has an X-ray powder diffraction pattern comprising two or more peaks at °20 at 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15,6 ⁇ 0.2.
  • crystalline Form B has an XRPD pattern substantially as shown in FIG. 5 A or in FIG, 5B.
  • crystalline Form B is characterized by having negligible weight loss up to 1 1 1°C and having an endothermic peak onset at about 118°C with a heat of fusion of 49 J/g as measured by DSC.
  • crystalline Form B has a DSC thermogram substantially as shown in FIG. 6.
  • Form B 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 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B as measured by TGA is characterized by having a negligible weight loss of mass for crystalline Form B up to about 111 °C until the onset of degradation at about 250°C
  • crystalline Form B has a TGA profile substantially as shown in FIG. 7.
  • Form B 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 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B as measured by DVS is characterized by having a weight gain of 0.2 wt% between 5% and 55% RH, increasing by 3.5% between 55% and 95% RH.
  • the weight gain corresponds to 1.3 mol water. During desorption, the weight gain was lost with some hysteresis.
  • crystalline Form B has a DVS isotherm substantially as shown in FIG. 8.
  • crystalline Form B as measured by DVS as shown in FIG. 8 is characterized by having a weight gain from about 0.6 % at 60 % RH to 2.9 % at 70 % RH, further increasing to 2.5 % at 90 % RH. Following a weight loss to 2.2% from 90% RH to 70% RH, a rapid weight loss is observed from 70 to 50 % RH with a weight change from 2.2 % to 0.4 %. Constant gentle decrease in weight to 0 % from 50 to 0 % RH is observed. Cycles repeat showing little hysteresis.
  • Form B 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 5.8 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.6 ⁇ 0.2, 15.9 ⁇ 0.2, 16.7 ⁇ 0.2, 17.5 ⁇ 0.2, 17.9 ⁇ 0.2, 18.1 ⁇ 0.2, 18.8 ⁇ 0.2, 19.5 ⁇ 0.2, 19.9 ⁇ 0.2, 21.4 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.7 ⁇ 0.2 and 24.7 ⁇ 0.2.
  • crystalline Form B is substantially free of residual organic solvents.
  • the crystalline form is designated crystalline Form C.
  • crystalline Form C has an X-ray powder diffraction pattern comprising at least one characteristic peak at °20 value selected from 16.4 ⁇ 0.2 and 19.7 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present.
  • crystalline Form C has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.7 ⁇ 0.2, 9.0 ⁇ 0.2, 11.0 ⁇ 0.2, 11.3 ⁇ 0.2, 12.3 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.1 ⁇ 0.2, 15.5 ⁇ 0.2, 15.8 ⁇ 0.2, 16.4 ⁇ 0.2, 17.1 ⁇ 0.2, 17.3 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 18.4 ⁇ 0.2, 18.6 ⁇ 0.2, 19.3 ⁇ 0.2, 19.7 ⁇ 0.2, 21.1 ⁇ 0.2, 21.5 ⁇ 0.2, 21.8 ⁇ 0.2, 23.1 ⁇ 0.2, 23.2 ⁇ 0.2, 23.6 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2, 24.7 ⁇ 0.2, 25.2 ⁇ 0.2, 26.3 ⁇ 0.2, 26.7 ⁇ 0.2, 27.2 ⁇ 0.2, 28.1 ⁇ 0.2, 29.0 ⁇ 0.2, 29.4 ⁇ 0.2 and 29.8 ⁇ 0.2.
  • crystalline Form C has an X-ray powder diffraction pattern comprising two or more peaks at °20 values at 5, 7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C has an XRPD pattern substantially as shown in FIG. 9. [0198] In one embodiment, crystalline Form C is characterized by having a small endothermic peak onset about 58°C and a strong endothermic peak onset at about 118°C by DSC. In one embodiment, crystalline Form C has a DSC thermogram substantially as shown in FIG. 10.
  • Form C 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 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2, 19.7 ⁇ 0.2, 23.2 ⁇ 0.2, 23.7 ⁇ 0.2, 24.4 ⁇ 0.2 and 26.7 ⁇ 0.2.
  • crystalline Form C as measured by TGA is characterized by having a gradual loss of mass for crystalline Form C of 1.2% from about 45°C to about 86°C until the onset of degradation at about 260°C.
  • crystalline Form C has a TGA profile substantially as shown in FIG. 10.
  • Form C 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 5.7 ⁇ 0.2, 13.3 ⁇ 0.2, 13.9 ⁇ 0.2, 14.2 ⁇ 0.2, 15.5 ⁇ 0.2, 16.4 ⁇ 0.2, 17.8 ⁇ 0.2, 18.0 ⁇ 0.2,
  • crystalline Form C is substantially free of residual organic solvents.
  • crystalline Form C is a hydrate
  • the crystalline form is designated crystalline Form D.
  • crystalline Form D has an X-ray powder diffraction pattern comprising at least one characteristic peak.
  • crystalline Form D has an X-ray powder diffraction pattern at a °20 value of 4.4 ⁇ 0.2.
  • crystalline Form D has an X-ray powder diffraction pattern comprising peaks at °20 values of 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.1 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D has an X-ray powder diffraction pattern comprising peaks at °20 values of 4.4 ⁇ 0.2, 8.9 ⁇ 0.2, 10.0 ⁇ 0.2, 11.2 ⁇ 0.2, 12.3 ⁇ 0.2, 12.7 ⁇ 0.2, 13.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 14.3 ⁇ 0.2, 15.2 ⁇ 0.2, 16.1 ⁇ 0.2, 16.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 18.6+0.2, 19.2 ⁇ 0.2, 20.1+0.2, 21.2 ⁇ 0.2, 21.8 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0+0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 24.7+0.2, 25.2 ⁇ 0.2, 26.1 ⁇ 0.2, 26.3 ⁇ 0.2, 27.2 ⁇ 0.2, 27.6 ⁇ 0.2, 27.9+0.2, 28.3 ⁇ 0.2, 29.0 ⁇ 0.2 and 29.2 ⁇ 0.2.
  • crystalline Form I has an X-ray powder diffraction pattern comprising two or more peaks at °20 value at 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13,8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D has XRPD pattern substantially as shown in FIG. 13.
  • crystalline Form D is characterized by having an endothermic peak maximum at about 84°C and another endothermic peak with a peak maximum at about 110°C by differential scanning calorimetry. In one embodiment, crystalline Form D has a DSC thermogram substantially as shown in FIG. 14.
  • crystalline Form D 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 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D as measured by TGA is characterized by having a gradual loss of mass for crystalline Form D of 4.3% from about 45°C to about. 116°C until the onset of degradation at about 260°C.
  • crystalline Form D has a TGA profile substantially as shown in FIG. 14.
  • crystalline Form D 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 4.4 ⁇ 0.2, 13.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.2 ⁇ 0.2, 16.3 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 20.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.0 ⁇ 0.2, and 27.6 ⁇ 0.2.
  • crystalline Form D is substantially free of residual organic solvents
  • crystalline Form D is a hydrate.
  • the crystalline form is designated crystalline Form E.
  • crystalline Form E has an X-ray powder diffraction pattern comprising at least one characteristic peak.
  • crystalline Form E has an X-ray powder diffraction pattern comprising at least one characteristic peak at °20 values selected from 5.2 ⁇ 0.2 and 10.2 ⁇ 0.2. In some embodiments only a single characteristic peak is present. In some embodiments two characteristic peaks are present.
  • crystalline Form E has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.2 ⁇ 0.2, 9.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11.2 ⁇ 0.2. 11.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 15.4 ⁇ 0.2, 16.4 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 18.0 ⁇ 0.2, 19.4 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2, 21.0 ⁇ 0.2, 21.3 ⁇ 0.2, 21.9 ⁇ 0.2, 22.4 ⁇ 0.2, 22.7 ⁇ 0.2, 23.1 ⁇ 0.2, 23.8 ⁇ 0.2, 24.2 ⁇ 0.2, 25.7 ⁇ 0.2, 26.8 ⁇ 0.2, 27.2 ⁇ 0.2, 27.4 ⁇ 0.2, 27.9 ⁇ 0.2, 28.6 ⁇ 0.2 and 29.0 ⁇ 0.2.
  • crystalline Form E has an X-ray powder diffraction pattern comprising peaks at °20 values of 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.9 ⁇ 0.2
  • crystalline Form E has an X-ray powder diffraction pattern comprising two or more peaks at °20 value at 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11 .8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.9 ⁇ 0.2.
  • crystalline Form E has XRPD pattern substantially as shown in FIG. 15.
  • crystalline Form E as measured by DSC is characterized by having an endothermic peak onset at about 99°C and a heat of fusion of 47 J/g.
  • crystalline Form E has a DSC thermogram substantially as shown in FIG. 16.
  • crystalline Form E 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 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 11,8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21 .9 ⁇ 0.2.
  • crystalline Form E as measured by TGA is characterized by having negligible loss of mass for crystalline Form E of up to about 94°C through the onset of degradation at about 240°C.
  • crystalline Form E has a TGA profile substantially as shown in FIG. 17.
  • crystalline Form E 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 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 1 1 .8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2,
  • crystalline Form E as measured by DVS is characterized by having a gradual weight gain of 1.2% between 5% to 96% RH. During desorption, the weight gained was lost with some hysteresis.
  • crystalline Form E has a DVS isotherm substantially as shown in FIG. 18.
  • crystalline Form E 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 5.2 ⁇ 0.2, 10.2 ⁇ 0.2, 1 1.8 ⁇ 0.2, 13.5 ⁇ 0.2, 14.3 ⁇ 0.2, 16.9 ⁇ 0.2, 17.7 ⁇ 0.2, 20.3 ⁇ 0.2, 20.5 ⁇ 0.2 and 21.9 ⁇ 0.2.
  • crystalline Form E is substantially free of residual organic solvents
  • crystalline Form A is obtained by the process comprising the steps: suspending 2-[(2S)-4-[7-(8-chloro-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 in heptane; temperature cycling the resulting suspension between about 25 °C to about 80 °C; and evaporating off the heptane to obtain crystalline Form A.
  • crystalline Form A is obtained by dissolving amorphous 2-
  • crystalline Form A is obtained by dissolving 2-[(2S)-4-[7-(8- chloro- l-naphthyl)-2-[[(2S)-l-methyIpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3, 4- d]pyrimidin-4-yl] ⁇ l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile in IPA at about at 50 °C, then allowing crystals of Form A to form over time upon cooling to sub-ambient temperature.
  • the process further comprises collecting the crystalline Form A. In other embodiments, the process further comprises drying the crystalline Form A in a vacuum oven prior to or after collection.
  • the water-immiscible organic solvent is heptane.
  • crystalline Form B is obtained by the process comprising the steps: (a) suspending 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’Jacetonitrile in a mixture of water and a water-miscible organic sol vent that has been heated to about 50 °C; and (c) slowly cooling the suspension to about 5 °C to obtain crystalline Form B.
  • the sample was cooled to about 5 °C at the rate of about 0.5 °C/min.
  • the process further comprises collecting the crystalline Form B. In other embodiments, the process further comprises drying the crystalline Form B in a vacuum oven prior to or after collection.
  • the process further comprises seeding the suspension with a predetermined amount of crystalline Form B when the suspension reaches a temperature of 30 °C during step (c) to assist in crystallization.
  • the suspension was seeded with crystalline Form B at 30 °C and then cooled to 5 °C.
  • the water-miscible organic solvent is 10% water in isopropyl alcohol.
  • the water-miscible organic solvent is isopropanol.
  • 2-enoyl)piperazin-2-yl]acetonitrile is dissolved in 10 % H2O in IPA at about 50 °C, then cooled to about 5 °C at about 0.5 °C/min. In this embodiment, when the solution reaches about 30 °C it is seeded with Form B and cooling continues, resulting in a partially crystalline solid at 5 °C. In another embodiment, additional seeding steps are employed before drying under vacuum. In some embodiments the solids are analyzed by X-ray powder diffraction to confirm Form B.
  • 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]acetonitriIe is dissolved in isopropanol/water (75/25 v/v) at about 70 °C, then cooled to about 40 °C over about 30 minutes.
  • a Form B seed slurry is added to the solution, held for about an hour at about 40 °C and then cooled to about 5 °C over about 10 hours.
  • solids are collected, for instance by vacuum filtration and dried.
  • the solids are analyzed by X-ray powder diffraction to confirm Form B.
  • 2-enoyl)piperazin-2-yl]acetonitrile is dissolved in isopropanol/heptane at about 60 °C, then cooled to about 45 °C over about 15 minutes, In this embodiment, a seed slurry is added to the solution, held at successively lower temperatures until reaching about 20 C C.
  • solids are collected, for instance by vacuum filtration, and dried. In some embodiments the solids are analyzed by X-ray powder diffraction to confirm Form B.
  • 2ff(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 dissolved in 30% water:IPA at about 50 °C, then cooled to about 25 °C and seeded Form B, then cooled to about 5 °C and stirred.
  • a slurry forms and is filtered and then dried to obtain solids.
  • the solids are analyzed by X-ray powder diffraction to confirm Form B.
  • crystalline Form C is prepared by placing 2-
  • crystalline Form D is prepared by dissolving 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 isopropanol at ambient temperature, evaporating the solution at ⁇ 40 °C to obtain powdered and glassy solids, adding water to the solids and stirring, and then collecting solids by filtration, preferably vacuum filtration. In some embodiments these solids are analyzed by X-ray powder diffraction to confirm Form D.
  • crystalline Form E is prepared by placing 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 Form D in the presence of phosphorus pentoxide. In some embodiments this is accomplished by placing the Form D crystals in an open container and placing that open container in a larger vessel containing the phosphorous pentoxide. In some embodiments the resulting Form E crystals are analyzed by X- ray powder diffraction.
  • the crystalline forms of the present invention are at least 40%,
  • the crystalline forms of the anhydrous free base Forms A through E may be formulated into pharmaceutical compositions.
  • the invention provides pharmaceutical compositions crystalline forms 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 KRas G12C inhibitor and salts thereof may be formulated by any method well known in the art. and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
  • the crystalline forms of the KRas G12C inhibitor or tartrate salt are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
  • the crystalline form is Form A. In another embodiment, the crystalline form is Form B. In one embodiment, the crystalline form is Form C. In another embodiment, the crystalline form is Form D. In one embodiment, the crystalline form is Form E. In one embodiment, the crystalline form is a mixture of any of Forms A - E.
  • compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • the preparation of pharmaceutically acceptable formulations is described in, e.g.. Remington's Pharmaceutical Sciences, 18th Edition, ed. .A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
  • the term pharmaceutically acceptable salt refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
  • examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, citric acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, glutamic acid, ascorbic acid, adipic acid, aspartic, acid, cinnamic acid, lauric acid, malonic acid, nicotinic acid, galactaric acid, gentisic acid, hippuric acid, glucoheptonic acid, thiocyanic acid
  • the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR ⁇ Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, — O-alkyl, tosylate, mesylate, besylate, sulfonate, phosphate, carboxylate (such as benzoate, succinate, acetate, fumarate, glycolate, maleate, malate, citrate, tartrate, oxalate, ascorbate, cinnamate, mandelate, gentisate, hippurate), aminoacid (such as aspartate, glutamate)
  • R is hydrogen, alkyl, or benzyl
  • Z is a counterion, including chloride, bromide, iodide, — O-alkyl, tosylate, mesy
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
  • a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to about 300 mg/kg, from about 0.1 to about 100 mg/kg per day, from about 0.5 to about 50 mg/kg per day, or from about 1 to about 25 mg/kg per day.
  • a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
  • the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
  • the pharmaceutical compositions of the present invention contain at least 95% of a crystalline form. In other embodiments, the pharmaceutical compositions of the present invention contain at least 90% of a crystalline form. In another embodiment, the pharmaceutical compositions of the present invention contain at least 80% of a crystalline form. In other embodiments, the pharmaceutical compositions of the present invention contain at least 70% of a crystalline form. In one embodiment, the pharmaceutical compositions of the present in vention 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. [0256] 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.
  • compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, colorectal, pancreas, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
  • these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
  • a method for treating cancer in a subject in need thereof comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a crystalline form of the KRas G12C inhibitor, alone or in combination with or pharmaceutically acceptable excipients and/or diluents.
  • the crystalline form is Form A.
  • the crystalline form is Form B.
  • the crystalline form is Form C.
  • the crystalline form is Form D.
  • the crystalline form is Form E.
  • the crystalline form is a mixture of any of Forms A - E.
  • a crystalline form of the KRas G12C inhibitor is administered as a capsule during the period of time.
  • a tablet or capsule comprises about 10 mg to about 1500 mg, for instance about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 0 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg and about 1500 mg.
  • the method comprises oral administration of a crystalline form once or twice a day on a daily basis (during a period of time), e.g., in an amount of about about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 nig, 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 GI 2C inhibitor occurs , for example, once a day on a daily basis (during a period of time).
  • the KRAS inhibitor is orally administered once daily.
  • the crystalline form of the KRAS G12C inhibitor is orally administered twice daily.
  • the methods provided herein can result in a 1 % to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1 % to 65%, 1% to 60%, 1 % to 55%, 1 % to 50%, 1% to 45%, 1% to 40%, 1 % to 35%, 1 % to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%,
  • 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).
  • time of survival means the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing the time of survival in a mammal having a cancer are described herein.
  • any of the methods described herein can result in an increase (e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1 % to 320%, 1 % to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1 % to 200%, 1% to 180%, 1% to 160%, 1% to 140%, 1% to 120%, 1% to 100%, 1 % to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% io 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to
  • This Example illustrates the preparation of amorphous free base of 2-[(2S)-4-[7-(8- ch]oro-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)piperazm-2-yl]acetonitrile.
  • Step 1 Preparation of 107
  • N,N-dimethyl acetamide (3.75 w/w) was charged to a reactor followed by the addition of benzyl (S)-2-(cyanomethyl) piperazine- 1 -carboxylate (105, 1 w/w).
  • the reaction mixture was agitated for 5 min. and cooled to 20°C.
  • Tert-butyl 2,4-dichloro-5,8-dihydropyrid (106, 1.11 w/w) was then charged into the reactor (1.11 w/w), followed by slow addition of N,N- diisopropylethylamine (0.75 w/w).
  • reaction mixture was agitated until the reaction was complete (IPC HPLC, NMT 5% of 105) then diluted with ethyl acetate (9 w/w) and purified water (10 w/w). After 20-30 min., the reaction mixture was allowed to settle, and the aqueous and organic phases were separated. The aqueous phase was extracted back by ethyl acetate (4.5 w/w). The combined organic phase was washed sequentially three times by purified water (10 w/w), 10% sodium chloride solution (1 1 w/w), dried over Na 2 SO 4 (0-5 w/w), and then filtered.
  • Step 2 Preparation of 109
  • the combined organic phase was washed twice sequentially with 1.5% L- Cysteine solution (21.33 w/w), 10% sodium chloride solution (22.35 w/w), dried over Na2SO4 (0.5 w/w), and filtered through Nutsche Filter.
  • the reactor and the filter bed were washed with ethyl acetate (2 w/w).
  • the organic phase was concentrated under reduced pressure and the resulting residue was purified by chromatography to afford 109.
  • the aqueous phase was extracted three times with dichloromethane ( 17 w/w).
  • the combined organic phases were collected and washed with 10% sodium chloride solution (9.35 w/w), dried over Na2SO4 (0.5 w/w), filtered through Nutsche Filter.
  • the reactor and the filter bed were washed with dichloromethane (2 w/w).
  • the reaction mixture was concentrated under reduced pressure, and the resulting crude 110 was used in the following step without further purification.
  • reaction mixture temperature was raised to 75-80°C and agitated for 12 hours. After reaction was complete (IPC HPLC, NMT 5% of II 0), the mixture was cooled to 25°C and filtered through a Celite bed. The filter bed was washed with ethyl acetate (4.5 w/w). The filtrate was diluted with water (5 w/w) and the phases were separated, The aqueous phase was extracted with ethyl acetate (4,5 w/w). The combined organic phase was washed with brine solution (1 w/w), dried over NasSCU (0.5 w/w) and concentrated under reduced pressure. The resulting residue was purified by chromatography to yield 115.
  • Step 5 Preparation of 116
  • the agitation was stopped, the phases were separated, and the organic phase was collected and washed with 10% sodium bisulphite solution (6,5 w/w).
  • the two aqueous phases were combined, extracted with ethyl acetate (4.5 w/w), and the pH was adjusted to 9-10 using sodium carbonate.
  • the mixture was further extracted with ethyl acetate (2x9 w/w).
  • the combined organic phase was washed with water (5.0 w/w) followed by brine solution (0,5 w/w), dried over NacSCfi (0.5 w/w), and concentrated under reduced pressure to afford 116.
  • Step 6 Preparation of 2-[(2S)-4-[7-(8-chloro- 1 -naphthyl)-2-[[(2S) l - - methylpyrrolidin-2-yI]methoxy ]-6,8-dihydro-5H-pyrido[3,4p-dy]rimidin-4 -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile
  • Step A 2-[(2S)-4-[7-(8-chloro-l-naphthyl)"2-[[(2S)-l- methylpyrrolidin-2- yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidm-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2- yl]acetonitrile.
  • the mixture was stirred at 0 °C for 1 hour.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Gemini 150 * 25 5u; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 55% - 85%, 12min).
  • the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150 * 30mm * 4um; mobile phase: [water (0.225% FA) - ACN]; B%: 20% - 50%, 10.5min).
  • the mixture was stirred at 90 °C for 10 h under nitrogen.
  • the mixture was cooled to room temperature and was filtered through Celite; the filter cake was washed with ethyl acetate (1.50 L x 2).
  • the filtrate was adjusted to pH 2 with 1 .0 M aqueous HC1 and was washed with ethyl acetate (1 L x 2) and separated.
  • the water layer was slowly neutralized with solid Na 2 CO 3 and was then extracted with ethyl acetate (1.5 L x 3).
  • the combined organic layer was dried over Na 2 SCri, filtered and concentrated under reduced pressure.
  • a BLD-35 spray dryer was used with a solution flow rate of -25-35 g/min, pressure swirl Schlick 2.0 atomizer, 120 psig atomization pressure and outlet temperature of 45 °C. Secondary’ drying of the resulting material was performed in a tray dryer at 30 °C for approximately 19 hours.
  • Example 1 A Preparation of Crystalline Form A of 2-[(2S)-4-[7-(8-Chloro-l-naphthy])-2-[[(2S)-
  • Example I B First .Additional Preparation of Crystalline Form A of 2-[(2S)-4-[7-(8-chloro-l- naphthyr)-2-[[(2S)-l-methylpyrrolidin-2-yI]methoxy]-6 5 8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-l -(2-fluoroprop-2 ⁇ enoyl)piperazin-2-yl]acetonitrile
  • the resulting suspension was cooled to 25 °C at 0.028°C/min with aging at 35 °C for 8h, at 30 °C for 4h, and at 25 °C for approximately 12h, filtered with vacuum pull at room temperature for approximately 12 h then dried at approximately 40 °C under vacuum for approximately 72h.
  • the resulting solid material was analyzed by XRPD, which showed crystalline material.
  • the X-ray powder diffraction pattern of a 2hr dried sample of crystalline Form A is shown in FIG. 1 B, and observed peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 1.
  • Example 1C Second Additional Preparation of Crystalline Form A of 2-[(2S)-4-[7-(8-chloro-l- naphthyI)-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
  • Example 2A Preparation of Crystalline Form B of2-[(2S) ⁇ 4-[7-(8"Chloro-l-naphthyl)-2-[[(2S)- l-methylpyrrolidin-2-yl]metlioxy]-6,8 ⁇ dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2 ⁇ fluoroprop-2-enoyl)piperazin-2-yi]acetonitrile
  • Example 2B First Additional Preparation of Crystalline Form B of 2-[(2S)-4-[7-(8-chloro-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
  • the sample formed a thin grey suspension when the temperature reached 30 °C and was seeded using a 38 day old crystal preparation to assist formation of Form B and cooling continued. At 5 °C the sample had formed a thick white suspension and XRPD analysis showed partially crystalline pattern. The sample was seeded again to further enhance crystal formation and left to stir at 5 °C for 48 h. The resulting suspension comprised crystalline Form B. Sample was dried for 2 h in a vacuum oven.
  • Example 2C Second Additional Preparation of Crystalline Form B of2-[(2S)-4-[7-(8-chloro-l- naphthyl)-2-[[(2S)-l-metIiyIpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
  • a seed slurry was prepared in a separate vial by stirring 1.0 g of Form B in isopropanol/water (75/25 v/v) (10 ml) for -1 hour. After the solution in the 2 L reactor reached 40 °C, the seed slurry 'was sonicated for -1 minute and then added to the solution in the 2 L reactor. The slurry was held for 1 hour at 40 °C and then cooled to 5 °C over 10 hours. After holding at 5 °C for 2 days, solids were collected by vacuum filtration. The reactor was washed with isopropanol/water (60/40 v/v) (-400 ml) and then the wash was collected and filtered with the wet cake.
  • Example 2D Third Additional Preparation of Crystalline Form B of2-[(2S)-4-[7-(8-chloro-I- naphthyl)-2-[[(2S)-l-melhylpyrroIidin ⁇ 2-yl]methoxy]-6,8-dihydro ⁇ 5H-pyrido[3,4-d]pyrimidin-4- yl]- 1 -(2-fluoroprop-2-enoyl)piperazin--2-yl]acetonitrile [0320] 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 (36.89 g)
  • a seed slurry was prepared in a separate vial by combining 559.9 mg of Form B in isopropanol/heptane (80/20 v/v) (6.5 ml). The seed slurry was sonicated for -2 minutes then stirred at ambient temperature for ⁇ 1 hour. After the solution in the 500 ml reactor reached 40 °C, the seed slurry was sonicated for 2 minutes and then added to the solution in the 500 ml reactor. The slurry was held for 2 hours at 45 °C, cooled to 30 °C over 4 hours, held for 4 hours at 30 °C, cooled to 20 °C over 3 hours and finally held at 20 °C for 8 hours.
  • Solids were collected by vacuum filtration. The wet cake was washed two times with isopropanol/heptane (80/20 v/v) (110 ml). Solids were collected and vacuum dried at 30-40 °C for 1 day. The solids were analyzed by X-ray powder diffraction and were composed of Form B.
  • the X-ray powder diffraction pattern for crystalline Form B made according to Example 2D is shown in FIG. 5A, and observed peaks are listed in Table 2. Characteristic peaks are marked with an asterisk.
  • Example 2E Fourth Additional Preparation of Crystalline Form B of 2-[(2S)-4-[7-(8-chloro-l- naphtihyI)-2-[[(2S)-l-methylpyrrolidm-2 ⁇ yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrinudin-4- yl]-l-(2-fluoroprop"2-enoyl)piperazin ⁇ 2-y1]acetonitrile
  • the sample was cooled to 25 °C at 0.5 °C per min and seeded with 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, Form B approx. 2 mg.
  • the sample was then cooled to 5 °C at 0.5 °C/min and stirred at 5 °C overnight.
  • Example 2F Fifth Additional Preparation of Crystalline Form B 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-f]uoroprop-2-enoyl)piperaz.in-2-yl]acetonitrile
  • a seed slurry was prepared by combining 225 mg of Form B in 1.5 mL isopropanol/heptane
  • Fig. 28 displays an XRPD pattern of crystalline Form B prepared according to
  • Example 2F The sample was examined using X-ray diffractometer (Broker D8 Focus), scanned from 3° to 42° (28), at a step size 0.02° (29). The tube voltage and current were 40kV and 40 mA, respectively. A subsample was placed onto a zero background XRPD-holder and slightly pressed to make the surface smooth for the analysis.
  • the solids were composed of Form E.
  • the X-ray powder diffraction pattern for crystalline Form E is shown in FIG. 15, and observed peaks and percent peak intensities obtained from the XRPD analysis are listed in Table 5. Characteristic peaks marked with an asterisk.
  • DSC analysis of a sample of crystalline Form A made according to Example 1 A was conducted using a TA Instruments Q2000 equipped with a 50-position auto-sampler per the manufacturer’s instructions.
  • a weighed amount of crystalline Form A was placed in a pin-holed aluminum pan, and heated using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds (period) (FIG. 2) or heated at 10 °C/min from 25 °C to 300°C (FIG. 3).
  • a purge of dry nitrogen at 50 ml/min was maintained over the sample.
  • the instrument control software used was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis.
  • the DSC thermogram profile of crystalline Form A made according to Example 1 A is shown in FIG. 2. As shown in FIG. 2, crystalline Form A has endothermic peak onset at about 107°C with a heat of fusion of 46 J/g.
  • TGA analysis was conducted using a TA Instruments Q500 TGA, equipped with a 16- position auto-sampler. A weighed sample was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample.
  • the instrument control software employed for the analysis was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis.
  • FIG. 3 having negligible weight loss below the onset of degradation at 200 °C as measured by
  • DVS isotherm profile of crystalline Form A is shown in FIG. 4. As shown in FIG. 4, Form A is characterized by having an observed weight gain from about 0.1 % at 40 % RH to 0.6
  • DSC analysis of a 50 sample of crystalline Form B was conducted using a TA Instruments Q2000 equipped with a 50-position auto-sampler per the manufacturer’s instructions. Briefly, 1.661 mg of a sample of crystalline Form B was placed in a pin-holed aluminium pan, and heated using an underlying heating rate of 2 °C/min and temperature modulation parameters of ⁇ 0.636 °C (amplitude) every 60 seconds (period) from 25 °C to 330°Cz. A purge of dry' nitrogen at 50 ml/min was maintained over the sample. The instrument control software used was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis. [0336] The DSC thermogram profile of a sample of crystalline Form B is shown in FIG. 6.
  • crystalline Form B is characterized by having an endothermic peak onset at about 109°C with a heat of fusion of 49 J/g.
  • a second DSC thermogram profile of a sample of crystalline Form B is shown in FIG.
  • crystalline Form B is characterized by having an endothermic peak onset at about 122°C with a heat of fusion of 61 J/g.
  • a third DSC thermogram profile of a sample of crystalline Form B is shown in FIG, 22.
  • crystalline Form B is characterized by having an endothermic peak onset at about 112°C with a heat of fusion of 62 J/g.
  • TGA analysis was conducted using a TA Instruments Q500 TGA. equipped with a Id- position auto-sampler. Briefly, a sample of crystalline Form B was loaded onto a pre-tared aluminium DSC pan and heated at 10 °C/min from ambient temperature to 350 °C. A nitrogen purge at 60 ml/min was maintained over the sample.
  • the instrument control software employed for the analysis was Advantage for Q Series and Thermal Advantage and the data were analyzed using Universal Analysis.
  • TGA thermogram profile of crystalline Form B is shown in FIG. 7.
  • a shown in FIG. 7, crystalline Form B is characterized by having a negligible weight loss of mass up to about 111 °C until the onset of degradation at about 250°C. ⁇
  • Sorption isotherms of crystalline Form B were obtained using a SMS DVS Intrinsic moisture sorption analyzer, controlled by D VS Intrinsic Control software.
  • the sample temperature was maintained at 25 °C by the instrument controls.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min.
  • the relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH was constantly monitored by a microbalance (accuracy ⁇ 0.005 mg).
  • DVS isotherm profile of crystalline Form B is shown in FIG. 8.
  • crystalline Form B is characterized by having from about 0.6 % at 60 % RH to 2.9 % at 70 % RH, further increasing to 2.5 % at 90 % RH.
  • a weight loss to 2.2% from 90% RH to 70% RH a rapid weight loss is observed from 70 to 50 % RH with a weight change from 2.2 % to 0.4 %.
  • Constant gentle decrease in weight to 0 % from 50 to 0 % RH is observed. Cycles repeat showing little hysteresis.
  • crystalline Form C is characterized by having a small endothermic peak onset about 58°C and a strong endothermic peak onset at about 1 18°C.
  • TG analysis was performed using a Mettler-Toledo TGA/DSC3 ⁇ analyzer.
  • Temperature and enthalpy adjustments were performed using indium, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate.
  • the sample was placed in an open aluminum pan. The pan was hermetically sealed, the lid pierced, then Inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Data was collected from 25 °C to 350 °C at 10 Q C/min.
  • the TGA thermogram profile of crystalline Form C is shown in FIG. 10.
  • a shown in FIG. 10, crystalline Form C is characterized by having a stepwise loss of mass of 1.2% from about 45°C to about 86°C until the onset of degradation at about 260°C.
  • Sorption isotherms of crystalline Form C are obtained using a SMS DVS Intrinsic moisture sorption analyzer, controlled by DVS Intrinsic Control software.
  • the sample temperature is maintained at 25 °C by the instrument controls.
  • the humidity is controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min.
  • the relative humidity is measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH is constantly monitored by a microbalance (accuracy ⁇ 0.005 mg).
  • a sample of crystalline Form C is placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample is loaded and unloaded at 40 % RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm is performed as outlined below (2 scans per complete cycle).
  • the standard isotherm is performed at 25 °C at 10 % RH intervals over a 0 - 90 % RH range.
  • a double cycle (4 scans) is carried out. Data analysis is carried out within Microsoft Excel using the DVS Analysis Suite.
  • the DSC thermogram profile of a sample of crystalline Form D is shown in FIG. 14. As shown in FIG. 14, crystalline Form D is characterized by having a broad endothermic peak with a maximum at about 84°C and another endothermic peak with a peak with a maximum at about 1 KFC.
  • TG analysis was performed using a Mettler-Toledo TGA/DSC3 ⁇ analyzer.
  • Temperature and enthalpy adjustments were performed using indium, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate.
  • the sample was placed in an open aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Data was collected from 25 °C to 350 °C at 10 c C/min. [0353]
  • the TGA thermogram profile of crystalline Form D is shown in FIG. 14. A shown in
  • FIG. 14 crystalline Form D is characterized by having a stepwise loss of mass of 4.3% from about 45°C to about 1 16°C until the onset of degradation at about 260°C.
  • Sorption isotherms of crystalline Form D are obtained using a SMS DVS Intrinsic moisture sorption analyzer, controlled by D VS Intrinsic Control software.
  • the sample temperature is maintained at 25 °C by the instrument controls.
  • the humidity is controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml/min.
  • the relative humidity is measured by a calibrated Rotronic probe (dynamic range of 1.0 - 100 %RH), located near the sample.
  • the weight change, (mass relaxation) of the sample as a function of %RH is constantly monitored by a microbalance (accuracy ⁇ 0.005 mg).
  • a 50 day dried sample of crystalline Form D is placed in a tared mesh stainless steel basket under ambient conditions.
  • the sample is loaded and unloaded at 40 % RH and 25 °C (typical room conditions).
  • a moisture sorption isotherm is performed as outlined below' (2 scans per complete cycle).
  • the standard isotherm is performed at 25 °C at. 10 % RH intervals over a 0 - 90 % RH range.
  • a double cycle (4 scans) is carried out. Data analysis is carried out within Microsoft Excel using the DVS Analysis Suite.
  • crystalline Form E by having an endothermic peak onset at about 99°C and a heat of fusi on of 47 J/g.
  • TG analysis was performed using a Mettler-Toledo TGA/DSC3 ⁇ analyzer.
  • Temperature and enthalpy adjustments were performed using indium, tin, and zinc, and then verified with indium. The balance was verified with calcium oxalate.
  • the sample was placed in an open aluminum pan. The pan was hermetically sealed, the lid pierced, then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan v/as placed on the reference platform. The furnace was heated under nitrogen. Data was collected from 25 °C to 350 °C at 10 °C/min.
  • TGA thermogram profile of crystalline Form E is shown in FIG. 17. A shown in
  • FIG. 17 there was a negligible loss of mass up to about 94°C and through the onset of degradation at about 240°C.
  • Vapor sorption data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH increments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours.
  • DVS isotherm profile of crystalline Form E is shown in FIG. 18. As shown in FIG. 18,
  • the crystal structure solved from a small needle was found to be a neat form of 2-[(2S)-4-[7-(8-chloro-l- naphthyl)-2-[[(2S)-1 -methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4- yl]-1 -(2-fluoroprop"2-enoyl)piperazin ⁇ 2-yl]acetonitrile.
  • the absolute configuration of the molecule was confirmed to be (S, S).
  • the structure of a plate crystal was also solved and appeared to be neat as well based on difference electron density maps. Both structures were solved under ambient conditions. The structures were designated as Form A and Form B as shown in Table 6 below;
  • the crystalline bulk crystal (needle and plate, FIG. 23) was found to be a mixture of Form A and Form B (FIG. 24).
  • the X-ray intensity data were measured (X :::: 1.54178 A) under ambient conditions.
  • a total of 1458 frames were collected.
  • the total exposure time was 11.58 hours.
  • the frames were integrated with the Bruker SAINT software package using a narrowframe algorithm.
  • the goodness-of-fit was 0.970.
  • the largest peak in the final difference electron density synthesis was 0.209 e-/A3 and the largest hole was -0.214 e-/A3 with an RMS deviation of 0.050 e-/A3.
  • the calculated density was 1.295 g/cm3 and F(000), 636 e-.
  • the total exposure time was 9.97 hours.
  • the frames were integrated with the Broker SAINT software package using a narrow-frame algorithm.
  • the goodness-of-fit was 1 .182.
  • the largest peak in the final difference electron density synthesis was 0.195 e-/A3 and the largest hole was -0.251 e-/A3 with an RMS deviation of 0.052 e-/A3.
  • the calculated density was 1.294 g/cm3 and F(OOO), 1272 e-.
  • a needle crystal was freshly isolated from mother liquor and immediately cooled at 223K on the single-crystal X-ray diffractometer equipped with a LT device.
  • the crystal structure solved from the data was a monohydrate 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, and its simulated pattern matched Form C.
  • a second dataset was then collected on the same needle crystal at 293K.
  • the structure solved was completely dehydrated and matched previously solved structure of Form B.
  • Form C and Form B are isomorphous (FIG. 27).
  • the water molecule in the monohydrate formed two hydrogen bonds, as H-bond donor, with the carbonyl oxygen and pyrrolidine nitrogen of -849 molecule.
  • Departure of water from crystal lattice was accompanied by conformational change of -849 molecule, mainly a —134° rotation of N-methylpyrrolidine group, as indicated by the torsion angle O-C-C-N, 68.55° in monohydrate and -65.31° in dehydrated structure.
  • the goodness-of-fit was 1.065.
  • the largest peak in the final difference electron density synthesis was 0,344 e-/ ⁇ 3 and the largest hole was -0.267 e-/A3 with an RMS deviation of 0.062 e-/A,3.
  • the calculated density was 1.309 g/cm3 and F(000), 1312 e-.
  • the goodness-of-fit was 1 .069.
  • the largest peak in the final difference electron density synthesis was 0.168 e-/A3 and the largest hole was -0.197 e-/A3 with an RMS deviation of 0.044 e-/A3.
  • the calculated density was 1.296 g/cm3 and F(000), 1272 e ⁇ .
  • Form B polymorph was shown to be chemically and/or physically more stable than amorphous form of 2“[(2S)-4-[7-(8-chloro-l ⁇ naphthyl)-2-[[(2S)-l-methylpyrrolidin-2- yi]methoxy] ⁇ 6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyI)piperazin-2- yl]acetonitrile described in Comparati ve Example 4.
  • XRPD of the material of Comparative Example 4 was consistent with amorphous material.
  • Figure 21 shows the XRPD pattern of the spray dried material of Comparative Example 4 compared to the starting material constituted of a mixture of crystalline Forms A and B.
  • a comparative stability study was performed for crystalline forms (Form A and Form B) and amorphous MRTX849 Drug Substance (DS) material.
  • the study of amorphous, Form A (unmilled) and Form B (unmilled) materials was completed in accordance with study protocol which is briefly as follows: samples were stored at 25°C/60% RH. 40°C/75%RH and 60°C in loosely capped, foil-wrapped small glass vials. Data was obtained for up to two weeks for samples stored at 60°C and up to two months for samples stored at 25°C/60% RH and 40°C/75%RH. In addition, data was generated from photostability study performed on all three lots as a part of the protocol.
  • Table 8 illustrates appearance, purity and impurities stability results for crystalline forms (Form A and Form B) and amorphous MRTX849 Drug Substance.
  • Table 9 illustrates photostability (1/2 ICH conditions): Vis Stress at 600 klux-hrs, UV

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
US11845761B2 (en) 2020-12-18 2023-12-19 Erasca, Inc. Tricyclic pyridones and pyrimidones
US20240374525A1 (en) * 2022-08-19 2024-11-14 Mirati Therapeutics, Inc. Adagrasib solid pharmaceutical compositions
US12162893B2 (en) 2020-09-23 2024-12-10 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2025019688A3 (en) * 2023-07-20 2025-04-10 Mirati Therapeutics, Inc. Crystalline forms of salts of adagrasib
WO2025145207A1 (en) 2023-12-29 2025-07-03 Bristol-Myers Squibb Company Combination therapy of kras inhibitor and treg-depleting agent
WO2026003808A1 (en) 2024-06-28 2026-01-02 Assia Chemical Industries Ltd. Solid state form of adagrasib and process for preparation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022500385A (ja) * 2018-09-10 2022-01-04 ミラティ セラピューティクス， インコーポレイテッド 組み合わせ療法
CA3112043A1 (en) * 2018-09-10 2020-03-19 Mirati Therapeutics, Inc. Combination therapies

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190144444A1 (en) * 2017-11-15 2019-05-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
US20190270743A1 (en) * 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021061749A1 (en) * 2019-09-24 2021-04-01 Mirati Therapeutics, Inc. Combination therapies

Family Cites Families (222)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2432578C (en) 2001-01-02 2008-04-01 F. Hoffmann-La Roche Ag Quinazolone derivatives as alpha 1a/b adrenergic receptor antagonists
WO2002088079A2 (en) 2001-05-01 2002-11-07 Bristol-Myers Squibb Company Dual inhibitors of pde 7 and pde 4
US7105667B2 (en) 2001-05-01 2006-09-12 Bristol-Myers Squibb Co. Fused heterocyclic compounds and use thereof
KR100955015B1 (ko) 2001-08-15 2010-04-28 이코스 코포레이션 2ｈ-프탈라진-1-온 및 이것의 사용 방법
GB0310726D0 (en) 2003-05-09 2003-06-11 Merck Sharp & Dohme Therapeutic agents
US7928107B2 (en) 2004-09-02 2011-04-19 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
WO2007009911A1 (en) 2005-07-21 2007-01-25 F. Hoffmann-La Roche Ag PYRIDO [2 , 3-D] PYRIMIDINE-2 , 4-DIAMINE COMPOUNDS AS PTPlB INHIBITORS
US20080051387A1 (en) 2006-06-09 2008-02-28 Yuelian Xu Tetrahydropyrido[3,4-d]pyrimidines and related analogues
US9259426B2 (en) 2006-07-20 2016-02-16 Gilead Sciences, Inc. 4,6-di- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections
CA2673299C (en) 2006-12-21 2016-04-12 Sloan-Kettering Institute For Cancer Research Pyridazinone compounds for the treatment of proliferative diseases
WO2008103470A2 (en) 2007-02-21 2008-08-28 Trustees Of Columbia University In The City Of New York Oncogenic-ras-signal dependent lethal compounds
EP2209775A1 (en) 2007-10-09 2010-07-28 UCB Pharma, S.A. Heterobicyclic compounds as histamine h4-receptor antagonists
AR073354A1 (es) 2008-07-31 2010-11-03 Genentech Inc Compuestos de pirimidina, composiciones farmaceuticas y su uso en el tratamiento del cancer.
WO2010120996A1 (en) 2009-04-17 2010-10-21 Wyeth Llc 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses
US8455476B2 (en) 2009-04-22 2013-06-04 Janssen Pharmaceutica, Nv Azetidinyl diamides as monoacylglycerol lipase inhibitors
EP2518064A1 (en) 2009-12-25 2012-10-31 Mochida Pharmaceutical Co., Ltd. Novel aryl urea derivative
EP2519664A4 (en) 2009-12-30 2014-03-12 Avila Therapeutics Inc LIGAND-RELATED COVALENTS MODIFYING A PROTEIN
EP2836482B1 (en) 2012-04-10 2019-12-25 The Regents of The University of California Compositions and methods for treating cancer
WO2014011973A2 (en) 2012-07-13 2014-01-16 The Trustees Of Columbia University In The City Of New York Quinazolinone-based oncogenic-ras-selective lethal compounds and their use
JP6473133B2 (ja) 2013-03-15 2019-02-20 アラクセス ファーマ エルエルシー Ｋｒａｓｇ１２ｃの共有結合性阻害剤
UY35464A (es) 2013-03-15 2014-10-31 Araxes Pharma Llc Inhibidores covalentes de kras g12c.
US9745319B2 (en) 2013-03-15 2017-08-29 Araxes Pharma Llc Irreversible covalent inhibitors of the GTPase K-Ras G12C
AU2014331794C1 (en) 2013-10-10 2019-09-12 Araxes Pharma Llc Inhibitors of KRAS G12C
TWI659021B (zh) 2013-10-10 2019-05-11 亞瑞克西斯製藥公司 Ｋｒａｓ ｇ１２ｃ之抑制劑
JP2015124211A (ja) 2013-12-27 2015-07-06 大日本住友製薬株式会社 キナゾリノン誘導体
MA40074A (fr) 2014-05-30 2015-12-03 Univ Columbia Composés liant ras multivalents
WO2016025650A1 (en) 2014-08-13 2016-02-18 Celgene Avilomics Research, Inc. Combinations of an erk inhibitor and a cdk4/6 inhibitor and related methods
EP3189049B1 (en) 2014-09-05 2024-03-20 Genentech, Inc. Phthalazine derivatives of formula (i) as pcaf and gcn5 inhibitors for use in the treatment of cancer
JO3556B1 (ar) 2014-09-18 2020-07-05 Araxes Pharma Llc علاجات مدمجة لمعالجة السرطان
ES2826443T3 (es) 2014-09-25 2021-05-18 Araxes Pharma Llc Inhibidores de proteínas mutantes KRAS G12C
US10011600B2 (en) 2014-09-25 2018-07-03 Araxes Pharma Llc Methods and compositions for inhibition of Ras
WO2016049565A1 (en) 2014-09-25 2016-03-31 Araxes Pharma Llc Compositions and methods for inhibition of ras
WO2016130460A2 (en) 2015-02-09 2016-08-18 The Johns Hopkins University Phthalazinone pyrazole derivatives for treating retinal degenerative disease
US10017540B2 (en) 2015-03-11 2018-07-10 California Institute Of Technology Cyclic peptide binder against oncogenic K-Ras
JP2018513853A (ja) 2015-04-10 2018-05-31 アラクセス ファーマ エルエルシー 置換キナゾリン化合物およびその使用方法
JP6789239B2 (ja) 2015-04-15 2020-11-25 アラクセス ファーマ エルエルシー Ｋｒａｓの縮合三環系インヒビターおよびその使用の方法
WO2016172692A1 (en) 2015-04-24 2016-10-27 H. Lee Moffitt Cancer Center And Research Institute, Inc. Mutant kras inhibitors
BR112017023821A2 (pt) 2015-05-06 2018-07-31 Leidos Biomedical Res Inc moduladores de k-ras
US10144724B2 (en) 2015-07-22 2018-12-04 Araxes Pharma Llc Substituted quinazoline compounds and methods of use thereof
JP6877414B2 (ja) 2015-09-24 2021-05-26 アイオニス・ファーマシューティカルズ・インコーポレイテッドＩｏｎｉｓ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｋｒａｓ発現のモジュレーター
EP3356354A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
EP3356353A1 (en) 2015-09-28 2018-08-08 Araxes Pharma LLC Inhibitors of kras g12c mutant proteins
WO2017058915A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
US10647703B2 (en) 2015-09-28 2020-05-12 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
US10882847B2 (en) 2015-09-28 2021-01-05 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
WO2017058902A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
WO2017058807A1 (en) 2015-09-28 2017-04-06 Araxes Pharma Llc Inhibitors of kras g12c mutant proteins
JP2018533939A (ja) 2015-10-19 2018-11-22 アラクセス ファーマ エルエルシー Ｒａｓの阻害剤をスクリーニングするための方法
JP6953400B2 (ja) 2015-10-22 2021-10-27 ザ スクリプス リサーチ インスティテュート システイン反応性プローブとその使用
WO2017080980A1 (en) 2015-11-09 2017-05-18 Astrazeneca Ab Dihydropyrrolopyrazinone derivatives useful in the treatment of cancer
WO2017079864A1 (en) 2015-11-12 2017-05-18 Hangzhou Yier Biotech Co., Ltd. Treatment of cancers related to chronically active ras
KR20180081596A (ko) 2015-11-16 2018-07-16 아락세스 파마 엘엘씨 치환된 헤테로사이클릭 그룹을 포함하는 2-치환된 퀴나졸린 화합물 및 이의 사용 방법
WO2017100546A1 (en) 2015-12-09 2017-06-15 Araxes Pharma Llc Methods for preparation of quinazoline derivatives
US20170283445A1 (en) 2016-04-05 2017-10-05 University Of South Carolina Small Molecule Inhibitors Selective For Polo-Like Kinase Proteins
JP7039489B2 (ja) 2016-05-18 2022-03-22 ミラティ セラピューティクス， インコーポレイテッド Ｋｒａｓ ｇ１２ｃ阻害剤
US10646488B2 (en) 2016-07-13 2020-05-12 Araxes Pharma Llc Conjugates of cereblon binding compounds and G12C mutant KRAS, HRAS or NRAS protein modulating compounds and methods of use thereof
US10280172B2 (en) 2016-09-29 2019-05-07 Araxes Pharma Llc Inhibitors of KRAS G12C mutant proteins
EP3523289A1 (en) 2016-10-07 2019-08-14 Araxes Pharma LLC Heterocyclic compounds as inhibitors of ras and methods of use thereof
MX2019006296A (es) 2016-11-30 2019-11-12 Bantam Pharmaceutical Llc Métodos de uso de compuestos de pirazol y pirazol sustituido y para el tratamiento de enfermedades hiperproliferativas.
AU2017366901B2 (en) 2016-11-30 2022-09-29 Bantam Pharmaceutical, Llc Substituted pyrazole compounds and methods of using them for treatment of hyperproliferative diseases
BR112019012263A2 (pt) 2016-12-15 2020-01-28 The Regents Of The University Of California composições e métodos para tratar câncer
WO2018119183A2 (en) 2016-12-22 2018-06-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
JP7219218B2 (ja) 2016-12-22 2023-02-07 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規のベンジルアミノ置換キナゾリンおよびｓｏｓ１阻害剤としての誘導体
US10344026B2 (en) 2017-01-18 2019-07-09 Nantbio, Inc. Compositions and methods of targeting mutant K-ras
EP3573954A1 (en) 2017-01-26 2019-12-04 Araxes Pharma LLC Fused bicyclic benzoheteroaromatic compounds and methods of use thereof
WO2018140599A1 (en) 2017-01-26 2018-08-02 Araxes Pharma Llc Benzothiophene and benzothiazole compounds and methods of use thereof
WO2018140513A1 (en) 2017-01-26 2018-08-02 Araxes Pharma Llc 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1yl)prop-2-en-1-one derivatives and similar compounds as kras g12c modulators for treating cancer
CN110382482A (zh) 2017-01-26 2019-10-25 亚瑞克西斯制药公司 稠合的杂-杂二环化合物及其使用方法
US20200385364A1 (en) 2017-01-26 2020-12-10 Araxes Pharma Llc Fused n-heterocyclic compounds and methods of use thereof
WO2018140514A1 (en) 2017-01-26 2018-08-02 Araxes Pharma Llc 1-(6-(3-hydroxynaphthalen-1-yl)quinazolin-2-yl)azetidin-1-yl)prop-2-en-1-one derivatives and similar compounds as kras g12c inhibitors for the treatment of cancer
JOP20190186A1 (ar) 2017-02-02 2019-08-01 Astellas Pharma Inc مركب كينازولين
BR112019021899A2 (pt) 2017-04-20 2020-08-18 The Regents Of The University Of California moduladores de k-ras
AU2018271990A1 (en) 2017-05-25 2019-12-12 Araxes Pharma Llc Covalent inhibitors of KRAS
MA50077A (fr) 2017-09-08 2020-07-15 Amgen Inc Inhibiteurs de kras g12c et leurs procédés d'utilisation
ES3060664T3 (en) 2018-06-12 2026-03-27 Amgen Inc Kras g12c inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer
US11545829B2 (en) 2018-07-31 2023-01-03 Honda Motor Co., Ltd. Power prediction system, power prediction device, power prediction method, program, and storage medium
CN113038342B (zh) 2018-09-30 2022-10-14 荣耀终端有限公司 音频播放电路和终端
PT3735299T (pt) 2018-11-09 2024-11-25 Hoffmann La Roche Compostos de anéis fundidos
CN111193490B (zh) 2018-11-14 2025-05-13 天津大学 散热结构、带散热结构的体声波谐振器、滤波器和电子设备
CN113164418A (zh) 2018-12-05 2021-07-23 米拉蒂治疗股份有限公司 组合疗法
WO2020123395A1 (en) 2018-12-10 2020-06-18 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors
WO2020146613A1 (en) 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
US20220193242A1 (en) 2019-02-07 2022-06-23 The Regents Of The University Of California Immunophilin-dependent inhibitors and uses thereof
EP3924687A4 (en) 2019-02-11 2022-11-02 Mesomat Inc. SENSING FIBERS FOR STRUCTURAL STRESS MONITORING
KR102747104B1 (ko) 2019-02-18 2024-12-27 한국과학기술연구원 단백질 키나아제 저해 활성을 갖는 신규한 피리도[3,4-d]피리미딘-8-온 유도체 및 이를 포함하는 암의 예방, 개선 또는 치료용 약학 조성물
WO2020172332A1 (en) 2019-02-20 2020-08-27 Fred Hutchinson Cancer Research Center Binding proteins specific for ras neoantigens and uses thereof
GB201902392D0 (en) 2019-02-21 2019-04-10 Cambridge Entpr Ltd Modular binding proteins
EP3931564A4 (en) 2019-02-26 2023-04-26 Cell Response, Inc. Methods for treating map3k8 positive cancers
WO2020177629A1 (zh) 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
AU2019432235B2 (en) 2019-03-05 2024-02-01 Questor Technology Inc. Gas incinerator system
ES3010507T3 (en) 2019-03-05 2025-04-03 Astrazeneca Ab Fused tricyclic compounds useful as anticancer agents
US12448429B2 (en) 2019-03-06 2025-10-21 Dana-Farber Cancer Institute, Inc. T cell receptors specific to b-cell maturation antigen for treatment of cancer
US20220160714A1 (en) 2019-03-22 2022-05-26 Icahn School Of Medicine At Mount Sinai Methods for treating colorectal cancer
WO2020205473A1 (en) 2019-03-29 2020-10-08 Decerna Pharmaceuticals, Inc. Compositions and methods for the treatment of kras associated diseases or disorders
AU2020254492A1 (en) 2019-03-29 2021-11-11 Kura Oncology, Inc. Methods of treating Squamous Cell Carcinomas with farnesyltransferase inhibitors
KR102222693B1 (ko) 2019-04-04 2021-03-04 금정제약 주식회사 H-rev107 유래 펩타이드의 신규한 용도
US12528796B2 (en) 2019-04-15 2026-01-20 Tosk, Inc. Modulators of RAS GTPase
US20200335182A1 (en) 2019-04-16 2020-10-22 Uratim Ltd. Method and apparatus for facilitating the binding of biological macromolecules with the use of gluing molecular agents with applications in RAS mutations and related conditions
US20220251109A1 (en) 2019-04-28 2022-08-11 Genfleet Therapeutics (Shanghai) Inc. Oxaazaquinazoline-7(8h)-ketone compound, preparation method therefor and pharmaceutical application thereof
MX2021013662A (es) 2019-05-10 2022-03-11 Deciphera Pharmaceuticals Llc Inhibidores de la autofagia de heteroarilaminopirimidina amida y metodos de uso de estos.
EP3966207B1 (en) 2019-05-10 2023-11-01 Deciphera Pharmaceuticals, LLC Phenylaminopyrimidine amide autophagy inhibitors and methods of use thereof
ES3025633T3 (en) 2019-05-13 2025-06-09 Novartis Ag New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2(trifluoromethyl)isonicotinamide as raf inhibitors for the treatment of cancer
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
WO2020230091A1 (en) 2019-05-14 2020-11-19 Janssen Biotech, Inc. Combination therapies with bispecific anti-egfr/c-met antibodies and third generation egfr tyrosine kinase inhibitors
CN114096544B (zh) 2019-05-20 2025-08-12 加州理工学院 Kras g12c抑制剂及其用途
AU2020277398B2 (en) 2019-05-21 2026-01-29 Amgen Inc. Solid state forms
CN118359609A (zh) 2019-05-21 2024-07-19 益方生物科技(上海)股份有限公司 杂环化合物，其制备方法和用途
WO2020234103A1 (en) 2019-05-21 2020-11-26 Bayer Aktiengesellschaft Identification and use of kras inhibitors
NZ782284A (en) 2019-05-21 2024-11-29 Amgen Inc Solid state forms
AU2020289484A1 (en) 2019-06-07 2021-12-23 Emory University KRAS G12V mutant binds to JAK1, inhibitors, pharmaceutical compositions, and methods related thereto
US20220304984A1 (en) 2019-06-12 2022-09-29 Vanderbilt University Amino acid transport inhibitors and the uses thereof
AU2020291936A1 (en) 2019-06-12 2022-02-03 Vanderbilt University Dibenzylamines as amino acid transport inhibitors
CN110256421A (zh) 2019-06-26 2019-09-20 微境生物医药科技(上海)有限公司 Kras-g12c抑制剂
TW202115089A (zh) 2019-07-01 2021-04-16 大陸商江蘇恆瑞醫藥股份有限公司 喹唑啉酮類衍生物、其製備方法及其在醫藥上的應用
MX2022001421A (es) 2019-08-02 2022-06-08 Shanghai Jemincare Pharmaceuticals Co Ltd Compuesto tetracíclico, método de preparación y uso del mismo.
TWI752580B (zh) 2019-08-07 2022-01-11 大陸商北京加科思新藥研發有限公司 Kras突變蛋白抑制劑
WO2021027943A1 (zh) 2019-08-14 2021-02-18 正大天晴药业集团南京顺欣制药有限公司 哒嗪酮并嘧啶类衍生物及其医药用途
CN112390797A (zh) 2019-08-15 2021-02-23 微境生物医药科技(上海)有限公司 新型螺环类K-Ras G12C抑制剂
US20220363681A1 (en) 2019-08-16 2022-11-17 Genfleet Therapeutics (Shanghai) Inc. Oxo six-membered cyclopyrimidine compound, preparation method and medical use thereof
CN114286676A (zh) 2019-08-22 2022-04-05 密歇根大学董事会 治疗kras相关癌症的方法
CN114269735B (zh) 2019-08-26 2024-02-23 南京创济生物医药有限公司 二氢或四氢喹唑啉类化合物及其中间体、制备方法和应用
WO2021041671A1 (en) 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2021043322A1 (zh) 2019-09-06 2021-03-11 正大天晴药业集团南京顺欣制药有限公司 氮杂环庚烷并嘧啶类衍生物及其医药用途
CN112771053A (zh) 2019-09-06 2021-05-07 伟迈可生物有限公司 基于生物标志物的治疗组合物
EP4028044A4 (en) 2019-09-10 2023-09-27 The Board of Trustees of the Leland Stanford Junior University Methods of treating kras mutant cancers
TW202124374A (zh) 2019-09-13 2021-07-01 美商拜歐斯瑞克斯公司 Ras蛋白降解劑、其醫藥組合物及其治療應用
EP4031542B1 (en) 2019-09-18 2025-10-15 Merck Sharp & Dohme LLC Small molecule inhibitors of kras g12c mutant
CA3155066A1 (en) 2019-09-20 2021-03-25 Shanghai Jemincare Pharmaceuticals Co., Ltd Fused pyridone compound, and preparation method therefor and use thereof
US20230010886A1 (en) 2019-09-23 2023-01-12 Suzhou Puhe BioPharma Co., Ltd. Shp2 inhibitors and uses thereof
US20210094919A1 (en) 2019-09-25 2021-04-01 Jacobio Pharmaceuticals Co., Ltd. Kras mutant protein inhibitors
WO2021058018A1 (en) 2019-09-29 2021-04-01 Beigene, Ltd. Inhibitors of kras g12c
WO2021063346A1 (zh) 2019-09-30 2021-04-08 上海迪诺医药科技有限公司 Kras g12c抑制剂及其应用
CN114555586B (zh) 2019-10-10 2023-06-23 信达生物制药(苏州)有限公司 Krasg12c蛋白抑制剂及其制备方法和用途
JP6754125B1 (ja) 2019-10-15 2020-09-09 学校法人東京理科大学 Ｂｒａｐ２作用増強剤
WO2021076655A1 (en) 2019-10-15 2021-04-22 Amgen Inc. Combination therapy of kras inhibitor and shp2 inhibitor for treatment of cancers
WO2021080359A1 (ko) 2019-10-23 2021-04-29 에스케이바이오팜 주식회사 바이사이클릭 화합물 및 이의 용도
CN112694475B (zh) 2019-10-23 2025-09-23 苏州泽璟生物制药股份有限公司 环烷基类和杂环烷基类抑制剂及其制备方法和应用
EP4684786A3 (en) 2019-10-24 2026-04-08 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
CN114867726B (zh) 2019-10-28 2023-11-28 默沙东有限责任公司 Kras g12c突变体的小分子抑制剂
PT4053118T (pt) 2019-10-30 2024-12-05 Genfleet Therapeutics Shanghai Inc Composto cíclico fundido heterocíclico substituído, método de preparação deste e utilização farmacêutica deste
WO2021084765A1 (en) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd 4-aminobut-2-enamide derivatives and salts thereof
WO2021085653A1 (en) 2019-10-31 2021-05-06 Taiho Pharmaceutical Co., Ltd. 4-aminobut-2-enamide derivatives and salts thereof
WO2021091956A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
CN120699039A (zh) 2019-11-04 2025-09-26 锐新医药公司 Ras抑制剂
MX2022005359A (es) 2019-11-04 2022-06-02 Revolution Medicines Inc Inhibidores de ras.
WO2021088458A1 (en) 2019-11-04 2021-05-14 Jacobio Pharmaceuticals Co., Ltd. Kras mutant protein inhibitor
CN112778301A (zh) 2019-11-07 2021-05-11 苏州泽璟生物制药股份有限公司 四氢吡啶并嘧啶类抑制剂及其制备方法和应用
PE20221323A1 (es) 2019-11-07 2022-09-09 Chugai Pharmaceutical Co Ltd Compuesto de peptidos ciclicos que tiene accion inhibidora de kras
TW202128688A (zh) 2019-11-08 2021-08-01 美商銳新醫藥公司 雙環雜芳基化合物及其用途
WO2021093758A1 (zh) 2019-11-15 2021-05-20 四川海思科制药有限公司 一种嘧啶并环衍生物及其在医药上的应用
EP4065231A1 (en) 2019-11-27 2022-10-05 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2021106231A1 (en) 2019-11-29 2021-06-03 Taiho Pharmaceutical Co., Ltd. A compound having inhibitory activity against kras g12d mutation
US20230061083A1 (en) 2019-11-29 2023-03-02 Evopoint Biosciences Co., Ltd. Kras g12c inhibitor compound and use thereof
US12479834B2 (en) 2019-11-29 2025-11-25 Taiho Pharmaceutical Co., Ltd. Phenol compound or salt thereof
BR112022010254A2 (pt) 2019-12-02 2022-09-06 Shanghai Yingli Pharm Co Ltd Composto heterocíclico contendo oxigênio representado pela fórmula i, método para preparar o composto heterocíclico contendo oxigênio, composto, composição farmacêutica e uso composto heterocíclico contendo oxigênio
WO2021113595A1 (en) 2019-12-06 2021-06-10 Beta Pharma, Inc. Phosphorus derivatives as kras inhibitors
WO2021120045A1 (en) 2019-12-18 2021-06-24 InventisBio Co., Ltd. Heterocyclic compounds, preparation methods and uses thereof
WO2021126799A1 (en) 2019-12-18 2021-06-24 Merck Sharp & Dohme Corp. Macrocyclic peptides as potent inhibitors of k-ras g12d mutant
WO2021121371A1 (zh) 2019-12-19 2021-06-24 贝达药业股份有限公司 Kras g12c抑制剂及其在医药上的应用
WO2021121397A1 (zh) 2019-12-19 2021-06-24 首药控股(北京)股份有限公司 取代的炔基杂环化合物
CA3165238A1 (en) 2019-12-19 2021-06-24 Jacobio Pharmaceuticals Co., Ltd. Kras mutant protein inhibitors
TR201920922A2 (tr) 2019-12-20 2020-06-22 Ankara Ueniversitesi 3/4-((2E,6E)-3,7,11-Trimetildodeka-2,6,10-trieniltiyo)benzamid Türevi Bileşikler
EP4076667A1 (en) 2019-12-20 2022-10-26 Erasca, Inc. Tricyclic pyridones and pyrimidones
CN114929704B (zh) 2019-12-27 2024-07-23 微境生物医药科技(上海)有限公司 含螺环的喹唑啉化合物
CN113045565A (zh) 2019-12-27 2021-06-29 微境生物医药科技(上海)有限公司 新型K-Ras G12C抑制剂
WO2021139678A1 (zh) 2020-01-07 2021-07-15 广州百霆医药科技有限公司 吡啶并嘧啶类kras g12c突变蛋白抑制剂
TWI770760B (zh) 2020-01-08 2022-07-11 大陸商蘇州亞盛藥業有限公司 螺環四氫喹唑啉
US20210269434A1 (en) 2020-01-10 2021-09-02 Incyte Corporation Tricyclic compounds as inhibitors of kras
CN115175908B (zh) 2020-01-13 2024-07-23 苏州泽璟生物制药股份有限公司 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
KR102382613B1 (ko) 2020-01-15 2022-04-06 한국과학기술연구원 단백질 키나아제 저해 활성을 갖는 7-아미노-3,4-디히드로피리미도피리미딘-2-온 유도체 및 이를 포함하는 치료용 약학 조성물
KR102396930B1 (ko) 2020-01-15 2022-05-12 한국과학기술연구원 피리도[3,4-d]피리미딘 유도체 및 이를 포함하는 치료용 약학 조성물
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
WO2021147965A1 (zh) 2020-01-21 2021-07-29 南京明德新药研发有限公司 作为kras抑制剂的大环类化合物
GB202001344D0 (en) 2020-01-31 2020-03-18 Redx Pharma Plc Ras Inhibitors
EP4077328A4 (en) 2020-02-20 2023-11-29 Beta Pharma, Inc. PYRIDOPYRIMIDE DERIVATIVES AS KRAS INHIBITORS
CN114845997B (zh) 2020-02-24 2024-03-29 上海喆邺生物科技有限公司 芳香类化合物及其在制备抗肿瘤药物中的应用
TW202140450A (zh) 2020-02-24 2021-11-01 大陸商泰勵生物科技（上海）有限公司 用於癌症治療的ｋｒａｓ抑制劑
US20210292330A1 (en) 2020-02-28 2021-09-23 Erasca, Inc. Pyrrolidine-fused heterocycles
WO2021175199A1 (zh) 2020-03-02 2021-09-10 上海喆邺生物科技有限公司 一类芳香杂环类化合物及其在药物中的应用
KR20210111711A (ko) 2020-03-03 2021-09-13 웰마커바이오 주식회사 Kras 돌연변이 및 활성화된 ron이 존재하는 암의 예방 또는 치료용 약학 조성물
CA3172812A1 (en) 2020-03-05 2021-09-10 The Regents Of The University Of Michigan Inhibitors of egfr, kras, braf, and other targets and use of the same
MX2022010977A (es) 2020-03-05 2022-12-02 Univ Michigan Regents Inhibidores de egfr, kras, braf y otros objetivos y uso de los mismos.
KR102822517B1 (ko) 2020-03-12 2025-06-19 디3 바이오 (우씨) 컴퍼니, 리미티드 피리미도헤테로사이클릭 화합물 및 이의 응용
WO2021185233A1 (en) 2020-03-17 2021-09-23 Jacobio Pharmaceuticals Co., Ltd. Kras mutant protein inhibitors
CA3170068A1 (en) 2020-03-25 2021-09-30 Yuli Xie Spiro ring-containing quinazoline compound
AU2021248363B2 (en) 2020-04-03 2024-02-15 Medshine Discovery Inc. Octahydropyrazinodiazanaphthyridine dione compounds
US20220370416A1 (en) 2020-04-06 2022-11-24 Arvinas Operations, Inc. Compounds and methods for targeted degradation of kras
WO2021203768A1 (zh) 2020-04-08 2021-10-14 江苏恒瑞医药股份有限公司 嘧啶并二环类衍生物、其制备方法及其在医药上的应用
CA3179692A1 (en) 2020-04-16 2021-10-21 Incyte Corporation Fused tricyclic kras inhibitors
WO2021216770A1 (en) 2020-04-22 2021-10-28 Accutar Biotechnology Inc. Substituted tetrahydroquinazoline compounds as kras inhibitors
EP4138875A4 (en) 2020-04-23 2024-08-28 The Regents of the University of California RAS INHIBITORS AND USES THEREOF
WO2021215544A1 (en) 2020-04-24 2021-10-28 Taiho Pharmaceutical Co., Ltd. Kras g12d protein inhibitors
WO2021218110A1 (zh) 2020-04-29 2021-11-04 上海凌达生物医药有限公司 一类苯并噻唑基联芳基类化合物、制备方法和用途
CN115135636B (zh) 2020-04-29 2024-08-23 北京泰德制药股份有限公司 喹喔啉酮衍生物作为kras g12c突变蛋白的不可逆抑制剂
CN116194456B (zh) 2020-04-30 2025-08-29 上海科州药物股份有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
US11739102B2 (en) 2020-05-13 2023-08-29 Incyte Corporation Fused pyrimidine compounds as KRAS inhibitors
CN113666923A (zh) 2020-05-15 2021-11-19 苏州泽璟生物制药股份有限公司 烷氧基烷基取代杂环基类抑制剂及其制备方法和应用
WO2021236475A1 (en) 2020-05-18 2021-11-25 Asinex Corporation Compounds that inhibit asparagine synthetase and their methods of use
TWI799871B (zh) 2020-05-27 2023-04-21 大陸商勁方醫藥科技(上海)有限公司 三環并環類化合物，其製法與醫藥上的用途
US20230210852A1 (en) 2020-05-29 2023-07-06 Syros Pharmaceuticals, Inc. Methods of treating cancer in patients with an anomalous kras gene or deletions within chromosome 9
WO2021245055A1 (en) 2020-06-02 2021-12-09 Boehringer Ingelheim International Gmbh Annulated 2-amino-3-cyano thiophenes and derivatives for the treatment of cancer
EP4161934A1 (en) 2020-06-04 2023-04-12 Antengene Discovery Limited Inhibitors of kras g12c protein and uses thereof
MX2022015253A (es) 2020-06-04 2023-03-14 Pillai Universal Llc Moleculas peque?as novedosas para la degradacion dirigida de kras no dirigibles en la terapia contra el cancer.
WO2021248083A1 (en) 2020-06-05 2021-12-09 Sparcbio Llc Heterocyclic compounds and methods of use thereof
US20230023009A1 (en) 2020-06-05 2023-01-26 Sparcbio Llc Heterocyclic compounds and methods of use thereof
WO2021248079A1 (en) 2020-06-05 2021-12-09 Sparcbio Llc Heterocyclic compounds and methods of use thereof
WO2021248082A1 (en) 2020-06-05 2021-12-09 Sparcbio Llc Heterocyclic compounds and methods of use thereof
US20230026856A1 (en) 2020-06-05 2023-01-26 Sparcbio Llc Heterocyclic compounds and methods of use thereof
WO2021252339A1 (en) 2020-06-08 2021-12-16 Accutar Biotechnology, Inc. Substituted purine-2,6-dione compounds as kras inhibitors
WO2021249563A1 (zh) 2020-06-12 2021-12-16 苏州泽璟生物制药股份有限公司 芳基或杂芳基并吡啶酮或嘧啶酮类衍生物及其制备方法和应用
EP4168414A1 (en) 2020-06-18 2023-04-26 Shy Therapeutics LLC Substituted thienopyrimidines that interact with the ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease
WO2021259331A1 (zh) 2020-06-24 2021-12-30 南京明德新药研发有限公司 八元含n杂环类化合物
WO2022002102A1 (en) 2020-06-30 2022-01-06 InventisBio Co., Ltd. Quinazoline compounds, preparation methods and uses thereof
EP4182313A4 (en) 2020-07-16 2024-10-09 Mirati Therapeutics, Inc. KRAS-G12D INHIBITORS
TW202214608A (zh) 2020-07-20 2022-04-16 大陸商江蘇恆瑞醫藥股份有限公司 稠合噠嗪類衍生物、其製備方法及其在醫藥上的應用
CN115052870B (zh) 2020-08-02 2024-02-20 上海喆邺生物科技有限公司 一种芳香类化合物及其在抗肿瘤药物中的应用
EP4192585A4 (en) 2020-08-04 2024-08-21 Mirati Therapeutics, Inc. Kras g12d inhibitors
WO2022028492A1 (en) 2020-08-05 2022-02-10 Beigene, Ltd. Imidazotriazine and pyrrolopyrimidine derivatives as kras g12c inhibitors
WO2022036176A1 (en) 2020-08-13 2022-02-17 Albert Einstein College Of Medicine N-cyclyl-sulfonamides useful for inhibiting raf
CN113999226B (zh) 2020-12-22 2023-01-06 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
JP2024520791A (ja) 2021-06-10 2024-05-24 レデックス・ファーマ・パブリック・リミテッド・カンパニー 化合物
US20240409558A1 (en) 2021-09-13 2024-12-12 Biomea Fusion, Inc. Irreversible inhibitors of kras

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190144444A1 (en) * 2017-11-15 2019-05-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2019099524A1 (en) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Kras g12c inhibitors
US20190270743A1 (en) * 2017-11-15 2019-09-05 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021061749A1 (en) * 2019-09-24 2021-04-01 Mirati Therapeutics, Inc. Combination therapies

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ALAMGEER ET AL., CURRENT OPIN PHARMCOL, vol. 13, 2013, pages 394 - 401
DOGAN ET AL., CLIN CANCER RES, vol. 18, no. 22, 26 September 2012 (2012-09-26), pages 6169 - 6177
FELL JAY B., FISCHER JOHN P., BAER BRIAN R., BLAKE JAMES F., BOUHANA KARYN, BRIERE DAVID M., BROWN KARIN D., BURGESS LAURENCE E., : "Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer", JOURNAL OF MEDICINAL CHEMISTRY, vol. 63, no. 13, 9 July 2020 (2020-07-09), US , pages 6679 - 6693, XP055788094, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b02052
SAMATARPOULIKAKOS, NAT REV DRUG DISC, vol. 13, no. 12, 2014, pages 928 - 942
SANTOS ET AL., SCIENCE, vol. 223, 1984, pages 661 - 664
See also references of EP4210833A4

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WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
US20240374525A1 (en) * 2022-08-19 2024-11-14 Mirati Therapeutics, Inc. Adagrasib solid pharmaceutical compositions
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WO2025019688A3 (en) * 2023-07-20 2025-04-10 Mirati Therapeutics, Inc. Crystalline forms of salts of adagrasib
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US20230357231A1 (en) 2023-11-09
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US12281113B2 (en) 2025-04-22
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