CN113527294A - Crystal form of MRTX849 compound and preparation method and application thereof - Google Patents
Crystal form of MRTX849 compound and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- 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
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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
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- 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
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Abstract
The invention relates to a crystal form of a MRTX849 compound (compound I), a preparation method, a pharmaceutical composition containing the crystal form and application of the crystal form in preparing a medicine for treating related diseases caused by KRAS G12C gene mutation. The crystal form of the compound I provided by the invention has important value for the development of the medicine in the future.
Description
Technical Field
The present invention relates to the field of pharmaceutical chemistry. In particular to a crystal form of a MRTX849 compound, a preparation method and application thereof.
Background
The KRAS gene coding protein is a signal transduction protein in intracellular signal transduction pathways, and has important influence on functions of cell such as growth, survival, differentiation and the like. When KRAS gene is mutated, normal RAS protein can not be produced, so that intracellular signal transduction is disturbed, and cell proliferation is out of control and cancerated. KRAS G12C mutations typically occur in about 13% of lung cancer patients, 3% of colorectal and appendiceal cancer patients, and 1% to 3% of other solid tumor patients. KRAS is a member of the RAS family of oncogenes, mutations of which may induce constitutive signal transduction, leading to tumor cell growth, proliferation, invasion and metastasis.
MRTX849 is an orally available KRAS G12C small molecule inhibitor, targets oncogenic KRAS to replace mutant G12C, and has potential anti-tumor activity. MRTX849 may block KRAS signaling by irreversibly binding to KRAS G12C and locking it in its inactive, GDP-bound state. Clinical phase II research results show that MRTX849 shows good clinical curative effect in patients with non-small cell lung cancer, colorectal cancer and appendiceal cancer.
The chemical name of the compound MRTX849 is (2S) -4- [7- (8-chloro-1-naphthalene) -5,6,7, 8-tetrahydro-2- [ [ ((2S) -1-methyl-2-pyrrolidinyl ] methoxy ] pyridinyl [3,4-d ] pyrimidin-4-yl ] -1- (2-fluoro-1-oxo-2-propen-1-yl) -2-piperazineacetonitrile (hereinafter referred to as "compound I"), which has the following structural formula:
the crystal form is a solid form of crystal lattices formed by long-range ordered arrangement of solid molecules of the compound in a microscopic three-dimensional structure. Drug polymorphism refers to the phenomenon of a solid drug molecule in two or more different crystal forms. Because different crystal forms have different physicochemical properties, different crystal forms of solid drug molecules can be dissolved and absorbed in vivo differently, so that the clinical curative effect and safety of the drug are influenced to a certain extent, and especially for insoluble solid drugs, the influence of the crystal forms on the bioavailability is larger. Therefore, the drug crystal form is an important ring in the research and development process of solid drugs and is also an important content of drug quality control.
The inventor of the application unexpectedly discovers that different crystal forms of the compound I provided by the invention have advantages in the aspects of physicochemical properties, preparation processing performance, bioavailability and the like, for example, at least one of the aspects of melting point, solubility, hygroscopicity, purification effect, stability, adhesiveness, compressibility, fluidity, in-vivo and in-vitro dissolution, bioavailability and the like has advantages, provides a better choice for the development of a medicine containing the compound I, and has very important significance.
Disclosure of Invention
The invention mainly aims to provide a novel crystal form of a compound I and a preparation method and application thereof.
According to an object of the present invention, the present invention provides a crystalline form of compound I.
Further, the present invention provides that the crystalline form of compound I may be crystalline form DCIII (hereinafter referred to as crystalline form DCIII).
On the one hand, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at 1, 2 or 3 of diffraction angle 2theta values of 4.4 degrees +/-0.2 degrees, 8.9 degrees +/-0.2 degrees and 16.8 degrees +/-0.2 degrees.
Further, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at 1, 2 or 3 of diffraction angle 2theta values of 20.2 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees; preferably, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at 3 points with diffraction angle 2theta values of 20.2 degrees +/-0.2 degrees, 13.8 degrees +/-0.2 degrees and 14.2 degrees +/-0.2 degrees.
Further, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at 1, 2 or 3 of diffraction angle 2theta values of 22.6 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees; preferably, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at 3 points with diffraction angle 2theta values of 22.6 degrees +/-0.2 degrees, 15.2 degrees +/-0.2 degrees and 16.3 degrees +/-0.2 degrees.
On the other hand, by using Cu-Ka radiation, the X-ray powder diffraction of the crystal form DCIII has characteristic peaks at diffraction angle 2theta values of 21.7 degrees +/-0.2 degrees, 25.6 degrees +/-0.2 degrees, 23.1 degrees +/-0.2 degrees or at 1, 2 or 3.
Without limitation, the X-ray powder diffraction pattern of crystalline form DCIII is substantially as shown in figure 1.
Without limitation, crystalline form DCIII begins to show an endothermic peak near 100 degrees and a differential scanning calorimetry trace is substantially as shown in figure 2.
According to an object of the present invention, the present invention also provides a process for the preparation of said crystalline form DCIII, said process comprising:
and (2) putting the solid of the compound I into an alcohol solvent to form a solution, then dropwise adding water into the solution until the solution is turbid, stirring for a period of time at a certain temperature, and separating and drying to obtain the crystal form of the compound.
Further, the selected alcohol is preferably ethanol; the volume ratio of the water to the alcohol solvent is preferably 2: 1-1: 1.5, and more preferably 1.2: 1; the stirring temperature is preferably-20-30 ℃, and more preferably 5 ℃; the drying conditions are preferably 20 to 50 degrees.
According to the purpose of the present invention, the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of the crystalline form DCIII and a pharmaceutically acceptable carrier or adjuvant.
Further, the invention provides application of the DCIII crystal form in preparing KRAS G12C inhibitor medicines.
Further, the invention provides a use of crystalline form DCIII in the preparation of a medicament for the treatment of non-small cell lung cancer, colorectal cancer or appendiceal cancer.
In the present invention, the "stirring" is performed by a method conventional in the art, such as magnetic stirring or mechanical stirring, wherein the stirring speed is 50-1800 rpm, the magnetic stirring is preferably 300-.
The "separation" is carried out by methods conventional in the art, such as centrifugation or filtration, and the "centrifugation" is carried out by: the sample to be separated is placed in a centrifuge tube and centrifuged at 10000 rpm until the solids are all settled to the bottom of the centrifuge tube.
The "drying" may be carried out at room temperature or higher. The drying temperature is from room temperature to about 50 deg.C, or to 40 deg.C. The drying time can be 2-48 hours or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
In the present invention, "crystal" or "polymorph" refers to a solid as confirmed by characterization by X-ray powder diffractogram. It will be understood by those skilled in the art that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the apparatus, the preparation of the sample and the purity of the sample, and in particular, it is well known to those skilled in the art that the X-ray powder diffraction pattern will generally vary with the conditions of the apparatus, and it is specifically noted that the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so that the order of the intensities of the diffraction peaks cannot be considered as the sole or determining factor. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the intensities of the diffraction peaks shown in the present invention are illustrative and not used for absolute comparison. In addition, experimental errors in diffraction peak positions are typically 5% or less, and these position errors should also be taken into account, typically allowing an error of ± 0.2. In addition, due to the influence of experimental factors such as the thickness of the sample, the overall shift of the diffraction peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray powder diffraction patterns of the protected crystalline forms of the present invention need not be identical to the X-ray powder diffraction patterns of the examples referred to herein, and that any crystalline form having an X-ray powder diffraction pattern identical or similar to the characteristic peaks in these patterns is within the scope of the present invention.
One skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystalline form to confirm whether the two sets of patterns reflect the same or different crystalline forms.
In some embodiments, the crystalline DCI of the present invention is pure, substantially without any other crystalline admixtures. "substantially free" as used herein in reference to a novel form means that the form contains less than 20% by weight of other forms, particularly less than 10% by weight of other forms, more particularly less than 5% by weight of other forms, and even more particularly less than 1% by weight of other forms.
The term "about" when used in reference to a sensible value, such as mass, time, temperature, etc., means that there may be some fluctuation in the range around the specific value, which may be + -10%, + -5%, + -1%, + -0.5% or + -0.1%.
Drawings
FIG. 1 is an XRPD pattern of the crystalline form DCIII obtained according to example 1
Figure 2 is a DSC diagram of the crystalline form DCIII obtained according to example 1.
Detailed Description
The invention is illustrated in detail by the following examples describing in detail the methods of making and using the crystalline forms of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The abbreviations used in the present invention are explained as follows:
XRPD: powder X-ray diffraction
DSC: differential scanning calorimetry
The instrument and method for data acquisition:
the X-ray powder diffractogram according to the invention was collected on a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
x-ray Source Cu Ka
Kal (A): 1.54060；Ka2 (A) 1.54439
Ka 2/Ka 1 strength ratio: 0.50
Voltage: 30 kilovolt (kV)
Current: 10 milliampere (mA)
Scanning range: from 3.0 to 40.0 degrees
The Differential Scanning Calorimetry (DSC) chart is collected on a Mettler DSC3, and the method parameters of the Differential Scanning Calorimetry (DSC) are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Unless otherwise specified, the following examples are run at room temperature, where "room temperature" is not a specific temperature value and refers to a temperature range of 10-30 ℃.
According to the present invention, the compound I and/or a salt thereof as a starting material includes, but is not limited to, a solid form (crystalline or amorphous), an oil form, a liquid form and a solution. Preferably, compound I and/or its salt as starting material is in solid form.
The compounds I used in the following examples were prepared by the procedure described in literature.
Example 1: preparation method of crystal form DCIII
Example 1 a:
31mg of Compound I are weighed into a 5ml glass bottle, 1.155ml of EtOH are added at room temperature and the solution is clarified by stirring with vigorous shaking, and placed on a magnetic stirrer and stirred. 1.55ml of H are added dropwise2And O until the solution is turbid, transferring the solution to a 5 ℃ environment, stirring for 23 hours, and testing XRPD after centrifugal drying to obtain the crystal form DCIII.
Example 1b:
100mg of compound I are weighed into a 20ml glass bottle, 3.465ml of EtOH are added at room temperature and the solution is clarified by stirring with sufficient shaking, and placed on a magnetic stirrer and stirred. 3ml of H was added dropwise2O until the solution appeared cloudy, 1.5mg of seed crystal obtained in example 1a was added and after stirring at room temperature for 40min, transferred to a 5 ℃ environment and stirred for 3h further, followed by standing at 5 ℃ for 16h and after centrifugal drying the XRPD test gave crystalline form DCIII.
The XRPD pattern of the crystalline form DCIII obtained in example 1b is shown in FIG. 1, and the XRPD data are shown in Table 1.
DSC shows that an endothermic peak begins to appear when heated to about 100 ℃ as shown in FIG. 2.
TABLE 1
| Angle of diffraction 2theta | d value | Relative strength |
| 4.42 | 20.00 | 17.50% |
| 5.61 | 15.76 | 9.00% |
| 8.86 | 9.98 | 24.90% |
| 9.94 | 8.90 | 5.30% |
| 11.11 | 7.96 | 10.40% |
| 12.22 | 7.24 | 3.70% |
| 12.63 | 7.00 | 13.20% |
| 13.43 | 6.59 | 39.10% |
| 13.77 | 6.43 | 72.60% |
| 14.23 | 6.22 | 46.20% |
| 15.15 | 5.84 | 29.50% |
| 15.52 | 5.70 | 15.90% |
| 16.28 | 5.44 | 43.20% |
| 16.80 | 5.27 | 100.00% |
| 17.41 | 5.09 | 22.20% |
| 17.70 | 5.00 | 28.80% |
| 17.87 | 4.96 | 28.10% |
| 18.73 | 4.73 | 15.70% |
| 19.27 | 4.60 | 18.80% |
| 20.23 | 4.39 | 79.10% |
| 20.44 | 4.34 | 46.30% |
| 20.84 | 4.26 | 19.80% |
| 21.24 | 4.18 | 9.70% |
| 21.74 | 4.09 | 28.00% |
| 22.58 | 3.93 | 32.50% |
| 23.05 | 3.86 | 23.60% |
| 23.66 | 3.76 | 13.80% |
| 24.08 | 3.69 | 16.50% |
| 24.65 | 3.61 | 12.00% |
| 25.61 | 3.48 | 19.20% |
| 26.70 | 3.34 | 29.80% |
| 27.35 | 3.26 | 30.80% |
| 27.75 | 3.21 | 14.90% |
| 28.56 | 3.12 | 11.60% |
| 28.87 | 3.09 | 11.10% |
Example 2: dynamic solubility of crystalline DCIII
When performing drug solubility tests to predict in vivo performance of drugs, it is important to simulate in vivo conditions as much as possible, and for oral administration, the use of SGF (simulated gastric fluid), FaSSIF (fasted state simulated intestinal fluid), FeSSIF (fed state simulated intestinal fluid) can simulate in vivo conditions and predict the effect of feeding, and the solubility tested in such media is closer to that in the human environment.
About 20 mg of the DCIII crystal form is suspended in 1.5 mL of SGF, 1.5 mL of FeSSIF, 1.5 mL of FaSSIF and 1.5 mL of water respectively to prepare suspension, and after 1 hour, 4 hours and 24 hours of balance, the content (mg/mL) of a sample in the solution is tested by high performance liquid chromatography respectively.
Example 3: intrinsic dissolution rates of crystalline forms DCIII
Weighing about 100mg of the crystal form DCIII of the invention, and pouring into the inherent solutionDischarging, and keeping under 5 kN pressure for 1min to obtain surface area of 0.5 cm2The die with the sheet is transferred to a dissolution apparatus to test the intrinsic dissolution rate.
Example 4: stability of crystalline form DCIII
The crystal form DCIII prepared by the method is weighed to be about 5mg, and is respectively placed at the temperature of 25 ℃/60% RH, 40 ℃/75% RH, 60 ℃/75% RH and 80 ℃ to determine the purity and the crystal form by HPLC and XRPD.
Example 5: mechanical stability of crystalline DCIII
Taking a proper amount of the crystal form DCIII, selecting a proper tabletting mold, carrying out compression molding without pressure, and carrying out XRPD test before and after tabletting;
or the crystalline form DCIII was placed in a mortar and manually milled for 5 minutes before and after milling for XRPD testing.
Example 6: hygroscopicity of crystalline DCIII
Weighing about 10 mg of the DCIII crystal form, testing the hygroscopicity of the DCIII crystal form by using a dynamic moisture adsorption (DVS) instrument, circulating once under the relative humidity of 0-90-0 percent, and recording the mass change at each temperature.
Description of hygroscopicity characteristics and definition of hygroscopicity increase (guidance of hygroscopicity experiment of medicament 9103 in Chinese pharmacopoeia 2020 edition, experimental conditions: 25 + -1 deg.C, 80% relative humidity):
deliquescence: absorb sufficient water to form liquid
Has the characteristics of moisture absorption: the moisture-attracting weight gain is not less than 15.0 percent
Moisture absorption: the moisture-attracting weight gain is less than 15.0 percent but not less than 2.0 percent
Slightly hygroscopic: the moisture-drawing weight gain is less than 2.0 percent but not less than 0.2 percent
No or almost no hygroscopicity: the moisture-drawing weight gain is less than 0.2 percent.
Example 7: particle size distribution of crystalline form DCIII
Taking 10-30 mg of prepared crystal form DCIII, then adding about 5mL of isopar G (containing 0.2% lecithin), fully and uniformly mixing a sample to be tested, adding the sample to be tested into a Hydro MV dispersing device to enable the shading degree to reach a proper pattern, starting an experiment, carrying out a particle size distribution test after 30 seconds of ultrasonic treatment, and measuring the particle size distribution.
Example 8: flowability of crystalline DCIII form
In the preparation process, the flowability of powder or particles can be generally evaluated by adopting a Compressibility index (Compressibility index) or a Carr index (Carr index), and the determination method comprises the steps of filling a certain amount of crystal form DCIII powder particle size into a measuring cylinder and then measuring the volume before tapping; the powder is in the tightest state by tapping method, and the volume after tapping is measured: calculating the bulk density P0 and the tap density Pr: the compressibility factor was calculated according to the formula c = (Pr-P0)/Pr.
The definition standard of the compressibility factor to the powder flowability is referred to USP <1174>, and is detailed in Table 2.
TABLE 2
| Compressibility factor (%) | Fluidity of the resin |
| ≦10 | Is excellent in |
| 11-15 | Good taste |
| 16-20 | In general |
| 21-25 | Can accept |
| 26-31 | Difference (D) |
| 32-37 | Is very poor |
| >38 | Extreme difference |
Example 9: adhesion of crystalline DCIII
Adding about 30 mg of crystal form DCIII into 8mm circular flat punch, performing tabletting treatment by adopting the pressure of 10kN, keeping for about half a minute after tabletting, weighing the powder amount adsorbed by the punch, and recording the accumulated final adhesion amount of the punch, the highest adhesion amount in the pressing process and the average adhesion amount after continuously pressing twice by adopting the method.
Example 10: preparation of crystalline DCIII form
And (3) tablet preparation: taking a proper amount of the crystal form DCIII, uniformly mixing with auxiliary materials, rolling to prepare slices, crushing into granules, uniformly mixing with the additional auxiliary materials, and pressing and forming by using a proper mold.
And (3) capsule preparation: taking a proper amount of the crystal form DCIII, uniformly mixing with auxiliary materials, rolling to prepare slices, crushing into granules, uniformly mixing with the additional auxiliary materials, and canning into capsules with proper sizes.
Example 11: stability in crystalline DCIII formulations
And packaging the crystal form DCIII preparation by using an HDPE bottle, placing the crystal form DCIII preparation under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, sampling and detecting crystal forms and impurities, and inspecting the preparation stability of the crystal form DCIII.
Example 12: in vitro dissolution of crystalline DCIII formulations
The preparation containing the crystal form DCIII is tested for in-vitro dissolution, and the dissolution is measured according to 0931 dissolution and release measurement methods in 2020 edition of Chinese pharmacopoeia.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (9)
1. Compound I
2. The crystalline form of compound I according to claim 1, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 1 or 2 or 3 of values of 4.4 ± 0.2 °, 8.9 ± 0.2 °, 16.8 ± 0.2 ° at 2theta using Cu-Ka radiation.
3. The crystalline form of compound I according to claim 2, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 1 or 2 or 3 of values at 2theta of 20.2 ± 0.2 °, 13.8 ± 0.2 °, 14.2 ± 0.2 °, using Cu-Ka radiation.
4. The crystalline form of compound I according to claim 2, characterized in that its X-ray powder diffraction pattern has characteristic peaks at 3 from 1 or 2 of values of 22.6 ± 0.2 °, 15.2 ± 0.2 °, 16.3 ± 0.2 ° at 2theta using Cu-Ka radiation.
5. A process for preparing a crystalline form of compound I according to claim 2, characterized in that: and (2) putting the solid of the compound I into an alcohol solvent to form a solution, then dropwise adding water into the solution until the solution is turbid, stirring for a period of time at a certain temperature, and separating and drying to obtain the crystal form of the compound.
6. The method of claim 5, wherein the selected alcohol is preferably ethanol; the volume ratio of the water to the alcohol solvent is preferably 2: 1-1: 1.5, and more preferably 1.2: 1; the stirring temperature is preferably-20-30 ℃, and more preferably 5 ℃; the drying conditions are preferably 20 to 50 ℃.
7. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of compound I according to claim 1 and a pharmaceutically acceptable carrier or adjuvant.
8. Use of a crystalline form of compound I as claimed in claim 1 in the manufacture of a medicament of a KRAS G12C inhibitor.
9. Use of a crystalline form of compound I as claimed in claim 1 for the preparation of a medicament for the treatment of a disease associated with a mutation in the KRAS G12C gene.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| US12162893B2 (en) | 2020-09-23 | 2024-12-10 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10689377B2 (en) * | 2017-11-15 | 2020-06-23 | Mirati Therapeutics, Inc. | KRas G12C inhibitors |
| PL3966206T3 (en) * | 2019-05-10 | 2024-01-29 | Deciphera Pharmaceuticals, Llc | Heteroarylaminopyrimidinamide autophagy inhibitors and methods of their use |
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2021
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12162893B2 (en) | 2020-09-23 | 2024-12-10 | Erasca, Inc. | Tricyclic pyridones and pyrimidones |
| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
| WO2022235864A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors |
| WO2024206858A1 (en) | 2023-03-30 | 2024-10-03 | Revolution Medicines, Inc. | Compositions for inducing ras gtp hydrolysis and uses thereof |
| WO2024229406A1 (en) | 2023-05-04 | 2024-11-07 | Revolution Medicines, Inc. | Combination therapy for a ras related disease or disorder |
| WO2025034702A1 (en) | 2023-08-07 | 2025-02-13 | Revolution Medicines, Inc. | Rmc-6291 for use in the treatment of ras protein-related disease or disorder |
| WO2025080946A2 (en) | 2023-10-12 | 2025-04-17 | Revolution Medicines, Inc. | Ras inhibitors |
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| CN114920739A (en) | 2022-08-19 |
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