Crystalline fumarate of MRTX0902

Abstract

The present invention relates to the fumarate crystal of MRTX0902((R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile), a pharmaceutical composition containing the crystal, a process for preparing the crystal, and a method for using the same.

Description

TECHNICAL FIELD

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 545,133, filed on October 20, 2023, the entire contents of which are incorporated herein by reference in their entirety.

[0002] (FIELD OF THE INVENTION) The present invention relates to crystalline forms of the fumarate salt of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile (also known as "MRTX0902"), pharmaceutical compositions comprising the present crystalline forms, processes for preparing the present crystalline forms, and methods of use thereof.

BACKGROUND ART

[0003] The Ras family includes v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma viral oncogene homolog (HRAS), which critically regulate cell division, growth, and function in normal and altered states (including cancer) (see, e.g., Simanshu et al. Cell, 2017. 170(1): p. 17-33; Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12). RAS proteins are activated by upstream signals including receptor tyrosine kinases (RTKs) and transduce signals to several downstream signaling pathways, such as the mitogen-activated protein kinase (MAPK) / extracellular signal-regulated kinase (ERK) pathway. Overactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in the RAS gene or other genes in the RAS pathway. The identification of strategies to inhibit RAS and RAS signaling is expected to be useful for the treatment of cancer and RAS-mediated pathological conditions.

[0004] The RAS protein is a guanosine triphosphate phosphatase (GTPase) that alternates between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate-bound state. Son of sevenless homolog 1 (SOS1) is a guanine nucleotide exchange factor (GEF) that mediates the exchange of GDP to GTP, thereby activating the RAS protein. The RAS protein hydrolyzes GTP to GDP via endogenous GTPase activity, which is greatly promoted by GTPase-activating protein (GAP). This regulation mediated by GAP and GEF is a mechanism that strictly controls activation and inactivation under normal conditions. Mutations in several residues of all three RAS proteins are frequently observed in cancer, resulting in RAS overwhelmingly remaining in an activated state (Sanchez-Vega et al., Cell, 2018. 173: p. 321-337; Li et al., Nature Reviews Cancer, 2018. 18: p. 767-777). Mutations at codons 12 and 13 are the most frequent mutant RAS residues, inhibiting the interaction between the GAP protein and RAS, thereby preventing GAP-stimulated GTP hydrolysis. However, recent biochemical analyses have shown that these mutant proteins still require nucleotide cycling for activation that depends on endogenous GTPase activity and / or partial sensitivity to exogenous GTPases. Therefore, mutant RAS proteins are affected by the inhibition of upstream factors such as SOS1 or SHP2 (another upstream signaling molecule required for RAS activation) (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018).

[0005] The three main RAS-GEF families identified in mammalian cells are SOS, RAS-GRF, and RAS-GRP (Rojas, 2011). The SOS family is ubiquitous and plays a role in RTK signaling, while RAS-GRF and RAS-GRP are expressed in central nervous system cells and hematopoietic cells, respectively. The SOS family includes SOS1 and SOS2, and these proteins share approximately 70% sequence identity. SOS1 appears to be much more active than SOS2 because SOS2 is rapidly degraded. SOS2 knockout mice are viable, while SOS1 knockouts are embryonic lethal. To investigate the roles of SOS1 and SOS2 in adult mice, a tamoxifen-induced SOS1 knockout mouse model was used. It was shown that SOS1 knockout mice were viable, while SOS1 / 2 double knockout mice were not (Baltanas, 2013), suggesting that functional redundancy and selective inhibition of SOS1 may have a sufficient therapeutic index for treating SOS1-RAS activation disorders.

[0006] The SOS protein is recruited to phosphorylated RTKs via interaction with growth factor receptor-binding protein 2 (GRB2). Recruitment to the cell membrane brings SOS close to the RAS, enabling SOS-mediated RAS activation. The SOS protein binds to the RAS via a binding site that promotes nucleotide exchange, and via an allosteric site that enhances SOS function by binding to GTP-binding RAS family proteins (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97). Binding to the allosteric site is necessary for nucleotide exchange because it relieves steric occlusion of the RAS substrate binding site. After interaction with the allosteric site, the maintenance of the activated structure at the catalytic site is maintained in a separated state by enhanced interaction of the major domains in the activated state. SOS1 mutations are found in Noonan syndrome, as well as in several cancers, including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and granular cell tumors of the skin (see, for example, Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).

[0007] GTPase-activating proteins (GAPs) stimulate the low endogenous GTPase activity of RAS family members, thereby converting active GTP-binding RAS proteins into inactive GDP-binding RAS proteins (see, for example, Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease). In cancer, while activating changes in GEF SOS1 occur, inactivating mutations and loss-of-function changes in GAP neurofibromin 1 (NF-1) or neurofibromin 2 (NF-2) also occur, resulting in a state where SOS1 activation is not inhibited, and the activity of downstream pathways mediated by RAS proteins is increased.

[0008] Therefore, the compounds of the present invention that inhibit the interaction between SOS1 and RAS family members prevent the recycling of KRas to its active GTP-bound form, thereby potentially providing therapeutic effects against a wide range of cancers, particularly those associated with Ras family members. The compounds of the present invention have therapeutic effects as inhibitors of SOS1-KRas interaction and may be useful for negative regulation of KRas activity through inhibition of SOS1-KRas interaction in cells, for the treatment of various forms of cancer (Ras-related cancers, SOS1-related cancers, and NF1 / NF2-related cancers).

[0009] The SOS1 inhibitor compound (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile (also known as MRTX0902) has the following structure: [ka] It has.

[0010] MRTX0902 is described, for example, in Example 12-10 of the PCT application International Publication No. 2021 / 127429.

[0011] Process development for pharmaceutical compositions plays a crucial role in balancing the desired pharmacological properties of therapeutic agents in solid-state pharmaceutical compounds. For example, identifying appropriate crystalline and salt forms of solid therapeutic agents can positively impact the dissolution rate, solubility, bioavailability, manufacturing, packaging, and / or shelf life of the pharmaceutical composition. Furthermore, amorphous compounds may require capsule or spray-dried forms, while crystalline compounds may be compressed into tablets for oral administration.

[0012] For all the reasons mentioned above, there is a need to produce solid, crystalline salt forms of MRTX0902 that can ideally provide improved dissolution rate, solubility, bioavailability, manufacturing improvements, and / or shelf life of the pharmaceutical composition. The present invention beneficially addresses one or more of these needs. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Simanshu et al. Cell, 2017. 170(1): p. 17-33 [Non-Patent Document 2] Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12 [Non-Patent Document 3] Sanchez-Vega et al., Cell, 2018. 173: p. 321-337 [Non-Patent Document 4] Li et al., Nature Reviews Cancer, 2018. 18: p. 767-777 [Non-Patent Document 5] Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97 [Non-Patent Document 6] Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52 [Non-Patent Document 7] Simanshu, DK, Cell, 2017, Ras Proteins and their Regulators in Human Disease [Overview of the project]

[0014] In one embodiment of the present invention, fumarate crystals of the SOS1 inhibitor (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile ("MRTX0902") are provided herein.

[0015] In certain embodiments, the crystal form is fumarate crystal form A. In certain embodiments, the fumarate crystal form A has an X-ray powder diffraction pattern comprising at least one characteristic peak at a °2θ value selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2. In some embodiments, only one characteristic peak is included. In some embodiments, two characteristic peaks are included. In some embodiments, three characteristic peaks are included. In some embodiments, four characteristic peaks are included. In some embodiments, five characteristic peaks are included. In some embodiments, six characteristic peaks are included. In some embodiments, seven characteristic peaks are included. In some embodiments, eight characteristic peaks are included. In some embodiments, nine characteristic peaks are included. In some embodiments, ten characteristic peaks are included.

[0016] In certain embodiments, the fumarate crystal form A has an X-ray powder diffraction pattern comprising peaks at °2θ values of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0017] In another embodiment, the fumarate crystal form A has an X-ray powder diffraction pattern comprising peaks at °2θ values of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0018] In another embodiment, the fumarate crystal form A has an X-ray powder diffraction pattern comprising two or more peaks at °2θ values of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0019] In another embodiment, crystalline fumarate Form A has an X-ray powder diffraction pattern comprising three or more peaks at °2θ values of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0020] In another embodiment, crystalline fumarate Form A exhibits an XRPD pattern substantially as shown in Figure 1.

[0021] In one embodiment, crystalline fumarate Form A is characterized by having an endothermic peak onset at about 248°C as measured by differential scanning calorimetry ("DSC"). In another embodiment, crystalline fumarate Form A has a DSC thermogram substantially as shown in Figure 2.

[0022] In another embodiment, crystalline fumarate Form A has both 1) one or more of the DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0023] In another embodiment, crystalline fumarate Form A has both 1) one or more of the DSC characteristics described above; and 2) an X-ray powder diffraction pattern comprising peaks at °2θ of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0024] In one embodiment, crystalline fumarate Form A is characterized by exhibiting a mass loss of about 0.02 to 0.25% up to the onset of decomposition at about 150°C, as estimated by thermogravimetric analysis ("TGA"). In another embodiment, crystalline fumarate Form A has a TGA profile substantially as shown in Figure 2.

[0025] In another embodiment, fumarate crystal A has either 1) one or more of the above-mentioned TGA features; or 2) an X-ray powder diffraction pattern including at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0026] In one embodiment, fumarate crystal A is characterized by the observation of adsorption of approximately 0.13 to 0.16% water at 25°C / 80% relative humidity (RH) when measured by dynamic water vapor adsorption ("DVS").

[0027] In another embodiment, fumarate crystal A has DVS isotherms substantially as shown in Figure 3.

[0028] In another embodiment, fumarate crystal A has either 1) one or more DVS features as described above; or 2) an X-ray powder diffraction pattern including at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0029] In another embodiment, fumarate crystal A has both 1) one or more DVS features as described above; and 2) an X-ray powder diffraction pattern including peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0030] In one embodiment, fumarate crystal A is substantially free of residual organic solvents.

[0031] In one embodiment, the fumarate crystal of the present invention is at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% crystalline.

[0032] In another aspect of the present invention, a pharmaceutical composition is provided for use in a method characterized by at least one fumarate crystal A and a pharmaceutically acceptable excipient. The present invention also encompasses pharmaceutical compositions comprising any other fumarate crystal described herein.

[0033] The present invention also encompasses any mixture of the amorphous form of MRTX0902 and any of the described fumarate crystals.

[0034] In one embodiment, the fumarate crystal is a mixture of any of the described fumarate crystals and / or MRTX0902 fumarate amorphous material and fumarate crystal A.

[0035] In some embodiments, the pharmaceutical composition of the present invention comprises at least 95%, or at least 80%, or at least 70%, or at least 60%, or at least 50%, of fumarate crystal A of MRTX0902.

[0036] In one embodiment of the present invention, a method for inhibiting the SOS1 activity of cells is provided herein, comprising contacting cells in which inhibition of SOSI activity is desired with a therapeutically effective amount of the crystal of the present invention, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents. In one embodiment, the fumarate crystal is fumarate crystal A. In another embodiment, the fumarate crystal is any other crystal described herein.

[0037] In one embodiment of the present invention, a method for treating a target cancer requiring treatment is provided herein, comprising administering to the target a therapeutically effective amount of MRTX0902 fumarate crystals. In one embodiment, the cancer is an SOS1-associated cancer. In one embodiment, the SOS1-associated cancer is lung cancer.

[0038] In one embodiment, the fumarate crystal is fumarate crystal A. In another embodiment, the fumarate crystal is any other crystal described in this application.

[0039] Furthermore, the Specified Methods for Treating Target Cancers in Need of Treatment include (a) determining that the cancer is associated with an SOS1 mutation (e.g., an SOS1-associated cancer) (e.g., determined using a regulatory-approved (e.g., FDA-approved) assay or kit); and (b) administering to a patient a therapeutically effective amount of MRTX0902 fumarate crystals, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.

[0040] In one embodiment, the subjects are adult patients. In another embodiment, the subjects are pediatric patients.

[0041] In some embodiments of any of the methods described herein, prior to treatment with the composition or method of the present invention, the patient has been treated with one or more chemotherapy regimens, targeted anticancer agents, radiotherapy, and surgical procedures, where the prior treatments were unsuccessful; and / or the patient has undergone surgery, where the surgery was unsuccessful; and / or the patient has been treated with platinum-based chemotherapeutic agents, where the patient was previously measured to be unresponsive to treatment with platinum-based chemotherapeutic agents; and / or the patient has been treated with kinase inhibitors, where prior treatment with kinase inhibitors was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents.

[0042] In another embodiment of the present invention, a process for preparing fumarate crystals of MRTX0902 is provided herein. In one embodiment, the process describes the preparation of fumarate crystal A. In another embodiment, the process describes the preparation of other crystals of MRTX0902. [Brief explanation of the drawing]

[0043] [Figure 1] Figure 1 shows the X-ray powder diffraction (XRPD) patterns of fumarate crystal type A of MRTX0902 prepared from a 95% EtOH solvent system, a THF / 95% EtOH solvent system, and a fumarate standard. [Figure 2A] Figure 2A illustrates the integrated thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) profiles of fumarate crystal A prepared from a 95% EtOH solvent system. [Figure 2B] Figure 2B illustrates the integrated TGA and DSC profiles of fumarate crystal A prepared from a THF / 95% EtOH solvent system. [Figure 3A] Figure 3A illustrates the dynamic water vapor adsorption (DVS) isotherm profile of fumarate crystal A prepared from a 95% EtOH solvent system. [Figure 3B] Figure 3B illustrates the DVS isotherm profile of fumarate crystal A prepared from a THF / 95% EtOH solvent system. [Figure 4] Figure 4 shows the 1H-NMR profiles of fumarate crystal A prepared from a 95% EtOH solvent system, a THF / 95% EtOH solvent system, and a fumarate standard. [Figure 5] Figure 5 shows the compactability profiles of free base crystal F, free base crystal J, and fumarate crystal A of MTRX0902. [Figure 6] Figure 6 shows the tabletability profiles of free base crystal F, free base crystal J, and fumarate crystal A of MTRX0902. [Figure 7]Figure 7 shows the compressibility profiles of free base crystal F, free base crystal J, and fumarate crystal A of MTRX0902. [Modes for carrying out the invention]

[0044] This invention relates to the fumarate crystal of the SOS1 inhibitor MRTX0902((R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile). In particular, this invention relates to fumarate crystal A, a pharmaceutical composition containing the crystal, a preparation process for the crystal, and a method of using the same.

[0045] (definition) Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. All patents, patent applications, and publications referenced herein are incorporated herein by reference.

[0046] As used herein, "SOS1" refers to the mammalian Son of Sevenless homolog 1 (SOS1) enzyme.

[0047] As used herein, "SOS1-related disease or disorder" refers to a disease or disorder associated with, mediated by, or involving an active SOS1 mutation. Examples of active SOS1 mutations include SOS1 N233S and SOS1 N233Y mutations.

[0048] As used herein, "SOS1 N233S" refers to a variant of the mammalian SOS1 protein containing a serine amino acid substitution of glutamine at amino acid position 233. The assignment of amino acid codons and residue positions for human SOS1 is based on the amino acid sequence identified in UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Ser.

[0049] As used herein, "SOS1 N233Y" refers to a variant of the mammalian SOS1 protein containing a tyrosine substitution of glutamine at amino acid position 233. The assignment of amino acid codons and residue positions for human SOS1 is based on the amino acid sequence identified in UniProtKB / Swiss-Prot Q07889: Variant p.Gln233Tyr.

[0050] As used herein, “SOS1 inhibitor” refers to the compounds of the present invention represented by formula (I) as described herein. These compounds can negatively inhibit all or part of the interaction between SOS1 and Ras family variants or SOS1 activating variants, thereby reducing and / or regulating the nucleotide exchange activity of the Ras family member-SOS1 complex.

[0051] As used herein, “NF-1 / NF-2 related disease or disorder” refers to a disease or disorder that is associated with, mediated by, or has a loss-of-function mutation in the neurofibromin (NF-1) gene or the neurofibromin 2 (NF-2) gene.

[0052] As used herein, “loss-of-function mutation” means any point mutation, splice site mutation, fusion, nonsense mutation (in which an amino acid is mutated into a stop codon), insertion and deletion, in-frame or frameshift mutation, and homozygous deletion of a gene encoding a protein in a target cell or cancer cell, resulting in a partial or complete loss of the presence, activity, and / or function of the encoded protein.

[0053] As used herein, the term "fumarate" includes, but is not limited to, compositions in which the chemical amounts of acid and base are approximately 1:1.

[0054] As used herein, the term "solvate" refers to the fumarate crystal of MRTX0902 containing a solvent.

[0055] As used herein, the term "hydrate" refers to a solvate in which the solvent contains water.

[0056] As used herein, the term "residual organic solvent" refers to organic volatile chemicals used or generated in a crystallization / manufacturing process that are not completely removed by the manufacturing technique.

[0057] As used herein, the term "substantially free of residual organic solvents" means that a manufactured pharmaceutical formulation (for example, a pharmaceutical formulation containing MRTX0902 fumarate crystals) contains less than 1.0% by weight of residual organic solvents, less than 0.5% by weight of residual organic solvents, less than 0.4% by weight of residual organic solvents, less than 0.3% by weight of residual organic solvents, less than 0.2% by weight of residual organic solvents, or less than 0.1% by weight of residual organic solvents.

[0058] As used herein, "SOS1-related disease or disorder" refers to a disease or disorder that is associated with, mediated by, or involves an SOS1 mutation. Examples of SOS1-related diseases or disorders include, but are not limited to, SOS1-related cancers.

[0059] As used herein, the terms “subject,” “individual,” and “patient” are used interchangeably and refer to any animal, including mammals (e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans). In some embodiments, the patient is human. In some embodiments, the subject has experienced and / or exhibits at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed with cancer having an SOS1 mutation (e.g., determined using a regulatory-approved assay or kit, e.g., FDA-approved). In some embodiments, the subject has a tumor that is SOS1 mutation-positive (e.g., determined using a regulatory-approved assay or kit). The subject may have a tumor that is SOS1 mutation-positive (e.g., identified as positive using a regulatory-approved assay or kit, e.g., FDA-approved). The subject may have a tumor that has an SOS1 mutation (e.g., the tumor was identified as such using a regulatory-approved kit, e.g., FDA-approved). In some embodiments, the subject is suspected of having an SOS1 gene-associated cancer. In some embodiments, the subject has a clinical record indicating that they have a tumor with an SOS1 mutation (where applicable, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0060] As used herein, the term "pediatric patient" refers to a patient who was under 16 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups: neonates (from birth to 1 month of age); infants (1 month to 2 years of age); boys (2 years to under 12 years of age); and adolescents (12 years to 21 years of age (before their 22nd birthday)). [References: Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: WB Saunders Company, 1996; Rudolph AM, et al. Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.]

[0061] In any of the embodiments of the methods or uses described herein, the assay is used to determine whether a patient has the SOS1 mutation using a sample (e.g., a biological or biopsy sample (e.g., paraffin-embedded biopsy specimen)) of a patient (e.g., a patient suspected of having SOS1-related cancer, a patient with one or more symptoms of SOS2-related cancer, and / or a patient at high risk of developing SOS1-related cancer), and examples of such methods include next-generation sequencing, immunohistochemical staining, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification methods (e.g., RT-PCR and quantitative real-time RT-PCR, allele-specific genotyping, or ddPCR). As is well known in the art, the assay is typically performed using, for example, at least one labeled nucleic acid probe or at least one labeled antibody or its antigen-binding fragment.

[0062] The term "regulatory authority" refers to a national agency responsible for approving the medical use of a drug in that country. An example of a regulatory authority that is not limited to this is the U.S. Food and Drug Administration (FDA).

[0063] As used herein, a “therapeutic effective dose” of MRTX0902 fumarate crystals means an amount sufficient to alleviate or reduce symptoms in any way, halt or reverse disease progression, or negatively modulate or inhibit SOS1 activity. Such a dose may be a single dose or administered according to a regimen to produce an effect.

[0064] As used herein, "treatment" means any method that improves or otherwise beneficially alters the symptoms or pathology of a medical condition, disorder, or disease. Treatment also encompasses any medicinal use of the compositions herein.

[0065] As used herein, improvement of symptoms of a particular disorder by administration of a particular pharmaceutical composition means any relief that may be caused by or associated with the administration of such composition, whether permanent or temporary, sustained or transient.

[0066] As used herein, the term "about" means, when used to modify a numerically defined parameter (for example, the dose or duration of treatment of MRTX0902 fumarate crystals as described herein), that the parameter may vary within a range of ±10% from the numerical value stated for that parameter. For example, a dose of about 5 mg / kg may vary within the range of 4.5 mg / kg to 5.5 mg / kg. When used at the beginning of a list of parameters, "about" means modifying 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. Similarly, 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.

[0067] As used herein, the term "approximately" refers, when used with respect to XRPD peak position, to the inherent variability of the peak due to instrument calibration, the processes used to prepare the crystals of the present invention, the changes in the crystals over time, and the type of instrument used for the analysis. The variability of the instrument used for the XRPD analysis was approximately ±0.2°²θ.

[0068] General methods and apparatus The general methods outlined below were used in the examples unless otherwise noted.

[0069] To confirm the formation of preferred fumarate crystals of MRTX0902, the crystals may be analyzed using any suitable analytical method or assay procedure, including, but not limited to, X-ray powder diffraction, NMR, differential scanning calorimetry, thermogravimetric analysis, and dynamic water vapor adsorption. The crystals are typically produced in amounts greater than 50%, 60%, 70%, 80%, 90%, or 95% by weight as isolation yield.

[0070] In one embodiment, the crystalline material of the present invention is at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% crystalline.

[0071] Apparatus and method

[0072] X-ray powder diffraction (XRPD) Equipment:Panalytical Empyrean Parameters: X-ray tube Cu (Kα radiation); tube voltage 45kV; tube current 40mA Scan range: 2~40 2θ(°) Step size: 0.01° Scanning speed: 1.31°(2θ) / min

[0073] Thermogravimetric analysis (TGA) Equipment: TA Instruments Discovery TGA Parameters: Heating rate 10°C / min, 25-300°C, 50 mL / min N2 sweep

[0074] Differential Scanning Calorimetry (DSC) Equipment: TA Instruments Discovery DSC Parameters: Heating rate 10°C / min, up to 300°C

[0075] Dynamic water vapor adsorption measurement (DVS)

[0076] Dynamic water vapor adsorption was performed using a TA Instruments Q5000SA DVS under a nitrogen stream at 25°C. The amount of substance was approximately 10-15 mg. The samples were analyzed by the following method.

[0077] About anhydrous substances: 0% RH to 90% RH (in 10% RH increments) 90% RH to 0% RH (in increments of 10% RH)

[0078] nuclear magnetic resonance (NMR) Equipment: Bruker 400MHz UltraShield Software: Topspin 3.2

[0079] Polymorphic screening experiment 1. Addition of poor solvent - Approximately 30 mg of the solid was dissolved in a solvent to prepare a saturated solution, and a poor solvent was added up to a maximum of 20 times its volume. The resulting solid was characterized by XRPD. 2. Solid vapor diffusion - Approximately 30 mg of solid was stored in a 4 mL HPLC vial, and the vial was placed in a 20 mL glass vial containing solvent. After 14 days, the obtained solid was characterized by XRPD. 3. Liquid vapor diffusion - Approximately 30 mg of the solid was dissolved in a solvent, and a saturated solution was prepared in a 4 mL HPLC vial. The vial was then placed in a 20 mL glass vial containing a poor solvent. After 10 days, the obtained solid was characterized by XRPD. 4. Slurry at room temperature - Approximately 30 mg of solid was slurryed in a 4 mL HPLC vial at room temperature using a stirring bar in various solvents. After 7 days, the solid in the slurry was characterized by XRPD. 5. Slurry at 50°C - Approximately 30 mg of solid was slurryed at 50°C in a 4 mL HPLC vial using a machine, in various solvents. After 3-5 days, the solid in the slurry was characterized by XRPD. 6. Slow evaporation at 6.50°C - Approximately 30 mg of solid was dissolved in a solvent, and a saturated solution was prepared in a 4 mL HPLC vial. The vial was covered with paraffin film and 3-5 holes were made. The obtained solid was characterized by XRPD. 7. Temperature Cycling - Approximately 30 mg of the solid was slurryed in a solvent, and a suspension was prepared in a 4 mL glass vial at room temperature. The vial was placed in a mechanical shaker, and three cycles were performed, cooling from a starting temperature of 50°C to 5°C. The resulting solid was characterized by XRPD. 8. Slow Cooling - Approximately 30 mg of the solid was dissolved in a solvent, and a saturated solution was prepared in a 4 mL glass vial. The vial was placed in a mechanical shaker and treated at the following five temperature settings: 50°C for 3 hours, 40°C for 4 hours, 25°C for 4 hours, 10°C for 5 hours, and 5°C for 5 hours. The resulting solid was characterized by XRPD. 9. Polymer-induced crystallization - Approximately 30 mg of solid was dissolved in a solvent to prepare a saturated solution. PVP, PVA, or PVC was added to the saturated solution to induce heteronucleation.

[0080] Abbreviations related to solvents The abbreviations for the solvents used are listed in the table below. [Table 1]

[0081] Polymorphic screening experiment and results [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0082] Approximate solubility (MRTX0902 fumarate) [Table 12] [Table 13]

[0083] SOS1 inhibitors In one aspect of the present invention, fumarate crystals of MRTX0902, also known as (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile, are provided herein.

[0084] The method for manufacturing MRTX0902 is known. For example, MRTX0902 is described in Example 12-10 of PCT International Publication No. 2021 / 127429.

[0085] Fumarate crystals of MRTX0902

[0086] In one embodiment, the crystalline material is fumarate crystal A. In one embodiment, fumarate crystal A has an X-ray powder diffraction pattern ("XRPD") that includes at least one characteristic peak at a °2θ value selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2. In some embodiments, it includes only one characteristic peak. In some embodiments, it includes two characteristic peaks. In some embodiments, it includes three characteristic peaks. In some embodiments, it includes four characteristic peaks. In some embodiments, it includes five characteristic peaks. In some embodiments, it includes six characteristic peaks. In some embodiments, it includes seven characteristic peaks. In some embodiments, it includes eight characteristic peaks. In some embodiments, it includes nine characteristic peaks. In some embodiments, it includes ten characteristic peaks.

[0087] In one embodiment, fumarate crystal A has an X-ray powder diffraction pattern that includes peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0088] In another embodiment, fumarate crystal A has an X-ray powder diffraction pattern that includes peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0089] In another embodiment, fumarate crystal A has an X-ray powder diffraction pattern that includes two or more peaks at °2θ of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0090] In another embodiment, fumarate crystal A has an X-ray powder diffraction pattern that includes three or more peaks at °2θ of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0091] In other embodiments, fumarate crystal A has substantially the XRPD pattern shown in Figure 1.

[0092] In one embodiment, it is characterized by having an endothermic peak onset at approximately 248°C when measured by differential scanning calorimetry ("DSC"). In another embodiment, fumarate crystal A has a DSC thermogram substantially as shown in Figure 2.

[0093] In another embodiment, fumarate crystal A has both 1) one or more DSC features as described above; and 2) an X-ray powder diffraction pattern including at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0094] In another embodiment, fumarate crystal A has both 1) the characteristics of one or more DSCs described above; and 2) an X-ray powder diffraction pattern including peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0095] In one embodiment, fumarate crystal A is characterized by a mass loss of approximately 0.02–0.25% until decomposition begins at approximately 150°C, as estimated by thermogravimetric analysis ("TGA"). In another embodiment, fumarate crystal A has substantially the TGA profile shown in Figure 2.

[0096] In another embodiment, fumarate crystal A has either 1) one or more of the above-mentioned TGA features; or 2) an X-ray powder diffraction pattern including at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0097] In one embodiment, fumarate crystal A is characterized by the observation of adsorption of approximately 0.13 to 0.16% water at 25°C / 80% relative humidity (RH) when measured by dynamic water vapor adsorption ("DVS").

[0098] In another embodiment, fumarate crystal A has DVS isotherms substantially as shown in Figure 3.

[0099] In another embodiment, fumarate crystal A has either 1) one or more DVS features as described above; or 2) an X-ray powder diffraction pattern including at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.2.

[0100] In another embodiment, fumarate crystal A has both 1) one or more DVS features as described above; and 2) an X-ray powder diffraction pattern including peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.2.

[0101] In one embodiment, fumarate crystal A is substantially free of residual organic solvents.

[0102] In one embodiment, the fumarate crystal of the present invention is at least 40%, 50%, 60%, 70%, 80%, 90%, or 95% crystalline.

[0103] In another aspect of the present invention, a pharmaceutical composition is provided for use in a method characterized by at least one fumarate crystal A and a pharmaceutically acceptable excipient. The present invention also encompasses pharmaceutical compositions comprising any other fumarate crystal described herein.

[0104] The present invention also encompasses any mixture of the amorphous form of MRTX0902 and any of the described fumarate crystals.

[0105] In one embodiment, the fumarate crystal is a mixture of any of the described fumarate crystals and / or MRTX0902 fumarate amorphous material and fumarate crystal A.

[0106] In some embodiments, the pharmaceutical composition of the present invention comprises at least 95%, or at least 80%, or at least 70%, or at least 60%, or at least 50%, of fumarate crystal A of MRTX0902.

[0107] In one embodiment of the present invention, a method for inhibiting the SOS1 activity of cells is provided herein, comprising contacting cells in which inhibition of SOSI activity is desired with a therapeutically effective amount of the crystal of the present invention, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents. In one embodiment, the fumarate crystal is fumarate crystal A. In another embodiment, the fumarate crystal is any other crystal described herein.

[0108] In one embodiment of the present invention, a method for treating a target cancer requiring treatment is provided herein, comprising administering to the target a therapeutically effective amount of MRTX0902 fumarate crystals. In one embodiment, the cancer is an SOS1-associated cancer. In one embodiment, the SOS1-associated cancer is lung cancer.

[0109] In one embodiment, the fumarate crystal is fumarate crystal A. In another embodiment, the fumarate crystal is any other crystal described in this application.

[0110] Furthermore, the Specified Methods for Treating Target Cancers in Need of Treatment include (a) determining that the cancer is associated with an SOS1 mutation (e.g., an SOS1-associated cancer) (e.g., determined using a regulatory-approved (e.g., FDA-approved) assay or kit); and (b) administering to a patient a therapeutically effective amount of MRTX0902 fumarate crystals, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.

[0111] In one embodiment, the subjects are adult patients. In another embodiment, the subjects are pediatric patients.

[0112] In some embodiments of any of the methods described herein, prior to treatment with the composition or method of the present invention, the patient has been treated with one or more chemotherapy regimens, targeted anticancer agents, radiotherapy, and surgical procedures, where the prior treatments were unsuccessful; and / or the patient has undergone surgery, where the surgery was unsuccessful; and / or the patient has been treated with platinum-based chemotherapeutic agents, where the patient was previously measured to be unresponsive to treatment with platinum-based chemotherapeutic agents; and / or the patient has been treated with kinase inhibitors, where prior treatment with kinase inhibitors was unsuccessful; and / or the patient has been treated with one or more other therapeutic agents.

[0113] In another embodiment of the present invention, a process for preparing fumarate crystals of MRTX0902 is provided herein. In one embodiment, the process describes the preparation of fumarate crystal A. In another embodiment, the process describes the preparation of other crystals of MRTX0902.

[0114] Pharmaceutical composition

[0115] In another embodiment, the present invention provides a pharmaceutical composition comprising MRTX0902 fumarate crystals and a pharmaceutically acceptable carrier, excipient, or diluent, which may be used in the methods disclosed herein. The MRTX0902 crystals may be formulated in any method known in the art and prepared for administration by any route (including, but not limited to, parenteral, oral, sublingual, transdermal, topical, nasal, intratracheal, or rectal). In certain embodiments, the MRTX0902 fumarate crystals are administered intravenously in a hospital setting. In some embodiments, administration may be via the oral route.

[0116] In one aspect of the present invention, a pharmaceutical composition is provided for use in a method comprising at least one fumarate crystal A in a therapeutically effective amount and a pharmaceutically acceptable excipient. The present invention also encompasses pharmaceutical compositions comprising any other fumarate crystal described herein.

[0117] The present invention also encompasses any mixture of the amorphous form of MRTX0902 and any of the described fumarate crystals.

[0118] In some embodiments, the pharmaceutical composition of the present invention comprises at least 95%, or at least 80%, or at least 70%, or at least 60%, or at least 50%, of fumarate crystal A of MRTX0902.

[0119] The characteristics of the carrier vary depending on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic substance that is compatible with a biological system (e.g., cells, cell cultures, tissues, or organisms) and does not interfere with the efficacy of the biological activity of the active ingredient. Therefore, the compositions of the present invention may, in addition to the inhibitor, include diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances well known in the art. Preparation of pharmaceutically acceptable formulations is described, for example, in Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0120] The active compound is contained in a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective dose to the patient without causing serious toxicity to the patient being treated. In one embodiment, the dose of the active compound for all of the above conditions ranges from about 0.01 to about 300 mg / kg, about 0.1 to about 100 mg / kg per day, about 0.5 to about 50 mg / kg per day, or about 1 to about 25 mg / kg per day. A typical topical dose would be in the range of 0.01 to 3% by weight / kg in a suitable carrier. The effective dose range of a pharmaceutically acceptable derivative can be calculated based on the weight of the parent compound being delivered. If the derivative is active on its own, the effective dose can be estimated using the weight of the derivative as described above, or by other methods known to the parties.

[0121] A pharmaceutical composition containing MRTX0902 fumarate crystals may be used in the manner of use described herein.

[0122] How to use

[0123] The compositions and methods provided herein may be used to treat a variety of cancers, including tumors such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, and testicular cancer. More specifically, cancers that can be treated with the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds include: heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; digestive system: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma) ), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary system: gallbladder cancer, ampulla cancer, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cystoma Cell tumors, osteochondroma (chondrodystomas), benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors; nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteoosteitis), meninges (meningiomas, meningiosarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymal cell tumors, germ cell tumors (pineal gland tumors), glioblastoma multiforme, oligodendroglioma, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);Gynecological: Uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma), fallopian tube (cancer); blood System: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: may be used to treat neuroblastoma.

[0124] Furthermore, the Specified Provisions also provide a method for treating a target cancer in need of treatment, comprising: (a) determining that the cancer is associated with an SOS1 mutation (e.g., an SOS1-associated cancer) (e.g., determined using a regulatory-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a therapeutically effective amount of MRTX0902 fumarate crystals, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.

[0125] In one embodiment, the subjects are adult patients. In another embodiment, the subjects are pediatric patients.

[0126] In one embodiment, the fumarate crystalline form of MRTX0902 is administered as a capsule during the period. In embodiments of the present invention, the tablets or capsules contain approximately 10 mg to approximately 1500 mg, for example, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 0 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, and approximately 1500 mg.

[0127] In one embodiment, the method includes oral administration of crystalline material in amounts of approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 250 mg, approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 500 mg, approximately 600 mg, approximately 700 mg, approximately 800 mg, approximately 900 mg, approximately 1000 mg, approximately 1100 mg, approximately 1200 mg, approximately 1300 mg, approximately 1400 mg, and approximately 1500 mg, once or twice daily (during the period). Oral administration of MRTX0902 crystalline material is performed, for example, once daily (during the period). In one embodiment, MRTX0902 is administered orally once daily. In one embodiment, MRTX0902 crystals are administered orally twice a day.

[0128] Those skilled in the art will understand that both in vivo and in vitro studies using known and generally accepted appropriate cell and / or animal models predict the ability of a test compound included in a combination, or the combination thereof, to treat or prevent a particular disease.

[0129] Furthermore, those skilled in the art will understand that human clinical trials, including first-in-human trials, dose-finding trials, and efficacy trials, involving healthy subjects and / or subjects suffering from specific diseases, can be conducted in accordance with methods well known in the clinical and medical fields.

[0130] In some embodiments, the methods provided herein are for 1 day to 2 years (for example, 1 day to 22 months, 1 day to 20 months, 1 day to 18 months, 1 day to 16 months, 1 day to 14 months, 1 day to 12 months, 1 day to 10 months, 1 day to 9 months, 1 day to 8 months, 1 day to 7 months, 1 day to 6 months, 1 day to 5 months, 1 day to 4 months, 1 day to 3 months, 1 day to 2 months, 1 day to 1 month, 1 week to 2 years, 1 week to 22 months, 1 week to 20 months, 1 week to 18 months, 1 week to 16 months, 1 week to 14 months, 1 week to 12 months, 1 week to 10 months, 1 week to 9 months, 1 week to 8 months, 1 week ~7 months, 1 week~6 months, 1 week~5 months, 1 week~4 months, 1 week~3 months, 1 week~2 months, 1 week~1 month, 2 weeks~2 years, 2 weeks~22 months, 2 weeks~20 months, 2 weeks~18 months, 2 weeks~16 months, 2 weeks~14 months, 2 weeks~12 months, 2 weeks~10 months, 2 weeks~9 months, 2 weeks~8 months, 2 weeks~7 months, 2 weeks~6 months, 2 weeks~5 months, 2 weeks~4 months, 2 weeks~3 months, 2 weeks~2 months, 2 weeks~1 month, 1 month~2 years, 1 month~22 months, 1 month~20 months, 1 month~18 months, 1 month~16 months, 1 month~14 Months, 1-12 months, 1-10 months, 1-9 months, 1-8 months, 1-7 months, 1-6 months, 1-6 months, 1-5 months, 1-4 months, 1-3 months, 1-2 months, 2 months-2 years, 2-22 months, 2-20 months, 2-18 months, 2-16 months, 2-14 months, 2-12 months, 2-10 months, 2-9 months, 2-8 months, 2-7 months, 2-6 months, or 2-5 months, 2-4 months, 3 months-2 years, 3-22 months, 3-20 months, 3 months-1 After treatment with our therapy for a period of 8 months, 3-16 months, 3-14 months, 3-12 months, 3-10 months, 3-8 months, 3-6 months, 4 months-2 years, 4-22 months, 4-20 months, 4-18 months, 4-16 months, 4-14 months, 4-12 months, 4-10 months, 4-8 months, 4-6 months, 6 months-2 years, 6-22 months, 6-20 months, 6-18 months, 6-16 months, 6-14 months, 6-12 months, 6-10 months, or 6-8 months (for example,Compared to the size of one or more solid tumors in the patient before treatment, the volume of one or more solid tumors in the patient is 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%~55%, 2%~50%, 2%~45%, 2%~40%, 2%~35%, 2%~30%, 2%~25%, 2%~20%, 2%~15%, 2%~10%, 2%~5%, 4%~99%, 4%~95%, 4%~90%, 4%~85%, 4%~80%, 4%~75%, 4%~70% , 4%~65%, 4%~60%, 4%~55%, 4%~50%, 4%~45%, 4%~40%, 4%~35%, 4%~30%, 4%~25%, 4%~20%, 4%~15%, 4%~10%, 6%~99%, 6%~95%, 6%~90%, 6%~85%, 6%~80%, 6%~75 %, 6%~70%, 6%~65%, 6%~60%, 6%~55%, 6%~50%, 6%~45%, 6%~40%, 6%~35%, 6%~30%, 6%~25%, 6%~20%, 6%~15%, 6%~10%, 8%~99%, 8%~95%, 8%~90%, 8%~85%, 8%~ 80%, 8%~75%, 8%~70%, 8%~65%, 8%~60%, 8%~55%, 8%~50%, 8%~45%, 8%~40%, 8%~35%, 8%~30%, 8%~25%, 8%~20%, 8%~15%, 10%~99%, 10%~95%, 10%~90%, 10%~85 %, 10%~80%, 10%~75%, 10%~70%, 10%~65%, 10%~60%, 10%~55%, 10%~50%, 10%~45%, 10%~40%, 10%~35%, 10%~30%, 10%~25%, 10%~20%, 10%~15%, 15%~99%, 15% ~95%, 15%~90%, 15%~85%, 15%~80%, 15%~75%, 15%~70%, 15%~65%, 15%~60%, 15%~55%, 15%~50%, 15%~55%, 15%~50%, 15%~45%, 15%~40%, 15%~35%, 15%~30%,15%~25%、15%~20%、20%~99%、20%~95%、20%~90%、20%~85%、20%~80%、20%~75%、20%~70%、20%~65%、20%~60%、20%~55%、20%~50%、20%~45%、20%~40%、20%~35%、20%~30%、20%~25%、25%~99%、25%~95%、25%~90%、25%~85%、25%~80%、25%~75%、25%~70%、25%~65%、25%~60%、25%~55%、25%~50%、25%~45%、25%~40%、25%~35%、25%~30%、30%~99%、30%~95%、30%~90%、30%~85%、30%~80%、30%~75%、30%~70%、30%~65%、30%~60%、30%~55%、30%~50%、30%~45%、30%~40%、30%~35%、35%~99%、35%~95%、35%~90%、35%~85%、35%~80%、35%~75%、35%~70%、35%~65%、35%~60%、35%~55%、35%~50%、35%~45%、35%~40%、40%~99%、40%~95%、40%~90%、40%~85%、40%~80%、40%~75%、40%~70%、40%~65%、40%~60%、40%~55%、40%~60%、40%~55%、40%~50%、40%~45%、45%~99%、45%~95%、45%~95%、45%~90%、45%~85%、45%~80%、45%~75%、45%~70%、45%~65%、45%~60%、45%~55%、45%~50%、50%~99%、50%~95%、50%~90%、50%~85%、50%~80%、50%~75%、50%~70%、50%~65%、50%~60%、50%~55%、55%~99%、55%~95%、55%~90%、55%~85%、55%~80%、55%~75%、55%~70%、55%~65%、55%~60%、60%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、65%~99%、60%~95%、60%~90%、60%~85%、60%~80%、60%~75%、60%~70%、60%~65%、70%~99%、70%~95%、70%~90%、70%~85%、This can result in decreases of 70%-80%, 70%-75%, 75%-99%, 75%-95%, 75%-90%, 75%-85%, 75%-80%, 80%-99%, 80%-95%, 80%-90%, 80%-85%, 85%-99%, 85%-95%, 85%-90%, 90%-99%, 90%-95%, or 95%-100%.

[0131] The term "survival period" refers to the period from when a mammal is identified or diagnosed with cancer (e.g., any of the cancers listed in this document) by a medical professional until the mammal dies (from the cancer). Methods for extending the survival period of mammals with cancer are described in this document.

[0132] In some embodiments, any of the methods described herein may be used to compare patient survival (e.g., 1%-400%, 1%-380%, 1%-360%, 1%-340%, 1%-320%, 1%-300%, 1%-280%, 1%-260%, 1%-240%, 1%-220%, 1%-200%, 1%-180%, 1%-160%, 1%-140%, 1%-120%, 1%-100%, 1%-95%, 1%-90%, 1%-85%, 1%-80%) , 1%~75%, 1%~70%, 1%~65%, 1%~60%, 1%~55%, 1%~50%, 1%~45%, 1%~40%, 1%~35%, 1%~30%, 1%~25%, 1%~20%, 1%~15%, 1%~10%, 1%~5%, 5%~400%, 5%~380%, 5%~3 60%, 5%~340%, 5%~320%, 5%~300%, 5%~280%, 5%~260%, 5%~240%, 5%~220%, 5%~200%, 5%~180%, 5%~160%, 5%~140%, 5%~120%, 5%~100%, 5%~90%, 5%~80%, 5%~ 70%, 5%~60%, 5%~50%, 5%~40%, 5%~30%, 5%~20%, 5%~10%, 10%~400%, 10%~380%, 10%~360%, 10%~340%, 10%~320%, 10%~300%, 10%~280%, 10%~260%, 10%~24 0%, 10%~220%, 10%~200%, 10%~180%, 10%~160%, 10%~140%, 10%~120%, 10%~100%, 10%~90%, 10%~80%, 10%~70%, 10%~60%, 10%~50%, 10%~40%, 10%~30%, 10% ~20%, 20%~400%, 20%~380%, 20%~360%, 20%~340%, 20%~320%, 20%~300%, 20%~280%, 20%~260%, 20%~240%, 20%~220%, 20%~200%, 20%~180%, 20%~160%, 20% ~140%, 20%~120%, 20%~100%, 20%~90%, 20%~80%, 20%~70%, 20%~60%, 20%~50%, 20%~40%, 20%~30%, 30%~400%, 30%~380%, 30%~360%, 30%~340%, 30%~320%,30%~300%、30%~280%、30%~260%、30%~240%、30%~220%、30%~200%、30%~180%、30%~160%、30%~140%、30%~120%、30%~100%、30%~90%、30%~80%、30%~70%、30%~60%、30%~50%、30%~40%、40%~400%、40%~380%、40%~360%、40%~340%、40%~320%、40%~300%、40%~280%、40%~260%、40%~240%、40%~220%、40%~200%、40%~180%、40%~160%、40%~140%、40%~120%、40%~100%、40%~90%、40%~80%、40%~70%、40%~60%、40%~50%、50%~400%、50%~380%、50%~360%、50%~340%、50%~320%、50%~300%、50%~280%、50%~260%、50%~240%、50%~220%、50%~200%、50%~180%、50%~160%、50%~140%、50%~140%、50%~120%、50%~100%、50%~90%、50%~80%、50%~70%、50%~60%、60%~400%、60%~380%、60%~360%、60%~340%、60%~320%、60%~300%、60%~280%、60%~260%、60%~240%、60%~220%、60%~200%、60%~180%、60%~160%、60%~140%、60%~120%、60%~100%、60%~90%、60%~80%、60%~70%、70%~400%、70%~380%、70%~360%、70%~340%、70%~320%、70%~300%、70%~280%、70%~260%、70%~240%、70%~220%、70%~200%、70%~180%、70%~160%、70%~140%、70%~120%、~100%、70%~90%、70%~80%、80%~400%、80%~380%、80%~360%、80%~340%、80%~320%、80%~300%、80%~280%、80%~260%、80%~240%、80%~220%、80%~200%、80%~180%、80%~160%、80%~140%、80%~120%、80%~100%、80%~90%、90%~400%、90%~380%、90%~360%、90%~340%、90%~320%、90%~300%、90%~280%、90%~260%、90%~240%、90%~220%、90%~200%、90%~180%、90%~160%、90%~140%、90%~120%、90%~100%、100%~400%、100%~380%、100%~360%、100%~340%、100%~320%、100%~300%、100%~280%、100%~260%、100%~240%、100%~220%、100%~200%、100%~180%、100%~160%、100%~140%、100%~120%、120%~400%、120%~380%、120%~360%、120%~340%、120%~320%、120%~300%、120%~280%、120%~260%、120%~240%、120%~220%、120%~200%、120%~180%、120%~160%、120%~140%、140%~400%、140%~380%、140%~360%、140%~340%、140%~320%、140%~300%、140%~280%、140%~260%、140%~240%、140%~220%、140%~200%、140%~180%、140%~160%、160%~400%、160%~380%、160%~360%、160%~340%、160%~320%、160%~300%、160%~280%、160%~260%、160%~240%、160%~220%、160%~200%、160%~180%、180%~400%、180%~380%、180%~360%、180%~340%、180%~320%、180%~300%、180%~280%、180%~260%、180%~240%、180%~220%、180%~200%、200%~400%、200%~380%、200%~360%、200%~340%、200%~320%、200%~300%、200%~280%、200%~260%、200%~240%、200%~220%、220%~400%、220%~380%、220%~360%、220%~340%、220%~320%、220%~300%、220%~280%、220%~260%、220%~240%、240%~400%、240%~380%, 240%~360%, 240%~340%, 240%~320%, 240%~300%, 240%~280%, 240%~260%, 260%~400%, 260%~380%, 260%~360%, 260%~340%, 260%~320%, 260%~300%, 26 This can result in increases of 0% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%.

[0133] The following embodiments are intended to illustrate more specific embodiments of the present invention and are not intended to limit the scope of the invention. [Examples]

[0134] Example 1 Preparation of fumarate crystal A of MRTX0902 This example describes the preparation of fumarate crystal A of MRTX0902.

[0135] (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile fumarate - MRTX0902 fumarate crystal A. (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile dihydrate [40 g, 94.7 mmol, 1.0 equivalent] and EtOH [200 mL] were added to a 400 mL reactor. The suspension was heated to 70 °C to obtain a solution. Solid fumaric acid [12.1 g, 104 mmol, 1.1 equivalents] was then added all at once. Crystallization was observed within a few minutes, and stirring was continued at 70 °C for 1 hour. The reaction mixture was cooled to 20 °C over 0.25 hours, and then stirred at the same temperature for 1 hour. The suspension was filtered, and the collected solid was rinsed with EtOH [80 mL]. The moist cake was then dried under vacuum at 40°C to obtain 47.4 g of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile fumarate type A in 99% yield.

[0136] Melting point: 253.2–253.3°C.

[0137] 1 H NMR (400MHz, DMSO-d6)δ 9.01(s, 1H), 7.71(dd, J=7.9, 1.4Hz, 1H), 7.64-7.55(m, 2H), 7.42(s, 1H), 7.32(t, J=7.8Hz, 1H), 6.61(s, 2H), 5.51(s, 1H), 3.80-3.74(m, 4H), 3.73-3.66(m, 4H), 2.65(s, 3H), 2.56(s, 3H), 1.54(d, J=7.0Hz, 3H).

[0138] 13 C NMR (101MHz, DMSO-d6)δ 166.6, 159.9, 151.3, 149.7, 147.7, 146.3, 139.2, 134.6, 131.3, 129.7, 12 7.4, 125.3, 119.0, 114.3, 112.7, 93.7, 66.3, 47.1, 45.5, 21.8, 18.2, 17.2.

[0139] HRMS(ESI) C 22 H 25 N6O: Calculated value 389.2085 [M+H] + Actual measured value: 389.2085.

[0140] Example 2 Overview of the Characterization Analysis of Crystallization of Crystal A The obtained starting material (WX-80355 free base, batch number PCS0437, also known as MRTX0902) was subjected to X-ray powder diffraction (XRPD), polarized light microscopy (PLM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and proton nuclear magnetic resonance ( 1 The materials were characterized by 1H-NMR spectroscopy and high-performance liquid chromatography (HPLC). According to qNMR, the starting material had a purity of 90.5%.

[0141] As a first step, WX-80355 fumarate was successfully scaled up to a 5g scale in two different solvent systems (THF / 95%EtOH and 95%EtOH) using a systematic crystallization method with EasyMax102. Table 1 shows an overview of WX-80355 fumarate type A obtained from the two crystallization solvent systems. The same crystals were obtained in both methods.

[0142] Based on the approximate solubility of the starting materials in 20 different solvent systems, 100 polymorphism screening tests were performed using techniques such as poor solvent addition, solid vapor diffusion, liquid vapor diffusion, slurry at room temperature (RT) and 50°C, slow evaporation at room temperature and 50°C, slow cooling, and polymer-induced crystallization. A total of three crystalline forms were identified: Type A (anhydrous), Type B (anisole solvate), and Type C (DMSO solvate).

[0143] As part of the salt screening project in Q-3438, hygroscopicity was evaluated using dynamic water vapor adsorption (DVS). Based on the weight increase rate (%) up to a relative humidity (RH) of 80%, fumarate type A was identified as non-hygroscopic, and no changes in the crystal structure were observed after DVS evaluation.

[0144] Based on the characterization results, fumarate type A (anhydrous), which has good solid-state properties, was recommended for further development.

[0145] Table 1 shows the combined results of solid-state properties, solubility tests, and stability tests for two lots of fumarate type A. [Table 14]

[0146] Example 3 Preparation and characterization of MRTX0902 fumarate in 5g scale MRTX0902 fumarate crystal A was prepared using the EasyMax102 procedure. Details of the preparation procedure are shown in Tables 2 and 3 for the 95% EtOH and THF / 95% EtOH solvent systems, respectively. The substance was confirmed to be MRTX0902 fumarate crystal A by XRPD, and further characterization was performed by DSC, TGA, DVS, and NMR. Table 4 summarizes the characterization of the solid state obtained from both tests. [Table 15] [Table 16] [Table 17]

[0147] Example 4 Polymorphic screening experiment for MRTX0902 A total of 100 polymorph screening experiments were performed. Three types of crystals were identified: fumarate crystal A, crystal B, and crystal C. Table 5 summarizes the characterization of all solid crystals. Crystal A, the starting material fumarate crystal, was identified as an anhydride. Crystal B was found in a solvent system containing anisole and was identified as an anisole solvate. Crystal C was found in a DMSO system through slow evaporation or polymer-induced crystallization. NMR data suggested that crystal C was a DMSO solvate. Upon heating to approximately 160°C, crystal C was observed to dissociate into a free base after desolvation, suggesting that desolvation and salt disproportionation were proceeding simultaneously.

[0148] Table 5 shows an overview of the characterization of all crystals (crystals A, B, and C). [Table 18]

[0149] Example 5 Solid State Stability Test of Fumarate Crystal A The solid-state stability of fumarate crystal A (scale-up batch) was evaluated for two weeks under three open-dish conditions: (i) 25°C / 60%RH, (ii) 40°C / 75%RH, and (iii) 60°C. The test designs are shown in Table 6. After storage for 1 / 2 week under these conditions, the samples were collected and analyzed for appearance, crystal structure and crystallinity by XRPD, and purity (%) by HPLC (Table 7).

[0150] Fumarate crystal A showed no significant changes in crystalline structure or chemical purity, suggesting good physicochemical stability for at least two weeks. [Table 19] [Table 20]

[0151] Example 6 Formability, tabletability, and compressibility (CTC) profiles of MRTX0902 crystals F and J, and fumarate crystal A. Different free base polymorphs (types F and J) and fumarates of MRTX0902 were compressed using a compression simulator (Styl'One Evolution, MedelPharm, France) that simulated the tableting cycle of a Korsch XL100. The main compressive force ranged from 0.5 to 30 kN, and the powder was compressed using an 8 mm diameter circular flat punch (Natoli Engineering). Before each compression cycle, external lubrication in the form of magnesium stearate spray (Styl'One MIST) was applied to the die wall and punch tip. Tablet hardness and dimensions were measured using a Sotax ST50. True density was measured using Accupyc II (Micromeritics®). Flow function coefficient (FFc) and flowability were analyzed using a ring shear tester RST-XS (Dietmar Schultze). Single-crystal X-ray diffraction testing was performed using a Bruker SMART Pt135 CCD diffractometer equipped with CuKa radiation. The structure was analyzed using the direct method (SHELXT). Morphological evaluation of the API morphology was performed using a Phenom SEM (NanoScience). Particle size was measured using a Mastersizer 3000 (Malvern Panalytical). The tensile strength and solid content of the compressed API were calculated using the following equation.

number

[0152] result

[0153] Significant differences in the mechanical properties of MRTX0902 fumarate and free base were observed. The two free base crystal types, F and J, also exhibited variations in crystal packing. Compressibility, tabletability, and moldability (CTC) of MRTX0902 types F, J, and fumarate crystal A (2 lots) revealed significant differences in the mechanical properties of free base types J and F, and fumarate crystal A. As shown in Figures 5, 6, and 7, both free base types J and F showed lower tabletability and moldability compared to fumarate crystal A (both lots). On the other hand, type J had better tabletability than type F and exhibited higher tensile strength at tableting pressures of 100–200 MPa. Type F had lower moldability compared to type J and fumarate A, which was identified as an important factor in dosage form selection.

[0154] Furthermore, while fumarate crystal A (Lot 1 in Table 1) exhibited adhesion to the punch tip, this was significantly reduced in fumarate crystal A (Lot 2 in Table 1). Fumarate crystal A (Lot 2 in Table 1) showed remarkable improvements in CTC, adhesion, and flowability parameters. Since free base crystal J and fumarate crystal A have different advantages, both were recommended for further evaluation to identify scalable processes.

[0155] While the present invention has been described in relation to its specific embodiments, it should be understood that further modifications are possible. This application is intended to encompass any variations, uses, or applications that generally follow the principles of the present invention, and also includes deviations that are included in known or customary practices in the art to which the invention pertains and that may be applicable to the essential features of the invention described herein earlier. Furthermore, these are included within the scope of the appended claims.

Claims

1. (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile fumarate crystals.

2. Crystal A has an X-ray powder diffraction pattern that includes at least one peak at °2θ selected from 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.

2. The fumarate crystal according to claim 1.

3. Crystal A has an X-ray powder diffraction pattern that includes peaks at °2θ values ​​of 6.9±0.2, 13.8±0.2, 14.2±0.2, 18.4±0.2, and 23.8±0.

2. The fumarate crystal according to claim 1.

4. Crystal A has an X-ray powder diffraction pattern that includes two or more peaks at °2θ of 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.

22. The fumarate crystal according to claim 1.

5. Crystal A has an X-ray powder diffraction pattern that includes three or more peaks at °2θ: 6.9±0.2, 13.8±0.2, 14.2±0.2, 15.7±0.2, 18.4±0.2, 23.0±0.2, 23.8±0.2, 26.6±0.2, 27.3±0.2, and 28.6±0.

2. The fumarate crystal according to claim 1.

6. Crystal A has an XRPD pattern that is essentially as shown in Figure 1. The fumarate crystal according to claim 1.

7. Crystal A is characterized by exhibiting an endothermic peak with an onset at approximately 248°C, as determined by differential scanning calorimetry (DSC). The fumarate crystal according to claim 1.

8. Crystal A has a DSC thermogram that is essentially as shown in Figure 2. A fumarate crystal according to any one of claims 1 to 7.

9. Crystal A has a thermogravimetric analysis ("TGA") profile that is essentially as shown in Figure 2. A fumarate crystal according to any one of claims 1 to 8.

10. Crystal A, estimated by TGA, exhibits a weight loss of approximately 0.02–0.25% before decomposition begins at approximately 150°C. A fumarate crystal according to any one of claims 1 to 9.

11. Crystal A has a dynamic water vapor adsorption ("DVS") isotherm as shown in Figure 3. A fumarate crystal according to any one of claims 1 to 10.

12. Crystal A, when measured by dynamic water vapor adsorption ("DVS"), exhibits an adsorption of approximately 0.13–0.16% water at 25°C / 80% relative humidity (RH). A fumarate crystal according to any one of claims 1 to 11.

13. Substantially free of residual organic solvents, A fumarate crystal according to any one of claims 1 to 12.

14. It is a hydrate or dihydrate. The crystalline material according to any one of claims 1 to 13.

15. It is an anhydrous substance. The crystalline material according to any one of claims 1 to 13.

16. A pharmaceutical composition comprising a therapeutically effective amount of a fumarate crystalline form of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile according to any one of claims 1 to 15.

17. The pharmaceutical composition according to claim 16, further comprising at least one pharmaceutically acceptable excipient and / or diluent.

18. A method for inhibiting the SOS1 activity of cells, comprising contacting cells in which inhibition of SOS1 activity is desired with a therapeutically effective amount of the fumarate crystal described in any one of claims 1 to 18, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.

19. A method for treating a target cancer requiring treatment, comprising administering to the target a therapeutically effective amount of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)amino)ethyl)benzonitrile crystals according to any one of claims 1 to 15, either alone or in combination with one or more pharmaceutically acceptable excipients and / or diluents.

20. The method according to claim 19, wherein the therapeutically effective dose of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile fumarate crystals is approximately 0.01 to 100 mg / kg per day.

21. The method according to claim 19, wherein the therapeutically effective dose of (R)-2-methyl-3-(1-((4-methyl-7-morpholinopyrid[3,4-d]pyridazin-1-yl)aminoethyl)benzonitrile is approximately 0.1 to 50 mg / kg per day.

22. Cancers of the heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lungs: Bronchogenic carcinoma (squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenocarcinoma, sarcoma, lymphoma, chondrotoxic hamartoma, mesothelioma; Digestive system: Esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), Stomach (cancer, lymphoma, leiomyosarcoma), Pancreas (ductal adenocarcinoma, insulinoma, glucagon-producing tumor, gastrin-producing tumor, carcinoid tumor, bipoma), Small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibrous tumor) Organ cancers: colon (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma); genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoma, teratoma, fetal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary system: gallbladder cancer, ampulla cancer, cholangiocarcinoma; Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma (chondrodystostoma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthomas, degenerative osteitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymal cell tumor, germ cell tumor (pineal glandoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecological system: Uterus (endometrial cancer (serous cystadenoma, mucinous cystadenoma, sarcoma)); Selected from the group consisting of: cancers of the same name (unclassifiable cancers), granulosa-theca cell tumors, Sertoli-Leydig cell tumors, undifferentiated germ cell tumors, malignant teratomas), vulvas (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, staphyloid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer); hematological system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. The method according to claim 19.

23. The method according to claim 19, wherein the cancer is SOS1-associated cancer.

24. The method according to claim 19, wherein the cancer is non-small cell lung cancer.

25. The method according to claim 19, wherein the subject is an adult patient.

26. The method according to claim 19, wherein the subject is a pediatric patient.

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