TW202237118A - Compositions and methods for preventing brain metastases - Google Patents

Abstract

The disclosure provides compositions and methods comprising a compound of Formula I administered for the treatment of CNS metastasis (e.g., brain metastases), and for the prevention of CNS metastasis (e.g., brain metastases). The disclosure provides, within such compositions and methods, for the treatment and/or the prevention of CNS metastasis (e.g., brain metastases) in a subject suffering from a cancer, including a RET-associated cancer.

Description

Compositions and methods for preventing brain metastases

Despite advances in the diagnosis and treatment of many types of cancer, including RET (Rearranged during Transfection)-associated cancers, the treatment and prevention of brain metastases associated with progression remains a challenge. Central nervous system (CNS) metastases exhibit resistance to prophylactic and therapeutic approaches, whether in the onset/emergent state of disease or in the established state of disease. Typically, this resistance is largely due to insufficient penetration of the active agent across the blood-brain barrier (BBB). Brain metastases thus represent a devastating progression of cancer with limited options available to prevent their onset and appearance and to treat metastatic lesions once established. Therefore, there is a need to develop active agents and methods applicable to the prevention and treatment of brain metastases.

RET is a one-way transmembrane receptor belonging to the tyrosine kinase superfamily that is typically expressed at low levels in normal tissues. RET is required for the normal generation, maturation and maintenance of several tissues and cell types (Mulligan, L. M., Nature Reviews Cancer (2014) 14:173-186). The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a proximal membrane cysteine-rich region required for proper folding of the RET ectodomain, while the cytoplasmic portion of the receptor consists of Two tyrosine kinase subdomains.

RET signaling is mediated by the binding of a group of soluble proteins in the glial cell line-derived neurotrophic factor (GDNF) family ligand (GFL), which also includes neurturin (NTRN), Artemin (ARTN) and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev. (2005) 16:441-67). Unlike other receptor tyrosine kinases, RET does not bind directly to GFL and requires another co-receptor: that is, one of the four GDNF family receptor-α (GFRα) family members, which are activated by glycosylation Phosphatidylinositol bonds tether to the cell surface. GFL forms binary complexes with members of the GFRα family, which in turn bind to RET and recruit it to cholesterol-rich membrane subdomains called lipid rafts, where RET signaling occurs.

Following ligand-co-receptor complex binding, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adapter and signaling proteins to stimulate multiple downstream pathways. Binding of adapter proteins at these docking sites results in the activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways, or in the recruitment of the CBL family of ubiquitin ligases that are involved in the RET-mediated function of RET function in downregulation.

Abnormal RET expression and/or activity (e.g. caused by mutations with other proteins or chromosomal rearrangement/fusion) is associated with different cancers (e.g. lymphoma, thyroid and lung cancer (NSCLC)) and gastrointestinal disorders such as irritable bowel syndrome (IBS) relevant.

(式I)。 Selpercatinib (LOXO-292 or RETEVMO ^TM ) is a specific inhibitor of RET and is regulatory approved for the treatment of patients with metastatic RET fusion-positive NSCLC, RET mutant medullary thyroid carcinoma, and metastatic RET fusion Patients with positive thyroid cancer. Serpatinib or 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6 -diazabicyclo[3.1.1]hept-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile has the following chemical structure:

(Formula I).

The present invention relates to compounds, compositions and methods for preventing, reducing the occurrence and/or onset of CNS metastases in individuals suffering from cancer and/or for inhibiting or preventing the survival of metastatic cancer cells in individuals suffering from cancer , which comprises a compound of formula I (i.e. serpatinib) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof or an effective amount of serpatinib or a pharmaceutically acceptable salt thereof Salts, compositions in amorphous or polymorphic forms.

In one aspect, the invention relates to a method for preventing brain metastases in an individual suffering from cancer comprising administering to the individual in need thereof serpatinib or its equivalent in an amount effective to prevent brain metastases in the individual. A pharmaceutically acceptable salt or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method of reducing the risk of developing or developing brain metastases in an individual having cancer comprising administering to an individual in need thereof an amount effective to reduce the individual's risk of developing brain metastases. Erpatinib or a pharmaceutically acceptable salt thereof or a composition comprising Serpatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method of treating cancer that reduces the risk of developing detectable metastases of the cancer to the brain, the method comprising administering to the patient an amount effective to reduce the risk of detectable metastases to the brain of the individual. Individuals with cancer are administered serpatinib or a pharmaceutically acceptable salt thereof or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof.

In one aspect, the invention relates to a method for delaying the onset of brain metastases in an individual having cancer comprising administering to an individual in need thereof Serpatinib in an amount effective to delay the onset of brain metastases in the individual Or a pharmaceutically acceptable salt thereof or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention is directed to a method of preventing the onset of brain metastases in an individual having cancer comprising administering to an individual in need thereof an amount effective to prevent the onset of brain metastases in the individual. A pharmaceutically acceptable salt thereof or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a method for inhibiting metastatic progression of cancer in the brain of an individual having cancer comprising administering to an individual in need thereof an amount effective to inhibit metastatic progression of cancer in the individual Compositions with Serpatinib or a pharmaceutically acceptable salt thereof or comprising Serpatinib or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method for inhibiting the growth and/or survival of metastatic cancer cells in the brain of an individual suffering from cancer, comprising effectively inhibiting the metastatic cancer in the brain of an individual Amount of Growth and/or Survival of Cells Serpatinib or a pharmaceutically acceptable salt thereof or a composition comprising Serpatinib or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

In another aspect, the present invention relates to a method for inhibiting the progression of the cancer to metastatic brain cancer in an individual having cancer, comprising taking an amount in need thereof effective to inhibit the progression of the individual's primary tumor to the CNS. Serpatinib or a pharmaceutically acceptable salt thereof or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof is administered to an individual.

In another aspect, the present invention relates to a method for reducing the risk of the occurrence or onset of detectable brain metastases in an individual having cancer, the method comprising effectively reducing the individual's occurrence of detectable CNS tumors, such as brain Amount to Transfer Risk or Attack Risk Serpatinib or a pharmaceutically acceptable salt thereof or a composition comprising Serpatinib or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

In yet another aspect, the invention relates to a method of prolonging the period of survival of an individual with cancer comprising an amount effective to prolong the period of survival of the individual relative to the period of survival of the individual in the absence of administration of the drug. Serpatinib or a pharmaceutically acceptable salt thereof or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.

In one aspect, the present invention provides a compound of formula (I) (ie serpatinib) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof for use in the prevention of CNS tumors, such as In some specific embodiments for the prevention of brain metastases arising from cancers with RET alterations (eg, RET-associated cancers such as RET-mutated medullary thyroid cancer or RET fusion-positive lung cancer).

In other aspects, the present invention provides a compound of formula (I) (i.e. Serpatinib) or its pharmaceutically acceptable salt, amorphous form or polymorphic form or comprising Serpatinib or its Use of a pharmaceutically acceptable salt, composition in amorphous form or polymorphic form, for reducing the risk of occurrence or occurrence of CNS tumors, such as brain metastases, in an individual suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for reducing the risk of developing a detectable CNS tumor, such as cancer metastasizing to the brain, in an individual suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for delaying the onset of CNS tumors, such as brain metastases, in individuals suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for preventing the onset of CNS tumors, such as brain metastases, in individuals suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for inhibiting the metastatic progression of a CNS tumor, such as cancer in the brain, in an individual suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for inhibiting the growth and/or survival of CNS tumors, such as metastatic cancer cells, in the brain of an individual suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for inhibiting the progression of cancer to a CNS tumor, such as metastatic brain cancer, in an individual suffering from cancer.

In other aspects, the present invention provides a serpatinib or a pharmaceutically acceptable salt thereof, amorphous form or polymorphic form or comprising serpatinib or a pharmaceutically acceptable salt thereof, non-crystalline Use of a composition in crystalline or polymorphic form for reducing the risk of developing a CNS tumor, such as detectable brain metastases, or the onset of a CNS tumor, such as detectable brain metastases, in an individual suffering from cancer.

In other aspects, the present invention provides a compound of formula (I) (i.e. Serpatinib) or its pharmaceutically acceptable salt, amorphous form or polymorphic form or comprising Serpatinib or its Use of a composition of a pharmaceutically acceptable salt, amorphous form or polymorphic form for prolonging the period of survival of an individual suffering from cancer.

In any aspect related to the use of a compound of formula (I), ie serpatinib, the use may comprise the manufacture of a medicament for use in the prevention of CNS tumors in individuals with cancer, such as Brain metastases; for reducing the risk of developing or developing a CNS tumor, such as brain metastases, in an individual with cancer; for reducing the risk of a detectable CNS tumor, such as cancer metastasizing to the brain, in an individual with cancer; for delaying Onset of CNS tumors, such as brain metastases, in individuals with cancer; for preventing the onset of CNS tumors, such as brain metastases, in individuals with cancer; for inhibiting the onset of CNS tumors, such as cancer metastases in the brain, in individuals with cancer Sexual progression; for inhibiting the growth and/or survival of CNS tumors in the brain of an individual with cancer, such as metastatic cancer cells; for inhibiting the progression of cancer to a CNS tumor, such as metastatic brain cancer, in an individual with cancer ; for reducing the risk of a detectable CNS tumor, such as brain metastases, or the onset of a detectable CNS tumor, such as brain metastases, in an individual with cancer; and/or for prolonging the period of survival of an individual with cancer.

In one aspect, the present invention provides a use of serpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof in the manufacture of a medicament. In an embodiment of this aspect, the manufacture of a medicament can be used to prevent CNS tumors, such as brain metastases, and in some specific embodiments is used to manufacture a medicament for the prevention of CNS tumors, such as brain metastases, wherein the brain metastases are derived from having RET Altered cancers (eg, RET-associated cancers, such as RET-mutant medullary thyroid cancer or RET fusion-positive lung cancer).

In one aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for use in the prevention of brain metastases in an individual with cancer.

In another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of developing or developing brain metastases in an individual having cancer.

In yet another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of developing detectable brain metastases in an individual with cancer.

In yet another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for delaying the onset of brain metastases in a subject having cancer.

In another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for use in preventing the onset of brain metastases in an individual with cancer.

In yet another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for inhibiting the metastatic progression of cancer in the brain of a subject having cancer.

In yet another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for inhibiting the growth and/or survival of metastatic cancer cells in the brain of an individual with cancer.

In yet another aspect, disclosed herein is serpatinib, or a pharmaceutically acceptable salt thereof, for inhibiting progression of cancer to metastatic brain cancer in an individual having cancer.

In yet another aspect, disclosed herein is cerpatinib, or a pharmaceutically acceptable salt thereof, for use in reducing the risk of developing detectable brain metastases or the onset of detectable brain metastases in an individual having cancer.

In another aspect, disclosed herein is serpatinib, or a pharmaceutically acceptable salt thereof, for prolonging the period of survival of a subject with cancer.

Among the various aspects associated with cerpatinib or a pharmaceutically acceptable salt thereof for use in: preventing CNS tumors, such as brain metastases; reducing the risk of CNS tumors, such as brain metastases, occurring or appearing; reducing the risk of Individuals with cancer develop detectable risk of CNS tumors, such as cancer metastases to the brain; delay onset of CNS tumors, such as brain metastases, in individuals with cancer; prevent onset of CNS tumors, such as brain metastases, in individuals with cancer; inhibit CNS tumors in a subject with cancer, such as metastatic progression of cancer in the brain; inhibiting the growth and/or survival of CNS tumors in the brain of a subject with cancer, such as metastatic cancer cells; inhibiting the growth and/or survival of metastatic cancer cells in a subject with cancer Cancers that develop into CNS tumors, such as metastatic brain cancer; reduce the risk of developing a detectable CNS tumor, such as brain metastases, or the onset of a detectable CNS tumor, such as brain metastases, in an individual with cancer; and/or prolong the duration of cancer Some embodiments relate to CNS tumors, such as brain metastases from cancers with RET alterations (eg, RET-associated cancers, such as RET-mutant medullary thyroid cancer or RET fusion-positive lung cancer).

In some embodiments of any of the foregoing aspects, the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancer.

In some embodiments of any of the foregoing aspects, one or more cells of the cancer exhibit RET mutations and/or RET fusions and/or RET rearrangements associated with cancer.

In some embodiments of any of the foregoing aspects, the CNS tumor, such as a brain metastasis, comprises undetected or undetectable metastases.

In some embodiments of any of the foregoing aspects, the individual has no previous CNS tumors or metastases.

In some embodiments of any of the foregoing aspects, the individual was previously treated for a CNS tumor and/or previous metastasis.

In some embodiments of any of the foregoing aspects, the individual has advanced cancer.

In some embodiments of any of the foregoing aspects, the individual has a primary cancer that is associated with an increased risk and/or increased likelihood of metastatic progression to the CNS, or, more specifically, to the brain.

In some embodiments of any of the foregoing aspects, the individual is not known to have a CNS tumor, such as a brain metastasis, prior to administering the method.

In some embodiments of any of the foregoing aspects, the method further comprises administering to the individual another anticancer agent.

In some embodiments of any of the foregoing aspects, individuals are identified by detecting one or more of RET mutations, RET fusions, RET rearrangements, RET gene and/or RET protein expression, activity, or dysregulation.

In some embodiments of any of the foregoing aspects, administering or using to an individual selpatinib or a pharmaceutically acceptable salt thereof, an amorphous form comprising about 0.1 mg/kg to about 15.0 mg/kg body weight per day or a polymorphic form, or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof, an amorphous form or a polymorphic form.

In some embodiments of any of the foregoing aspects, administering or using to the individual a drug comprising 120 mg of selpatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph thereof when the individual weighs less than 50 kg form, or a composition comprising serpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof. In some other embodiments, administering or using to an individual comprises 160 mg of serpatinib or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, or comprises Compositions of serpatinib or pharmaceutically acceptable salts, amorphous forms or polymorphic forms thereof.

In some embodiments of any of the foregoing aspects, the method or use comprises administering Serpatinib or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof once or twice daily, or comprising Serpatinib Compositions of Patinib or pharmaceutically acceptable salts, amorphous or polymorphic forms thereof.

In some embodiments of any of the foregoing aspects, the method or use comprises serpatinib, or a pharmaceutically acceptable salt thereof, in a polymorphic form.

In some embodiments of any of the foregoing aspects, the method or use comprises serpatinib, or a pharmaceutically acceptable salt thereof, in amorphous form.

In some embodiments of any of the foregoing aspects, the method or use comprises serpatinib in the free amine form.

Other features, aspects, embodiments and advantages provided by the present invention will be apparent from the following embodiments.

This application claims the benefit of U.S. Provisional Application Serial No. 63/125,085, filed December 14, 2020, under 35 U.S.C. § 119(e); the disclosure of which is incorporated herein by reference.

CNS tumors, such as brain metastases, arise as a devastating progression of many different cancers. Existing methods for the prevention and treatment of brain metastases are very limited. Brain metastases can occur when cancer cells spread from their original site, such as the site of a primary cancer, to the brain. Typically, CNS tumors, such as brain metastases, arise and begin to proliferate when cancer cells travel from the original tumor through the bloodstream or lymphatic system and spread (metastasize) to the CNS, such as the brain. Metastatic cancer that has spread from its original location is usually identified by the name of the primary cancer. For example, cancer that has spread from the breast to the brain is called metastatic breast cancer, not brain cancer. While any cancer can spread to the brain, some cancers have an increased likelihood of causing brain metastases, including non-limiting examples of lung cancer, breast cancer, colorectal cancer, kidney cancer, melanoma, and RET-related cancers. CNS tumors, such as brain metastases, occur in 10% to 30% of adults with cancer. As a metastatic CNS tumor, such as a brain tumor, grows, it puts pressure on and alters the function of the surrounding CNS, such as the brain, tissue. Thus, CNS tumors and brain metastases can be differentiated by a variety of signs and symptoms. For example, signs and symptoms of brain metastases can include headaches, including headaches with vomiting or nausea; cognitive changes including, for example, increased occurrences of memory problems, seizures, vertigo, and the like.

As described in more detail below, the present invention is based on unexpected results showing that administration of a compound of formula I (serpatinib) is effective not only in the treatment of established brain cancers and brain metastases, but also in the prevention of CNS tumors in individuals at risk of metastasis, eg, brain metastases (eg, onset, appearance and/or progression of brain metastases).

definition

Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, unless otherwise specified, the following terms have the meanings ascribed thereto below.

CNS tumors are tumors of the central nervous system and include, but are not necessarily limited to, brain or spinal cord tumors and brain or spinal cord metastases.

As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties due to the order of the molecules in the crystal lattice. Different polymorphs of a single compound have one or more chemical, physical, mechanical, electrical, thermodynamic and/or biological properties that differ from each other. Differences in physical properties exhibited by polymorphic forms can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rate (important factor in determining bioavailability) , solubility, melting point, chemical stability, physical stability, powder fluidity, water absorption, compactness and particle shape. Differences in stability can result from changes in chemical reactivity (e.g. differential oxidation, such that a dosage form changes color faster when composed of one polymorph than another) or mechanical changes (e.g. Changes occur due to conversion of a kinetically favorable polymorph to a thermodynamically more stable polymorph) or both (eg, one polymorph is more hygroscopic than the other). Some transitions affect potency and/or toxicity due to solubility/dissolution differences. In addition, the physical properties of the crystals can play an important role in handling; for example, a polymorph is more likely to form solvates or may be difficult to filter and wash out impurities (i.e. particle shape and size distribution within a polymorphic form). may vary from one to the other). As used herein, "polymorph" does not include amorphous forms of a compound. As used herein, "amorphous" refers to a non-crystalline form of a compound, which may be a solid state form of the compound or a dissolved form of the compound. For example, "amorphous" refers to a compound having no molecules or regularly repeating arrangements of outer surface planes (eg, a solid form of the compound).

As used herein, the term "anhydrous" refers to the crystalline form of the compound of formula (I), which contains 1% by weight or less of water. For example, 0.5% by weight or less, 0.25% by weight or less, or 0.1% by weight or less of water.

As used herein, the term "solvate" refers to a crystalline form of a compound of formula (I), such as a polymorphic form of the compound, wherein the crystal lattice contains one or more solvents of crystallization.

The term "hydrate" or "hydrated polymorphic form" refers to a crystalline form of a compound of formula (I), such as a polymorphic form of the compound, wherein the crystal lattice contains water. As used herein, unless otherwise specified, the term "hydrate" means a "stoichiometric hydrate". Stoichiometric hydrates contain water molecules as an integral part of the crystal lattice, where removal of the water molecules will destabilize the crystal network. In contrast, non-stoichiometric hydrates contain water, but changes in water content do not cause significant changes in crystal structure. During non-stoichiometric hydrate drying, most of the water can be removed without significantly disturbing the crystal network, and the crystals can then be rehydrated to obtain the non-stoichiometric initial hydrated crystalline form. Unlike stoichiometric hydrates, dehydration and rehydration of non-stoichiometric hydrates is not accompanied by phase transitions, and thus all hydration states of non-stoichiometric hydrates represent the same crystalline form.

When used with reference to a composition comprising a polymorphic form of a compound of formula (I), "purity" means the relative amount of one particular polymorphic form relative to another polymorphic form of a compound of formula (I) in the referenced composition or percentage of amorphous form. For example, a composition comprising polymorphic form 1 with a purity of 90% will comprise 90 parts by weight of form 1 and 10 parts by weight of another polymorphic form and/or an amorphous form of a compound of formula (I).

As used herein, a compound or composition is "substantially free" of one or more other components if the compound or composition does not contain substantial amounts of such other components. For example, the composition may contain less than 5%, 4%, 3%, 2%, or 1% by weight of other components. Such components may include starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of the compounds and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of formula (I) is "substantially free" of other polymorphs if the particular polymorph comprises at least about 95% by weight of the compound of formula (I) present things. In some embodiments, if the particular polymorph is at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of formula (I) present, then the A particular polymorph is "substantially free" of other polymorphs. In certain embodiments, a particular polymorph of a compound of formula (I) is "substantially free" if the amount of water is no more than about 2%, about 1%, or about 0.5% by weight of the polymorph. "water.

As used herein, "substantially pure" when used with reference to polymorphic forms of a compound of formula (I) means greater than 90% of the compound by weight of the compound, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%, and also includes samples of polymorphic forms equal to about 100% of the compound. The remaining material comprises other forms of the compound, and/or its reaction impurities and/or processing impurities resulting from the preparation. For example, a polymorphic form of a compound of formula (I) may be considered substantially pure in that it is greater than 90% pure as a polymorphic form of a compound of formula (I), as is known in the art at this time and Measured in a recognized manner, wherein the remaining less than 10% of the substance comprises one or more other forms of the compound of formula (I) and/or reaction impurities and/or processing impurities. The presence of reaction impurities and/or process impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, or infrared spectroscopy.

In order to provide a more concise description, some quantitative expressions herein are described in the range of about amount X to about amount Y. It is understood that when a range is stated, that range is not limited to the upper and lower limits stated, but includes the entire range from about amount X to about amount Y, or any range therein.

"Room temperature" or "RT" refers to the ambient temperature of a typical laboratory, which is usually about 25°C.

As used herein, the term "excipient" refers to any substance required to formulate a composition into the desired form. For example, suitable excipients include, but are not limited to, diluents or fillers, binders or granulating or cohesive agents, disintegrants, lubricants, antiadherents, slip agents, dispersing or wetting agents, dissolution retardants, Stabilizers or enhancers, adsorbents, buffers, chelating agents, preservatives, colours, flavors and sweeteners.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, co-solvents, complexing agents, dispersion media, Coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is known in the art. Unless any conventional media or agent is incompatible with the active ingredients, they are considered for use in therapeutic formulations. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients, such as those commonly used in the art, may be included. These and other such compounds are described in the literature, for example, in the Merck Index, Merck & Company, Rahway, N.J. Considerations for including various components in pharmaceutical compositions are described, eg, in Gilman et al. (eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th ed., The McGraw-Hill Companies.

As used herein, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise.

As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes exact quantities. Thus, "about 5 grams" means "about 5 grams" as well as "5 grams". It is also understood that the ranges expressed herein include integers and fractions thereof within the range. For example, the range between 5 grams and 20 grams includes integer values such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 grams , and fractions within a range, including but not limited to 5.25, 6.5, 8.75 and 11.95 grams. The term "about" preceding a DSC, TGA, TG or DTA value (reported in degrees Celsius) has a permissible variation of +/- 5°C.

As used herein, "optional" or "optionally" means that the subsequently described event or circumstance occurs or does not occur and that the description includes the circumstances under which the event or circumstance occurred and the event or circumstance Situations that do not occur. For example, a reaction mixture that "optionally includes a catalyst" means that the reaction mixture contains a catalyst or does not contain a catalyst.

It is to be appreciated that certain features of the invention which are, for clarity, described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

The invention especially covers all combinations of embodiments of the aspects described herein, as if each and each combination were individually and explicitly stated, such combinations encompassing possible aspects in this respect. In addition, the invention specifically also covers all subcombinations of embodiments contained in aspects described herein and all subcombinations of embodiments contained in all other aspects described herein, just as each of all embodiments and each subcombination are expressly recited herein.

Method and use

A compound of formula (I), or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition thereof (such as any of the solid or liquid formulations described herein) may act as a RET inhibitor, This can be demonstrated, for example, by assays described in PCT Publication No. WO2018/071447 and US Patent Application Publication No. US 20180134702, each of which is incorporated herein by reference in its entirety.

As described throughout the present invention, as provided herein, the compound of formula I (serpatinib) can exhibit brain and/or central nervous system (CNS) penetrance. In some embodiments of the methods disclosed herein, the compounds are capable of crossing the blood-brain barrier and inhibiting RET kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood-brain barrier in amounts effective to prevent disease. In some embodiments, compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, treating a patient with cancer (e.g., cancer with metastatic potential, cancer at risk of metastatic spread, cancer likely to metastasize, RET-associated cancer, RET-associated brain or CNS cancer) can include administering to the patient ( For example, oral administration) compound. In some such embodiments, the compounds provided herein are useful in the treatment of primary or metastatic brain tumors. For example, RET-associated primary brain tumors or metastatic brain tumors.

Various aspects and embodiments of the invention relate to methods for preventing brain metastases. As used herein, "Metastasis" or plural "metastases" refers to the presence of one or more cancer cells at a location that is not physically adjacent to the original location of a cancer (eg, a primary cancer). By way of example and as discussed in more detail below, primary cancers can include lung cancer, breast cancer, melanoma, colorectal cancer, kidney cancer, renal cell carcinoma, thyroid cancer, mesothelioma, ovarian cancer, pancreatic cancer, Any one or more of sarcoma, leukemia, lymphoma, urothelial carcinoma, head and neck cancer, osteosarcoma, and bladder cancer, and in some embodiments, the primary cancer may include glioblastoma and/or astrocytoma cell tumor.

Metastatic growths, lesions, or clusters of cells can be detected using any known method that can be used to provide identification or diagnosis of metastasis, including, for example, magnetic resonance imaging, computerized tomography, or positron emission tomography. In some embodiments, a population of metastatic cells can include at least about ¹ x 107 cells. In some embodiments, detectable metastases can include clusters of cells greater than about 5 mm or about 10 mm in size. In some embodiments, the present invention provides methods for preventing brain metastases in individuals at risk of developing brain metastases and without detectable and/or undiagnosed metastatic growth. Accordingly, in some embodiments, the method of preventing brain metastases comprises administering a compound of formula I to an individual at risk of developing brain metastases and/or having an increased likelihood or chance of developing brain metastases.

Therefore, in embodiments of the methods disclosed herein, the compound of formula (I) (ie serpatinib) or a pharmaceutically acceptable salt, amorphous form, polymorphic form or pharmaceutical composition thereof (eg Any of the solid or liquid formulations described herein) are suitable for preventing brain metastases. As used herein, the term "prevention" means preventing or delaying completely or partially a disease or condition as described herein, such as brain metastases or the onset, recurrence or spread of symptoms thereof. In some embodiments, the term "treating" can also mean prolonging survival as compared to expected survival if not receiving the prophylactic method/therapy.

As used herein, the terms "treat" or "treatment" refer to curative or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, complete or partial remission of symptoms associated with a disease or disorder or condition, reduction in extent of disease, stabilization of disease status (i.e., not worsening), delay or slowing of disease progression, disease Amelioration or alleviation and remission (whether partial or total) of a condition (eg, one or more symptoms of a disease), whether detectable or not. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

As described in detail herein, including in the following illustrative examples, the present invention demonstrates comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition thereof, to a patient in need thereof (eg, any of the solid or liquid formulations described herein) can be used to prevent and/or treat brain metastases. Therefore, in various aspects and embodiments, the present invention provides a compound comprising formula (I) (serpatinib) or a pharmaceutically acceptable salt, amorphous form, polymorphic form or pharmaceutical composition (such as herein Compounds, compositions and dosage forms of any of the described solid or liquid formulations), and methods comprising administering the compounds/pharmaceutical compositions, are effective in inhibiting the onset and progression of brain metastatic lesions.

In some embodiments, the present invention provides a method of treating an individual with cancer comprising administering to an individual in need thereof an amount that inhibits metastatic progression of the cancer to the brain and/or metastatic progression of the cancer in the brain A certain amount of a compound of formula (I) (i.e. serpatinib) or a pharmaceutically acceptable salt, amorphous form, polymorphic form or pharmaceutical composition (such as in a solid or liquid formulation as described herein) either). In some embodiments, the cancer may comprise breast cancer, lung cancer, or RET-associated cancer. In some example embodiments, one or more cells of the individual's cancer exhibits a RET rearrangement or a dysregulated expression, activity or level of the RET gene and/or RET protein. In other example embodiments, one or more cells of the individual's cancer exhibit a RET mutation or RET fusion. In some embodiments, the individual is receptive to a diagnosis that identifies the cancer as a RET-associated cancer. In some embodiments, individuals can be diagnosed or identifiable as being at increased risk for developing brain metastases prior to undergoing prophylactic methods. In some embodiments, the individual is not known to have brain metastases prior to treatment. In other embodiments, serpatinib is a free amine, ie, a non-pharmaceutically acceptable salt.

In an embodiment, the present invention provides a method for treating an individual suffering from cancer comprising administering to the individual an amount of a compound of formula (I) (i.e. serpatinib) or a pharmaceutically acceptable A salt, an amorphous form, a polymorphic form, or a pharmaceutical composition (such as any of the solid or liquid formulations described herein) of , effectively inhibits the metastatic progression of cancer in the brain.

In some embodiments, the present invention provides a method for preventing brain metastases in an individual suffering from cancer, comprising administering to the individual an amount of a compound of formula (I) (ie, serpatinib) or a pharmaceutical thereof A pharmaceutically acceptable salt, amorphous form, polymorphic form or pharmaceutical composition, such as any of the solid or liquid formulations described herein, is effective in inhibiting metastatic progression of cancer in the brain.

In some embodiments, the present invention provides a method for inhibiting the growth and/or survival of metastatic cancer cells in the brain of an individual comprising administering to the individual an effective amount of a compound of formula (I) (ie, Ser Patinib) or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein) thereof. In certain embodiments, the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancers. In some other embodiments, one or more cells of the individual's cancer exhibit a cancer-associated RET mutation and/or RET fusion.

In some embodiments, the present invention provides a method of treating brain metastases in an individual, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) (ie serpatinib) or a pharmaceutically acceptable thereof A salt, an amorphous form, a polymorphic form, or a pharmaceutical composition (such as any of the solid or liquid formulations described herein). In some embodiments, the brain metastases are associated with a primary cancer comprising lung cancer, colorectal cancer, renal cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancers. In other embodiments, one or more cells of the individual's cancer express RET mutations and/or RET fusions associated with cancer and/or brain metastasis. In other embodiments, brain metastases may comprise detectable metastases. In some other embodiments, brain metastases may comprise undetected or undetectable metastases.

In some embodiments, the present invention provides a method of preventing cancer metastases to the brain in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I) (i.e. serpatinib) or a medicament thereof A pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein). In certain embodiments, the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancers. In other embodiments, one or more cells of the individual's cancer exhibit a cancer-associated RET mutation and/or RET fusion.

In some embodiments, the present invention provides a method of reducing the risk of developing detectable brain metastases or the onset of detectable brain metastases in an individual having cancer, the method comprising administering to the individual in need of risk reduction an effective amount of the formula ( I) Compound (i.e. Serpatinib) or a pharmaceutically acceptable salt, amorphous form, polymorphic form or pharmaceutical composition thereof (such as any of the solid or liquid formulations described herein) . In some embodiments, the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancers. In other embodiments, one or more cells of the individual's cancer exhibit a cancer-associated RET mutation and/or RET fusion.

In some embodiments, the present invention provides a method for prolonging the period of survival of an individual suffering from cancer comprising administering to the individual an effective amount of a compound of formula (I) (ie, serpatinib) or a medicament thereof A pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein). In some embodiments, the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancers. In other embodiments, one or more cells of the individual's cancer exhibit a cancer-associated RET mutation and/or RET fusion. In some embodiments, the individual has an advanced disease (ie, cancer), such as an advanced form of lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer, and/or RET-related cancer. In some embodiments, the individual with advanced cancer is known to have one or more brain metastases prior to treatment.

In some embodiments, the methods described herein can prolong the period of survival of an individual with cancer, for example, over a period of months to years (eg, about 1 month, about 2 months, about 3 months, about 4 months) months, about 6 months, about 8 months, about 10 months, about 12 months, about 14 months, about 18 months, about 20 months, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years or more).

In some embodiments of the methods described above, the individual may be known to have one or more metastases (eg, brain or other metastases) prior to treatment or may have previously been treated for previous metastases (ie, brain or other metastases). In some embodiments of the methods described above, the individual is not known to have brain metastases prior to the prophylactic method.

In some embodiments, the present invention provides a method of treating cancer cell metastasis in a subject in need of such treatment comprising administering to the subject an effective amount of a compound of formula (I) (ie, serpatinib) or a pharmaceutical thereof A pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein).

In some embodiments, the present invention provides a method of producing an anti-cancer effect in an individual suffering from cancer, comprising administering to the individual an effective amount of a compound of formula (I) (i.e. serpatinib) or a pharmaceutical thereof A pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein).

In various embodiments of the methods described above, the present invention provides: for treating an individual suffering from cancer, for inhibiting the growth and/or survival of cancer cells, for preventing and/or delaying cancer recurrence, for Inhibition of cancer cell invasion and use for prolonging the period of survival of an individual suffering from cancer, the methods comprising administering to the individual a therapeutically effective amount of a compound of formula (I) (i.e. serpatinib) or a pharmaceutically acceptable A salt, an amorphous form, a polymorphic form, or a pharmaceutical composition (such as any of the solid or liquid formulations described herein) of .

Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts, amorphous forms, polymorphic forms for use in the various indications discussed above, such as the prevention of RET-associated brain metastases. Described herein are brain metastases that can be prevented according to aspects and embodiments comprising the use of compounds of formula (I) or pharmaceutically acceptable salts, amorphous forms, polymorphic forms. In some embodiments, the use of compounds of formula (I) or pharmaceutically acceptable salts, amorphous forms, polymorphic forms in relation to the prevention of RET-associated brain metastases may also comprise performing in vitro assays using biological samples from patients Determining or detecting the presence of RET gene, RET kinase, or a disorder in the expression or activity or level of any of them; If detected and/or determined, a prophylactically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorphic form thereof is administered to the patient. In such uses, the biological sample can be a tumor sample and the tumor sample can be analyzed using methods known to those skilled in the art, such as genome/DNA sequencing. Additionally, in such uses, a sample may be obtained from the patient prior to the first administration of the compound of formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorphic form thereof. In these uses of the compound of formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorphic form, the use/administration may be based on having the expression or activity of the RET gene, RET kinase, or any of them or content of at least one disorder selected patients. In other embodiments of these uses, the use/administration may be based on a patient suspected of having a cancer suspected of having at least one dysregulation of the expression or activity or level of the RET gene, RET kinase, or either. Possibilities increase. In any embodiment of these uses, a compound of formula (I) as described herein or pharmaceutical Acceptable salts, amorphous forms, polymorphic forms.

In some embodiments, the methods and uses described herein may further comprise administering to the individual another anticancer agent as generally known in the art. In some example embodiments, the methods described herein may comprise administering to a subject a therapeutically effective amount of a compound of formula (I) (ie serpatinib) or a pharmaceutically acceptable salt thereof, an amorphous form thereof , a polymorphic form, or a pharmaceutical composition (such as any of the solid or liquid formulations described herein) and an effective amount of an anticancer agent that can penetrate the blood-brain barrier to achieve therapeutic levels, such as, for example, nitric acid Nimustine (N'-[(4-amino-2-methylpyrimidin-5-yl)methyl]-N-(2-chloroethyl)-N-nitrosourea or ACNU) , carmustine (carmustine) (dichloroethylnitrosourea, BiCNU or BCNU), lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea urea or CCNU), hydroxyurea, topotecan, temozolomide, dacarbazine, methotrexate, cytarabine (cytosine arabinoside or ara-C), capecitabine, cisplatin, vinorelbine, carboplatin, or combinations thereof.

As used herein, the terms "subject", "individual" or "patient" are used interchangeably to refer to any animal, including mammals such as 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 individual has experienced and/or exhibited at least one symptom of the disease or condition to be treated and/or prevented. In some embodiments, the individual has been identified or diagnosed with cancer, such as breast cancer, lung cancer, and/or a cancer with dysregulation of the expression or activity or level of the RET gene, RET protein, or either (RET-associated cancer) (e.g. , as determined using a regulatory agency-approved, eg, FDA-approved assay or kit or laboratory developed test (LDT)). In some embodiments, the individual has a tumor that is positive for RET gene, RET protein, or dysregulation of the expression or activity or level of either (eg, as determined using a regulatory agency approved assay or panel). The individual can be an individual with a tumor that is positive for a dysregulation of the expression or activity or level of the RET gene, RET protein, or either (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved assay or panel) . An individual may be one whose tumor has a dysregulation of the RET gene, RET protein, or expression or activity or level thereof (eg, using a regulatory agency-approved, eg, FDA-approved assay or panel to identify tumors with such dysregulation). In some embodiments, the individual is suspected of having a RET-associated cancer. In some embodiments, the individual's clinical records indicate that the individual has a tumor in which the expression or activity or amount of the RET gene, RET protein, or either is dysregulated (and optionally, the individual's clinical records indicate that the individual uses the methods provided herein). any one of the compositions for treatment). In some embodiments, the patient is a pediatric patient.

As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "pediatric" can be further divided into several subgroups, including: neonates (birth to first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 age to 21 years (up to but not including the twenty-second birthday)). Berhman R E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics, 15th ed., Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al., Rudolph's Pediatrics, 21st ed., New York: McGraw-Hill, 2002; and Avery M D, First L R. Pediatric Medicine, 2nd ed., Baltimore: Williams &Wilkins; 1994. In some embodiments, the pediatric patient is from birth to the first 28 days of life, 29 days to less than two years of age, two years to less than 12 years of age, or 12 years to 21 years of age (up to but excluding the twenty-second birthday). In some embodiments, the pediatric patient is birth to first 28 days of life, 29 days to less than 1 year, one month to less than four months, three months to less than seven months, six months to less than one year , 1 to less than 2 years, 2 to less than 3 years, 2 to less than 7 years, 3 to less than 5 years, 5 to less than 10 years, 6 to less than 13 years, 10 to less than 15 years or 15 years old to less than 22 years old.

In some embodiments of any of the methods or uses described herein, the primary cancer (eg, a cancer that is actively or has been treated (eg, a RET-related cancer)) is a blood cancer. In some embodiments of any of the methods or uses described herein, the primary cancer (eg, a RET-associated cancer) is a solid tumor (eg, an advanced solid tumor and/or a RET fusion-positive solid tumor). In some embodiments of any of the methods or uses described herein, the primary cancer (e.g., a RET-associated cancer) is lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer (e.g., papillary thyroid cancer) carcinoma, medullary thyroid carcinoma (eg, sporadic medullary thyroid carcinoma or hereditary medullary thyroid carcinoma), differentiated thyroid carcinoma, recurrent thyroid carcinoma, or refractory differentiated thyroid carcinoma), thyroid adenoma, endocrine gland neoplasm, lung adenocarcinoma , bronchiopulmonary cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, breast cancer, breast neoplasm, breast neoplasm, colorectal cancer ( eg metastatic colorectal cancer), papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, inflammatory myofibroblastic tumor, or cervical cancer. In some embodiments of any of the methods or uses described herein, the primary cancer (eg, RET-associated cancer) is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia ( AML), juvenile cancer, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, abnormal teratoid/rod tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, Brain tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, site tumors, tumors, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, embryo Sexual tumors, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing Sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, neoplasms by site , tumor, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, mammary duct carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, Sensitive neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer , gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational dystrophy, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic tumor, head and neck tumor, CNS tumor, original Primary CNS tumor, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Cabourg Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, bone malignancy Fibrous histiocytoma, osteosarcoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck carcinoma, midline tract carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple Myeloma, Mycosis Fungoides, Myelodysplastic Syndrome, Myelodysplasia/Myeloproliferative Neoplasms, Site Tumors, Tumors, Myeloid Leukemia, Myeloid Leukemia, Multiple Myeloma, Myeloproliferative Neoplasms, Nasal and Sinus Cancers, Nasal Pharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung cancer, lung cancer, lung cancer, respiratory tract cancer, bronchial cancer, bronchial cancer, Oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, paraganglioma Thyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell tumor, pleuropulmonary blastoma, pregnancy-related breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer Carcinoma, colorectal cancer, colon tumor, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, Sezary syndrome, skin cancer, Spitz tumors, small cell lung cancer, Small bowel cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, transitional cell cancer of the renal pelvis and urinary tract, unknown etiology Carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

In some embodiments, the primary cancer of the blood (eg, a cancer of the blood that is a RET-associated cancer) is selected from the group consisting of: leukemia, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also known as Hodgkin's lymphoma) and myelomas such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), Chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), pleomorphic large cell lymphoma (ALCL), former Lymphoblastic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplastic syndrome ( MDS), myeloproliferative disease (MPD) and multiple myeloma (MM). Other examples of hematologic primary cancers include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF/IPF/PMF ). In one embodiment, the hematological primary cancer (eg, a hematological cancer that is a RET-associated cancer) is AML or CMML.

In some embodiments, the primary cancer (eg, RET-associated cancer) is a solid tumor. Examples of solid tumors (e.g., as RET-associated cancers) include, e.g., thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer), lung cancer (e.g., lung adenocarcinoma, small cell lung cancer), pancreatic cancer, pancreatic ductal cancer , breast cancer, colorectal cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck cancer, neuroblastoma and melanoma. See eg Nature Reviews Cancer, 2014, 14, 173-186.

In some embodiments, the primary cancer is selected from the group consisting of lung cancer, papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, refractory differentiated thyroid cancer, type 2A or 2B multiple Sexual endocrine tumors (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, gangliomatosis of the gastrointestinal mucosa, and cervical cancer. In a preferred embodiment, the cancer includes lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer and/or RET-related cancer.

In embodiments related to methods of preventing brain metastases as described herein, an individual can be identified as being at risk, including an increased risk, for the occurrence or onset of one or more metastatic growths in the brain. In some embodiments, individuals can be identified by establishing and/or determining the stage of an underlying disease, such as identifying the stage of a primary (or underlying) cancerous disease. In some embodiments, an individual can be identified as having an underlying disease, such as a cancer type, that has a known risk of developing metastatic growth. In some embodiments, an individual can be identified by detection and/or determination of a primary (or potential) cancer disease as a RET-associated cancer. A discussion of RET-associated cancers, RET mutations, RET fusions, RET gene dysregulation, and diagnostic methods suitable for detecting such RET-based biomarkers is provided below.

In some embodiments, compounds provided herein exhibit potent and selective RET inhibition. For example, compounds provided herein exhibit nanomolar potency against wild-type RET and RET kinase encoded by RET genes including activating mutations or RET kinase inhibitor resistance mutations including, for example, KIF5B-RET fusions, G810R and G810S ATP cleft front mutations, M918T activating mutations, and V804M, V804L, and V804E gatekeeper gene mutations also had minimal activity against related kinases.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (eg, any of the solid or liquid formulations described herein) is selected from Sexually targets RET kinase. For example, a compound of formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein) may optionally Target the RET kinase rather than another kinase or non-kinase target. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition thereof (eg, any of the solid or liquid formulations described herein) is directed against A variant RET fusion protein encoded by a RET gene encoding a RET fusion protein (such as any of the RET fusion proteins described herein, including but not limited to, CCDC6-RET or KIF5B-RET) exhibiting nanomolar concentration potency, The RET gene includes a RET kinase inhibitor resistance mutation (such as any of the RET mutations described herein, including but not limited to, V804M, V804L, or V804E), such that the variant RET protein is a RET fusion protein that is derived from a RET kinase inhibitor RET kinase resistance is exhibited by the presence of resistant amino acid substitutions or deletions. Non-limiting examples include CCDC6-RET-V804M and KIF5B-RET-V804M. In some embodiments, the compounds provided herein exhibit nanomolar potency against a variant RET protein encoded by a RET gene comprising a RET mutation (such as any of the RET mutations described herein, including (but not limited to, C634W or M918T) and includes a RET kinase inhibitor resistance mutation (such as any of the RET kinase inhibitor resistance mutations described herein, including but not limited to, V804M, V804L, or V804E) , such that the variant RET protein includes a RET substitution caused by a RET mutation (eg RET initial mutation) and the variant RET protein exhibits RET kinase resistance due to the presence of a RET kinase inhibitor resistant amino acid substitution or deletion.

In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (eg, any of the solid or liquid formulations described herein) exhibits against RET kinase is at least 30-fold more selective than another kinase. For example, a compound of formula (I), or a pharmaceutically acceptable salt, amorphous form, polymorphic form, or pharmaceutical composition (such as any of the solid or liquid formulations described herein) exhibits selectivity against RET kinase At least 40-fold; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 200-fold; at least 300-fold; at least 400-fold; at least 500-fold At least 600 times; at least 700 times; at least 800 times; at least 900 times or at least 1000 times. In some embodiments, selectivity for a RET kinase is measured relative to another kinase in a cellular assay (eg, a cellular assay as provided herein).

In some embodiments, compounds provided herein can exhibit selectivity for a RET kinase (eg, VEGFR2) relative to a KDR kinase. In some embodiments, selectivity for RET kinase over KDR kinase was observed without loss of potency for RET kinase encoded by the RET gene including activating mutations or RET kinase inhibitor resistance mutations (eg, gatekeeper mutants). In some embodiments, the selectivity is at least 10-fold over KDR kinase (e.g., at least 40-fold selectivity; at least 50-fold selectivity; at least 60-fold selectivity; at least 70-fold selectivity; at least 70-fold selectivity) compared to inhibition of KIF5B-RET 80-fold selectivity; at least 90-fold selectivity; at least 100-fold selectivity; at least 150-fold selectivity; at least 200-fold selectivity; at least 250-fold selectivity; at least 300-fold selectivity; at least 350-fold selectivity; or at least 400-fold fold selectivity) (e.g. compounds are more potent for KIF5B-RET than KDR). In some embodiments, the selectivity for RET kinase is about 30-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 100-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 150-fold over KDR kinase. In some embodiments, the selectivity for RET kinase is at least 400-fold over KDR kinase. Without being bound by any theory, it is believed that potent KDR kinase inhibition is a common feature among multiple kinase inhibitors (MKIs) targeting RET and may be the source of the dose-limiting toxicity observed with such compounds.

In some embodiments, inhibition by V804M is similar to that observed for wild-type RET. For example, the inhibition of V804M is within about 2-fold (eg, about 5-fold, about 7-fold, about 10-fold) that of wild-type RET (ie, the compounds are similarly potent against wild-type RET and V804M). In some embodiments, selectivity is measured for a wild-type or V804M RET kinase over another kinase in an enzyme assay, such as the enzyme assays provided herein. In some embodiments, the compounds provided herein exhibit selective cytotoxicity against RET mutant cells.

In some embodiments, the inhibition of G810S and/or G810R is similar to that observed for wild-type RET. For example, the inhibition of G810S and/or G810R is within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of the inhibition of wild-type RET (e.g., compounds against wild-type RET and G810S and/or G810R performance is similar). In some embodiments, selectivity for a wild-type or G810S and/or G810R RET kinase over another kinase is measured in an enzyme assay, such as the enzyme assays provided herein. In some embodiments, the compounds provided herein exhibit selective cytotoxicity against RET mutant cells.

As used herein, the term "RET-associated disease or disorder" refers to a disorder related to the expression or activity or level of the RET gene, RET kinase (also referred to herein as the RET kinase protein), or any (eg, one or more) thereof ( For example, any type of dysregulation of the expression or activity or level of the RET gene, RET kinase, RET kinase domain, or any of those described herein) is associated with or has such a disorder or disorder. Non-limiting examples of RET-associated diseases or disorders include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

As used herein, the term "RET-associated cancer" refers to a cancer associated with or having a dysregulation of the RET gene, RET kinase (also referred to herein as RET kinase protein), or the expression or activity or level of either. Non-limiting examples of RET-associated cancers are described herein.

The phrase "disregulation of the expression or activity or content of the RET gene, RET kinase, or any of them" refers to a genetic mutation (such as a chromosomal translocation that causes expression of a fusion protein comprising the RET kinase domain and a fusion partner, causing RET gene mutations causing expression of RET protein with one amino acid deletion (compared to wild-type RET protein), RET gene mutations causing expression of RET protein with one or more point mutations (compared to wild-type RET protein) , a RET gene mutation causing the expression of a RET protein with at least one inserted amino acid (compared to a wild-type RET protein), a gene duplication causing an increased RET protein content in a cell, or a cell causing an increased RET protein content regulatory sequence (such as promoter and/or enhancer) mutations), alternative splicing forms of RET mRNA that result in a deletion of at least one amino acid in the RET protein (compared to wild-type RET protein), or due to abnormal Enhanced expression (eg, increased level) of wild-type RET kinase in mammalian cells resulting from dysregulation of cellular signaling and/or autocrine/paracrine signaling (eg, compared to control non-cancerous cells). As another example, a dysregulation of the expression or activity or level of either the RET gene, the RET protein, or any of them may be a mutation in the RET gene encoding a RET protein that is constitutively active or associated with RET that does not include the mutation. Compared with the protein encoded by the gene, it has increased activity. For example, dysregulation of the expression or activity or level of the RET gene, RET protein, or either may be the result of a gene or chromosomal translocation that results in a first portion of RET comprising a functional kinase domain and the expression of the fusion protein of the second part of the partner protein (ie, not RET). In some instances, dysregulation of the expression or activity or level of a RET gene, RET protein, or either may be the result of a genetic translocation of one RET gene with another non-RET gene. Non-limiting examples of RET fusion proteins, RET kinase protein mutations (e.g., point mutations/insertions/deletions, inhibitor resistance mutations, etc.) are known in the art and are described, for example, in U.S. Patent 10,786,489 (e.g., Tables 1 to 4), which is incorporated herein by reference in its entirety.

In some embodiments of the methods and uses described herein, the dysregulation of the expression or activity or level of the RET gene, RET kinase, or either may result from an activating mutation of the RET gene (see, e.g., listed herein and/or as Chromosomal translocations that result in expression of any fusion protein listed in Table 1 of US Patent 10,786,489, which is incorporated herein by reference). In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or either may result from a genetic mutation that results in, for example, increased inhibition of RET kinase as compared to wild-type RET kinase. Expression of RET kinase resistant to inhibition by multiple kinase inhibitors (MKIs) and/or multikinase inhibitors (see, e.g., amino acid substitutions disclosed herein, including substitutions at positions: 634 (e.g., C634W), 732 (e.g., E732K ), 778, 788 (such as I788N), 790 (such as L790F), 804 (such as V804M, V804L, V804E), 778 and 804, 804 and 805 (such as V804M/E805K), 806 (such as Y806C, Y806E, Y806S, Y806H , Y806N), 804 and 806 (such as V804M/Y806C), 810 (such as G810A, G810R, G810S, G810C, G810V and G810D), 865 (such as L865V), 870 (such as L870F), 891 (such as S891A), 904 ( such as S904F), 804 and 904 (such as V804M/S904C), 918 (such as M918T), and additional exemplary mutations that induce steric hindrance and/or active conformational effects, including L730P, G731V, E732K, G733V, E734K, L760M 、K761E、E762K、N763D、A764V、S765N、P766A、S767C、E768K、L779M、I788M、M868R、K869E、L870Q、V871M、H872R、R873P、D874Y、L881R、L895M、S896N、R897C、D898Y、V899G、Y900D、E901K , E902K, D903Y, S904C, Y905D, V906M, K907E, R908P, S909C, Q910R, G911C, and R912P and/or as listed in Tables 3 and 4 of U.S. Patent 10,786,489, which is incorporated herein by reference ). In some embodiments, dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them can be caused by a nucleic acid encoding a variant RET protein (e.g., a RET fusion protein or a RET protein with a mutation (e.g., an initial mutation)). Mutations result in the expression of a variant protein with increased resistance to inhibition by RET kinase inhibitors and/or multikinase inhibitors (MKIs), eg, compared to wild-type RET kinase. Such exemplary RET kinase amino acid substitutions, RET kinase point mutations, insertions and deletions (eg, as known and described in U.S. Patent 10,786,489, incorporated herein by reference) may result from activating mutations and/or may result from Causes expression of RET kinase with increased resistance to inhibition by RET kinase inhibitors and/or multikinase inhibitors (MKI).

The term "activating mutation" describes a mutation in the RET kinase gene which causes, for example, the expression of RET kinase with increased kinase activity compared to wild-type RET kinase, eg when assayed under the same conditions. For example, activating mutations can result in the expression of a fusion protein comprising the RET kinase domain and the fusion partner. In another example, the activating mutation can be a mutation in the RET kinase gene that results in one or more (e.g., two, three, four, five, six, seven, eight, nine, or Ten) expression of an amino acid substituted RET kinase (e.g. any combination of any of the amino acid substitutions described herein) that has, e.g., increased kinase activity compared to wild-type RET kinase, e.g. assayed under the same conditions Time. In another example, the activating mutation can be a mutation in the RET kinase gene that results in one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) a) The performance of the amino acid deleted RET kinase, eg compared to wild-type RET kinase, eg when assayed under the same conditions. In another example, the activating mutation can be a mutation in the RET kinase gene that results in at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8 , at least 9, at least 10, at least 12, at least 14, at least 16, at least 18 or at least 20) amino acid insertions RET kinase expression, and wild-type RET kinase, such as described herein Exemplary wild-type RET kinase compared, eg, when assayed under the same conditions. Other examples of activating mutations are known in the art.

The term "wild-type" or "wild-type" describes a nucleic acid (such as a RET gene or RET mRNA) or protein (such as a RET protein) that is found in individuals who do not have a RET-associated disease (such as a RET-related cancer) (and optionally not at increased risk of and/or suspected of having a RET-associated disorder), or in cells or tissues from individuals who do not have a RET-associated disorder (such as RET-related cancers) (and optionally also not at increased risk and/or not suspected of having a RET-related disease).

Formulation and Dosage

In some embodiments, solid formulations comprising a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof may be administered by a variety of routes depending on the desired treatment and the area to be treated and. In some embodiments, the administration is oral. Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration.

Compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof may be formulated in unit dosage form, each dose containing from about 1 to about 1,000 mg (1 g), more usually about 5 mg to about 100 mg active ingredient. The term "unit dosage form" means a physically discrete unit suitable in unit dosage form for human subjects and other patients, each unit containing a predetermined quantity of active material (i.e., a compound of formula (I) or its medicinal product) calculated to produce the desired therapeutic effect. pharmaceutically acceptable salts, amorphous or polymorphic forms), and suitable pharmaceutical excipients.

In some embodiments, the solid formulation is formulated as 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg , 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg dosage forms. In some embodiments, solid formulations are formulated as 10 mg, 20 mg, 60 mg, 80 mg, 120 mg, or 160 mg dosage forms.

In some embodiments, the compositions provided herein contain from about 1 mg to about 50 mg of the active ingredient. Those of ordinary skill in the art will appreciate that the embodied compound or composition contains about 1 mg to about 5 mg, 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of active ingredient. In some embodiments, the compositions provided herein contain about 10 mg of the active ingredient.

In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. Those of ordinary skill in the art will appreciate that the embodied compound or composition contains about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 120 mg to about 160 mg, about 150 mg to about 200 mg, about 200 mg mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of active ingredient.

In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of active ingredient. Those of ordinary skill in the art will appreciate that this comprising compound or composition contains about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

The daily dosage of a compound of formula (I) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof may vary within a wide range of 1.0 to 10,000 mg or more per adult per day or any range therein.

In some embodiments, for oral administration, the composition may be provided as a lozenge containing about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150 , 160, 200, 250 and 500 mg of active ingredient in order to adjust the dose according to the symptoms of the patient to be treated.

An effective amount of the drug is generally supplied in an administration amount of about 0.1 mg/kg to about 1000 mg/kg body weight per day, or any range therein. In some embodiments, the range is about 0.5/kg to about 500 mg/kg body weight per day, or any range therein. In some embodiments, from about 1.0 to about 250 mg/kg body weight per day, or any range therein. In some embodiments, from about 0.1 to about 100 mg/kg body weight per day, or any range therein. In some embodiments, the range is about 0.1 to about 50.0 mg/kg body weight per day, or any amount or range therein. In some embodiments, the range is about 0.1 to about 15.0 mg/kg body weight per day, or about 0.5 mg/kg to about 10 mg/kg, or 1 mg/kg to about 9 mg/kg, or about 2 mg/kg to about 8 mg/kg or about 3 mg/kg to 7 mg/kg. In addition, the compound of formula (I) can be administered, for example, in the following amounts: 1 mg/kg, 1.1 mg/kg, 1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3 mg/kg, 3.1 mg/kg, 3.2 mg/kg, 3.3 mg/kg, 3.4 mg/kg, 3.5 mg/kg, 3.6 mg/kg, 3.7 mg/kg, 3.8 mg/kg, 3.9 mg/kg, 4, mg/kg, 4.1 mg/kg, 4.2 mg/kg, 4.3 mg/kg, 4.4 mg/kg, 4.5 mg/kg, 4.6 mg/kg, 4.7 mg/kg, 4.8 mg/kg, 4.9 mg/kg, 5 mg/kg, 5.1 mg/kg, 5.2 mg/kg, 5.3 mg/kg, 5.4 mg/kg, 5.5 mg/kg, 5.6 mg/kg, 5.7 mg/kg, 5.8 mg/kg, 5.9 mg/kg, 6 mg/kg, 6.1 mg/kg, 6.2 mg/kg, 6.3 mg/kg, 6.4 mg/kg, 6.5 mg/kg, 6.6 mg/kg, 6.7 mg/kg, 6.8 mg/kg, 6.9 mg/kg, 7 mg/kg, 7.1 mg/kg, 7.2 mg/kg, 7.3 mg/kg, 7.4 mg/kg, 7.5 mg/kg, 7.6 mg/kg, 7.7 mg/kg, 7.8 mg/kg, 7.9 mg/kg, 8 mg/kg, 8.1 mg/kg, 8.2 mg/kg, 8.3 mg/kg, 8.4 mg/kg, 8.5 mg/kg, 8.6 mg/kg, 8.7 mg/kg, 8.8 mg/kg, 8.9 mg/kg, 9 mg/kg, 9.1 mg/kg, 9.2 mg/kg, 9.3 mg/kg, 9.4 mg/kg, 9.5 mg/kg, 9.6 mg/kg, 9.7 mg/kg, 9.8 mg/kg, 9.9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg , about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg g, about 60 mg/kg.

In one aspect, about 0.1 mg/kg to about 15.0 mg/kg body weight of cerpatinib or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof or comprising cerpatinib is administered to the individual per day. Compositions of Patinib or pharmaceutically acceptable salts, amorphous or polymorphic forms thereof.

The pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt, amorphous form or polymorphic form can be administered as a course of treatment 1 to 4 times a day. More preferably, Serpatinib or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof or a pharmaceutical comprising Serpatinib or the like is administered to the individual once or twice a day or in a single daily dose. Compositions in pharmaceutically acceptable salts, amorphous or polymorphic forms. Daily administration can be once daily or in multiple doses, eg twice daily (BID) administration. In one aspect, administration may be performed by administering 120 mg of serpatinib, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, to the subject when the subject weighs less than 50 kg, or a composition comprising serpatinib, or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof, and wherein 160 mg serpatinib is administered to the individual when the individual weighs more than 50 kg Or a pharmaceutically acceptable salt, an amorphous form or a polymorphic form thereof, or a composition comprising serpatinib or a pharmaceutically acceptable salt, an amorphous form or a polymorphic form thereof. In some aspects, serpatinib, or a pharmaceutically acceptable salt thereof, is a polymorph. Alternatively, serpatinib or a pharmaceutically acceptable salt thereof is amorphous. In certain aspects, serpatinib is a free amine.

The active compounds are effective over a wide dosage range, and are generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will thus be understood that the actual amount of compound administered will generally be at the discretion of the physician and will vary depending on the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition being treated and the progression of the disease condition. In addition, factors associated with the particular patient being treated, including patient response, age, weight, diet, time of administration and severity of patient symptoms, will give rise to the need to adjust dosage.

Mode (I) Polymorphic Forms of Compounds

In some embodiments, the solid formulation comprises a compound of formula (I), ie, a polymorphic form of serpatinib. Forms include, for example, free bases, solvates, hydrates, salts, and unsolvated forms of compounds of formula (I), including, for example, polymorphic forms 1 to 8 (eg, 1, 2, 7 and 8), which are incorporated herein by reference in their entirety. In some embodiments, polymorphic forms of compounds of formula (I) are pharmaceutically acceptable salts.

Mode (I) salt of

In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt. For example, pharmaceutically acceptable salts of compounds of formula (I) may include, but are not limited to, sulfate, tosylate, naphthalene-2-sulfonate, oxalate, phosphate, tartrate and Fumarate. In some embodiments, the compound of formula (I) is a sulfate or phosphate salt. In some embodiments, the sulfate salt is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of isopropanol (IPA) and water. In some embodiments, water is present in an amount of 10% by weight. In some embodiments, the compound of Formula (I) is the tosylate salt. In some embodiments, the tosylate salt is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of acetone and water. In some embodiments, water is present in an amount of 10% by weight. In some embodiments, the compound of formula (I) is naphthalene-2-sulfonate. In some embodiments, naphthalene-2-sulfonate is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of THF and water. In some embodiments, water is present in an amount of 10% by weight. In some embodiments, the compound of formula (I) is an oxalate salt. In some embodiments, the oxalate salt is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of 1,4-dioxane and water. In some embodiments, water is present in an amount of 10% by weight. In some embodiments, the oxalate salt is prepared by evaporation from a solvent mixture. In some embodiments, the solvent is a mixture of THF and water. In some embodiments, the compound of formula (I) is a tartrate salt. In some embodiments, the tartrate salt is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of IPA and water. In some embodiments, water is present in an amount of 10% by weight. In some embodiments, the compound of formula (I) is a fumarate. In some embodiments, the fumarate is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of THF and water. In some embodiments, the compound of formula (I) is a phosphate salt. In some embodiments, the phosphate is prepared in a solvent mixture. In some embodiments, the solvent is a mixture of acetone and water. In some embodiments, the solvent is a mixture of IPA and water. In some embodiments, water is present in an amount of 10% by weight. Salts of formula (I) and methods for preparing such salts are described in US Patent Nos. 10,584,124 and 10,786,489, both of which are incorporated herein by reference in their entirety.

for preparation (I) compound method

Compounds of formula (I) may be obtained from commercial sources or, in the alternative, they may be prepared by synthetic methods, such as those disclosed and described elsewhere (eg, US Patent 10,112,942, herein incorporated by reference in its entirety). For purposes of illustration only, Schemes 1 and 2 show general methods for the preparation of the compounds provided herein as well as key intermediates. More detailed descriptions of individual reaction steps are disclosed in US Patent 10,112,942 and International Patent Publication WO 2018/071447, both of which are incorporated herein by reference in their entirety. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.

Process 1

其中波浪線表示連接至包含X ¹、X ²、X ³及X ⁴之環的連接點。 Scheme 1 shows a general scheme for the synthesis of compounds of formula (I) (shown in Scheme 1 as compound 12), wherein B is -CH ₂ C(CH ₃ ) ₂ OH; X ¹ is N; X ² , X ³ and X ⁴ is CH; and D and E are represented by:

Wherein the wavy line indicates the connection point to the ring including X ¹ , X ² , X ³ and X ⁴ .

基磺醯基)羥胺處理市購3-溴-5-甲氧基吡啶(化合物1)而獲得。O-

基磺醯基羥胺可如Mendiola等人，Org. Process Res. Dev. (2009) 13(2):263-267所描述來製備。化合物2可與丙炔酸乙酯反應以得到化合物3A與3B之混合物，其典型地分別以大致2:1至9:1之比率獲得。化合物3A與3B之混合物可在高溫下用48% HBr處理，隨後再結晶或層析純化，以分離出作為次要異構體之化合物4A及作為主要異構體之化合物4B。分離之後，化合物4A可用POCl ₃處理，以提供化合物5。甲醯基可使用NH ₂OH轉化成肟基，以提供化合物6。肟基可使用乙酸酐轉化成腈基，以提供化合物7。化合物7之甲氧基可藉由用三氯化鋁處理化合物7而轉化成羥基，以提供化合物8。 Compound 2 is obtained by O-(

It can be obtained by treating commercially available 3-bromo-5-methoxypyridine (compound 1) with sulfonyl)hydroxylamine. O-

Sulfonyl hydroxylamine can be prepared as described by Mendiola et al., Org. Process Res. Dev. (2009) 13(2):263-267. Compound 2 can be reacted with ethyl propiolate to give a mixture of Compounds 3A and 3B, which are typically obtained in approximately 2:1 to 9:1 ratios, respectively. A mixture of compounds 3A and 3B can be treated with 48% HBr at elevated temperature followed by recrystallization or chromatographic purification to isolate compound 4A as the minor isomer and compound 4B as the major isomer. After isolation, compound 4A can be treated with POCl ₃ to provide compound 5. The formyl group can be converted to the oxime group using NH2OH to provide compound ₆ . The oxime group can be converted to a nitrile group using acetic anhydride to provide compound 7. The methoxy group of compound 7 can be converted to a hydroxyl group by treating compound 7 with aluminum trichloride to provide compound 8.

， 在存在適合之鹼(例如鹼金屬碳酸鹽，諸如碳酸鉀)的情況下反應，其中X為離去原子或基團(諸如鹵離子或三氟甲磺酸根)。在一些實施例中，化合物9可藉由在存在適合之鹼的情況下使化合物8與環氧化物試劑，諸如烷基化環氧化物反應來製備。化合物11接著可藉由使用適當的鈀催化之交叉偶合反應條件，例如鈴木偶合反應(Suzuki coupling reaction)條件(例如鈀催化劑及視情況存在之配位體，在存在無機鹼，例如含Pd(PPh ₃) ₄及Na ₂CO ₃之二㗁烷的情況下，在高溫下)使化合物9與對應硼酸酯化合物10 (其中環D為

其中波浪線指示環D連至包含X ¹、X ²、X ³及X ⁴之環的連接點，且星號指示連至P ¹之連接點；X ¹、X ²、X ³及X ⁴如上文所定義；P ¹為胺基保護基；Z為-B(OR ^x)(OR ^y)且R ^x及R ^y為H或(1-6C)烷基，或R ^x及R ^y連同其連接之原子形成5員至6員環，視情況經1至4個選自(C1-C3烷基)之取代基取代)偶合來製備。接著，化合物12可藉由以下自化合物11製備：在標準條件下移除保護基P ¹(例如可藉由在酸性條件，例如HCl下處理化合物11來移除Boc基團)，隨後在標準條件下官能化(亦即使化合物11與適當的試劑反應或用適當的試劑處理化合物11)以引入E基團。

In some embodiments, to prepare compound 9, compound 8 can be combined with reagents such as:

, where X is a leaving atom or group (such as a halide or triflate) in the presence of a suitable base (eg an alkali metal carbonate such as potassium carbonate). In some embodiments, compound 9 can be prepared by reacting compound 8 with an epoxide reagent, such as an alkylated epoxide, in the presence of a suitable base. Compound 11 can then be synthesized by using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (such as a palladium catalyst and an optional ligand, in the presence of an inorganic base, such as a Pd(PPh ₃ ) In the case of ₄ and Na ₂ CO ₃ dioxane, at high temperature) compound 9 and the corresponding boronic acid ester compound 10 (where ring D is

where the wavy line indicates the connection point of ring D to the ring containing X ¹ , X ² , X ³ and X ⁴ , and the asterisk indicates the connection point to P ¹ ; X ¹ , X ² , X ³ and X ⁴ are as above Defined; P ¹ is an amino protecting group; Z is -B(OR ^x )(OR ^y ) and R ^x and R ^y are H or (1-6C)alkyl, or R ^x and R ^y together with their attached The atoms form a 5 to 6 membered ring, optionally substituted with 1 to 4 substituents selected from (C1-C3 alkyl) to prepare by coupling. Compound 12 can then be prepared from compound 11 by removal of protecting group P ¹ under standard conditions (e.g. the Boc group can be removed by treating compound 11 under acidic conditions, such as HCl), followed by removal under standard conditions Down functionalization (ie, reaction of compound 11 with or treatment of compound 11 with an appropriate reagent) to introduce the E group.

， 其中X為離去原子或基團(諸如鹵離子或三氟甲磺酸根)，以提供化合物11。接著可如上文所描述自化合物11製備化合物12。 Alternatively, cross-coupling reaction conditions such as Suzuki coupling reaction conditions (e.g. palladium catalyst and optional ligand in the presence of an inorganic base such as Pd(PPh ₃ ) ₄ and Na _{2CO 3bisoxane} at elevated temperature) to couple compound 8 with the corresponding boronic ester compound 10 to provide compound 11a. Compound 11a can then be _reacted with a reagent such as:

, wherein X is a leaving atom or group such as halide or triflate to provide compound 11. Compound 12 can then be prepared from compound 11 as described above.

Process 2

Scheme 2 shows another general scheme for the synthesis of compound 12, wherein B, X ¹ , X ² , X ³ and X ⁴ , rings D and E are as defined above for Scheme 1 .

Appropriate palladium-catalyzed cross-coupling reaction conditions may be used, such as Suzuki coupling reaction conditions (e.g., palladium catalyst and optional ligand, in an inorganic base, e.g., containing Pd( _PPh3 ) ₄ and _{Na2CO3 )} . In the presence of methane, at elevated temperature), compound 9 (e.g., prepared as described in Scheme 1) (wherein B is as defined above) and the corresponding boronic acid ester 13 (wherein X ¹ , X ² , X ³ and ^X4 is as defined above ^; L2 is a leaving group such as triflate or halide; Z ^is -B( ^{ORx)(ORy) and Rx and Ry are H} or (1-6C) Alkyl, or R ^x and R ^y together with the atoms to which they are attached, as a 5 to 6 membered ring optionally substituted with 1 to 4 substituents selected from (C1-C3 alkyl)) are coupled to provide compound 14 . Compound 16 can be synthesized by reacting compound 14 with compound 15 (where ring D is as defined above and P is ^an amino protecting group) under appropriate S _N Ar conditions (e.g., optionally in the presence of a base such as K ₂ CO ₃ and At high temperature) coupling to prepare.

The protecting group P on ring D of compound ¹⁶ can be removed under standard conditions (for example, the Boc group can be removed by treating compound 16 under acidic conditions such as HCl) to provide compound 12, wherein E is H (ie, ring D is deprotected). The deprotected ring D can then be functionalized (i.e., reacted with or treated with an appropriate reagent) under standard conditions such as those described below to introduce the E group to provide compound 12, wherein E is as defined above .

As used herein, the term "amine protecting group" refers to a derivative of a group commonly used to block or protect an amine group while allowing other functional groups of the compound to react. Examples of protecting groups suitable for use in any of the methods described herein include carbamates, amides, alkyl and aryl groups, imines, and various N-heteroatom derivatives which can be removed to render the desired amine base regeneration. Non-limiting examples of amine protecting groups are acetyl, trifluoroacetyl, tertiary butoxycarbonyl ("Boc"), benzyloxycarbonyl ("CBz"), and 9-fenylmethyleneoxy Carbonyl ("Fmoc"). Additional examples of these and other protecting groups are found in T. W. Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.

The hydroxy group can be protected with any suitable hydroxy protecting group, for example as described in: T. W. Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006. Examples include benzyl, trityl, silyl ether, and the like.

The nitrogen atom in any of the compounds described in the above methods can be protected with any suitable nitrogen protecting group, for example as described in: Greene and Wuts eds., "Protecting Groups in Organic Synthesis", Supplement 2nd Edition, New York; John Wiley & Sons, Inc., 1991. Examples of nitrogen protecting groups include acyl and alkoxycarbonyl groups such as tertiary butoxycarbonyl (BOC), phenoxycarbonyl and [2-(trimethylsilyl)ethoxy]methyl (SEM).

Other routes can be used to synthesize compounds of formula I, including, for example, the synthetic routes disclosed in US Pat. No. 10,786 489 (eg, Schemes 3 to 6), which is incorporated herein by reference.

identify individuals at risk and RET companion diagnostics

與野生型RET激酶相比，潛在地活化RET激酶蛋白質點突變、插入或缺失之非限制性實例可發生在以下胺基酸位置處：2、3、4、5、6、7、8、11、12、13、20、32 (例如S32L)、34 (例如D34S)、40 (例如L40P)、56 (例如L56M)、64 (例如P64L)、67 (例如R67H)、114 (例如R114H)、136 (例如麩胺酸至終止密碼子)、145 (例如V145G)、胺基酸位置180 (例如精胺酸至終止密碼子)、200、292 (例如V292M)、294、321 (例如G321R)、330 (例如R330Q)、338 (例如T338I)、360 (例如R360W)、373 (例如丙胺酸至纈胺酸(p.A373V)讀框轉移)、D378-G385delinsE、393 (例如F393L)、423 (例如G423R)、432、446 (例如G446R)、505-506 (外顯子7中之6-鹼基對框內生殖系缺失)、510 (例如A510V)、511 (例如E511K)、513 (例如G513D)、515 (例如C515R、C515S、C515W)、525 (例如R525W)、531 (例如C531R或9個鹼基對複製)、532 (例如複製)、533 (例如G533C、G533S)、550 (例如G550E)、591 (例如V591I)、593 (例如G593E)、595 (例如E595D及E595A)、600 (例如R600Q)、602 (例如I602V)、603 (例如K603Q、K603E)、606 (例如Y606C)、609 (例如C609Y、C609S、C609G、C609R、C609F、C609W、C609C)、611 (例如C611R、C611S、C611G、C611Y、C611F、C611W)、616 (例如E616Q)、618 (例如C618S、C618Y、C618R、C618T、C618G、C618F、C618W)、620 (例如C620S、C620W、C620R、C620G、C620L、C620Y、C620F)、623 (例如E623K)、624 (例如D624N)、630 (例如C630A、C630R、C630S、C630Y、C630F、C630W、C630G)、631 (例如D631N、D631Y、D631A、D631G、D631V、D631E)、632 (例如E632K、E632G)、632-633 (外顯子11中之6-鹼基對框內生殖系缺失)、633 (例如9個鹼基對複製)、634 (例如C634W、C634Y、C634S、C634R、C634F、C634G、C634L、C634A或C634T或插入ELCR或12個鹼基對複製或與A640G、A641A或A641T的組合) (例如引起MTC)、634/852 (例如C634R/I852M)、635 (例如R635G)、636 (例如T636P、T636M)、648 (例如V648I)、649 (例如S649L)、664 (例如A664D)、665 (例如H665Q)、666 (例如K666E、K666M、K666N、K666R)、675 (T675T、沉默核苷酸變化)、686 (例如S686N)、689 (例如S689T)、691 (例如G691S)、694 (例如R694Q)、700 (例如M700L)、706 (例如V706M、V706A)、713剪接變異體(例如E713K)、732 (例如E732K)、736 (例如G736R)、748 (例如G748C)、765 (例如S765P)、766 (例如P766S、P766M6)、768 (例如E768Q、E768D)、769 (例如L769L)、770 (例如R770Q)、771 (例如D771N)、777 (例如N777S)、778 (例如V778I)、781 (例如Q781R)、788 (例如I788I)、790 (例如L790F、L790T)、791 (例如Y791F、Y791N)、791/852 (例如Y791F /I852M)、802、804 (例如V804L、V804M、V804E、V804G、V804S) (例如引起MTC)、804/918 (例如V804M/M918T、V804L/M918T)、805 (例如E805K)、804/805 (例如V804M/E805K)、806 (例如Y806F、Y806C、Y806H、Y806Y)、810 (例如G810R、G810S、G810A、G810C、G810V)、818 (例如E818K)、819 (例如S819I)、823 (例如G823E)、826 (例如Y826M、Y826S)、833 (例如R833C)、841 (例如P841L、P841P)、843 (例如E843D)、844 (例如R844W、R844Q、R844L)、848 (例如M848T)、852 (例如I852M)、865 (例如L865V)、870 (例如L870F)、873 (例如R873W)、876 (例如A876V)、881 (例如L881V)、882、883 (例如A883F、A883P、A883S、A883T、A883Y)、884 (例如E884K)、886 (例如R886W)、891 (例如S891A)、897 (例如R897Q)、898 (例如D898V)、900 (例如Y900F)、901 (例如E901K)、904 (例如S904F、S904C)、905 (例如Y905F)、907 (例如K907E、K907M)、908 (例如R908K)、911 (例如G911D)、912 (例如R912P、R912Q)、918 (例如M918T、M918V、M918L、M918R) (例如引起MTC)、919 (例如A919V)、921 (例如E921K)、922 (例如S922P、S922Y)、930 (例如T930M)、961 (例如F961L)、972 (例如R972G)、981 (例如Y981F)、982 (例如R982C)、1009 (例如M1009V)、1015 (例如Y1015F)、1017 (例如D1017N)、1041 (例如V1041G)、1064 (例如M1064T)、1096 (例如Y1096F)、外顯子6及11中之框內缺失、外顯子15中之3bp框內缺失、核苷酸位置2136+2 (例如2136+2T＞G)、del632-636 ins6及RET細胞外半胱胺酸突變(其定義為包括以下半胱胺酸殘基中之至少一者的突變：609、611、618、620、630或634)。其他突變包括D631-liter633delinsE、E632-liter633del、A883F、D631-liter633delinsV、L790F、D898-E901del、D898_E901del + D903_S904delinsEP、K666 N、T636-V637insCRT及D378-G385delinsE。又其他突變包括D631-liter633delinsE、E632-liter633del、A883F、D631-liter633delinsV、L790F、D898-E901del、D898_E901del + D903 _S904delinsEP、K666 N、T636-V637insCRT及D378-G385delinsE。RET激酶蛋白質點突變、插入及缺失可為例如M918T、M918V、C634W、V804L或V804M。其他RET激酶蛋白質點突變/插入/缺失可不包括於本文中之清單中或尚未已知；然而，預期如本文所描述之式(I)化合物及方法及用途為預防腦轉移之有效抑制劑。 Dysregulation of the expression or activity or level of the RET gene, RET kinase, or either may be the result of one or more chromosomal translocations or inversions, resulting in a RET gene fusion (i.e., the gene translocation produces expressed protein, The expressed protein is a fusion protein containing residues from the non-RET partner protein and including a minimal functional RET kinase domain). Non-limiting examples of RET fusion partners and their associated cancers (e.g., those cancers that may be associated with brain metastases and/or increased risk of developing brain metastases) include ACBD5 (papillary thyroid cancer); AFAP1 (NSCLC); AFAP1L2 (papillary thyroid cancer); AKAP13 (papillary thyroid cancer); BCR (chronic myelomonocytic leukemia); C10orf118 (papillary thyroid cancer); CCDC6 (also known as PTC1, D10S170, or H4) (NSCLC, colorectal cancer , papillary thyroid carcinoma, adenocarcinoma, lung adenocarcinoma, metastatic colorectal carcinoma, adenosquamous carcinoma, breast cancer); CCDC88C (NSCLC); CCDC186-RET, CEP55 (diffuse gastric cancer); CGNL1 (pancreatic cancer); CLIP1 (adenocarcinoma); CUX1 (lung adenocarcinoma); DLG5 (nondegenerative thyroid carcinoma); DOCK1 (NSCLC); EML4 (papillary thyroid carcinoma); ERC1 (aka ELKS) (papillary thyroid carcinoma, breast cancer) ; ETV6 (salivary gland cancer); FGFR1OP (CMML, primary myelofibrosis with secondary acute myeloid leukemia); FKBP15 (papillary thyroid cancer); FOXP4 (lung adenocarcinoma); FRMD4A (NSCLC); GOLGA5 (also known as PTC5) (papillary thyroid carcinoma, spitzoid neoplasms); H4L (various); HOOK3 (papillary thyroid carcinoma); HRH4-RET (thyroid and/or papillary thyroid carcinoma) ; HTIF1 (various); KIAA1217 (also known as SKT) (papillary thyroid carcinoma, lung adenocarcinoma, NSCLC); KIAA1468 (also known as PTC9 and RFG9) (papillary thyroid carcinoma, lung adenocarcinoma); KIF13A (NSCLC) ; KIF5B (NSCLC, ovarian cancer, Spitz-like tumor, lung adenocarcinoma, adenosquamous carcinoma); KTN1 (also known as PTC8) (papillary thyroid carcinoma); MBD1 (also known as PCM1) (papillary thyroid carcinoma ); MPRIP (NSCLC); MYH10 (myofibromatosis of infancy); MYH13 (medullary thyroid cancer); NCOA4 (also known as PTC3, ELE1, and RFG) (papillary thyroid cancer, NSCLC, colorectal cancer, salivary gland cancer, metastatic Colorectal cancer, lung adenocarcinoma, adenosquamous carcinoma diffuse sclerosing variant of papillary thyroid carcinoma, breast cancer, acinar cell carcinoma, breast analog secreting cancer); OLFM4 (small bowel cancer); PARD3 (NSCLC); PCM1 ( papillary thyroid carcinoma); PIBF1 (bronchiolopulmonary cell carcinoma); PICALM (NSCLC); PPFIBP2 (papillary thyroid carcinoma); PRKAR1A (also known as PTC2) (papillary thyroid carcinoma); PTC1ex9 (novel CCDC6 rearrangement) (metastatic papillary thyroid carcinoma); PTC4 (novel NCO4/ELE1 rearrangement) (papillary thyroid carcinoma); RAB61P2 (papillary thyroid carcinoma) Thyroid cancer); RASAL2 (sarcoma); RASGEF1A (breast cancer); RBPMS (NSCLC); RFG8 (papillary thyroid cancer); RRBP1 (colorectal cancer); RUFY1 (colorectal cancer); RUFY2 (NSCLC; papillary thyroid cancer); RUFY3 (papillary thyroid cancer); SLC12A2 (NSCLC); SORBS2 (papillary thyroid cancer); SPECC1L (papillary thyroid cancer; thyroid cancer); SQSTM1 (papillary thyroid cancer); TAF3 (pancreatic cancer); TBL1XR1 (papillary thyroid cancer); thyroid cancer, thyroid cancer); TFG (pancreatic cancer); TIF1G (various); TRIM24 (also known as PTC6) (papillary thyroid cancer); TRIM27 (also known as RFP) (papillary thyroid cancer); AKAP13 ( papillary thyroid carcinoma); TRIM33 (also known as PTC7 and RFG7) (NSCLC, papillary thyroid carcinoma); and UEVLD (papillary thyroid carcinoma). The fusion protein can be, for example, KIF5B-RET. Fusions identified in single tumors included CCDC186-RET , ERC1-RET , KTN1-RET , and RUFY3-RET . Yet other RET fusion proteins may not be included in the list herein or are not yet known; however, it is expected that compounds comprising the same formula (I) and methods and uses as described herein are effective inhibitors for the prevention of brain metastases and are also in use It is effective in the method and application of preventing brain metastasis. Dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them may be caused by one or more point mutations, insertions, or deletions in the RET gene (compared to wild-type RET). For reference, the sequence of the mature human RET protein (SEQ ID NO: 1) is provided herein:

Non-limiting examples of potentially activating RET kinase protein point mutations, insertions or deletions can occur at the following amino acid positions compared to wild-type RET kinase: 2, 3, 4, 5, 6, 7, 8, 11 , 12, 13, 20, 32 (eg S32L), 34 (eg D34S), 40 (eg L40P), 56 (eg L56M), 64 (eg P64L), 67 (eg R67H), 114 (eg R114H), 136 (e.g. glutamic acid to stop codon), 145 (e.g. V145G), amino acid position 180 (e.g. arginine to stop codon), 200, 292 (e.g. V292M), 294, 321 (e.g. G321R), 330 (eg R330Q), 338 (eg T338I), 360 (eg R360W), 373 (eg alanine to valine (p.A373V) frame shift), D378-G385delinsE, 393 (eg F393L), 423 (eg G423R ), 432, 446 (eg G446R), 505-506 (6-base pair in-frame germline deletion in exon 7), 510 (eg A510V), 511 (eg E511K), 513 (eg G513D), 515 (eg C515R, C515S, C515W), 525 (eg R525W), 531 (eg C531R or 9 base pair duplication), 532 (eg duplication), 533 (eg G533C, G533S), 550 (eg G550E), 591 (such as V591I), 593 (such as G593E), 595 (such as E595D and E595A), 600 (such as R600Q), 602 (such as I602V), 603 (such as K603Q, K603E), 606 (such as Y606C), 609 (such as C609Y, C609S, C609G, C609R, C609F, C609W, C609C), 611 (such as C611R, C611S, C611G, C611Y, C611F, C611W), 616 (such as E616Q), 618 (such as C618S, C618Y, C618R, C618T, C618F, C618G, C618W), 620 (e.g. C620S, C620W, C620R, C620G, C620L, C620Y, C620F), 623 (e.g. E623K), 624 (e.g. D624N), 630 (e.g. C630A, C630R, C630S, C630Y, C630F, C630W, C630G) , 631 (such as D631N, D631Y, D631A, D631G, D631 V, D631E), 632 (e.g. E632K, E632G), 632-633 (6-base pair in-frame germline deletion in exon 11), 633 (e.g. 9 base pair duplication), 634 (e.g. C634W , C634Y, C634S, C634R, C634F, C634G, C634L, C634A or C634T or insertion into ELCR or 12 base pair duplication or combination with A640G, A641A or A641T) (e.g. causing MTC), 634/852 (e.g. C634R/I852M ), 635 (such as R635G), 636 (such as T636P, T636M), 648 (such as V648I), 649 (such as S649L), 664 (such as A664D), 665 (such as H665Q), 666 (such as K666E, K666M, K666N, K666R ), 675 (T675T, silent nucleotide change), 686 (eg S686N), 689 (eg S689T), 691 (eg G691S), 694 (eg R694Q), 700 (eg M700L), 706 (eg V706M, V706A) , 713 splice variant (eg E713K), 732 (eg E732K), 736 (eg G736R), 748 (eg G748C), 765 (eg S765P), 766 (eg P766S, P766M6), 768 (eg E768Q, E768D), 769 (eg L769L), 770 (eg R770Q), 771 (eg D771N), 777 (eg N777S), 778 (eg V778I), 781 (eg Q781R), 788 (eg I788I), 790 (eg L790F, L790T), 791 (such as Y791F, Y791N), 791/852 (such as Y791F /I852M), 802, 804 (such as V804L, V804M, V804E, V804G, V804S) (such as causing MTC), 804/918 (such as V804M/M918T, V804L/ M918T), 805 (e.g. E805K), 804/805 (e.g. V804M/E805K), 806 (e.g. Y806F, Y806C, Y806H, Y806Y), 810 (e.g. G810R, G810S, G810A, G810C, G810V), 818 (e.g. E818K) , 819 (such as S819I), 823 (such as G823E), 826 (such as Y826M, Y826S), 833 (such as R833C), 841 (such as P8 41L, P841P), 843 (e.g. E843D), 844 (e.g. R844W, R844Q, R844L), 848 (e.g. M848T), 852 (e.g. I852M), 865 (e.g. L865V), 870 (e.g. L870F), 873 (e.g. R873W) , 876 (eg A876V), 881 (eg L881V), 882, 883 (eg A883F, A883P, A883S, A883T, A883Y), 884 (eg E884K), 886 (eg R886W), 891 (eg S891A), 897 (eg R897Q), 898 (such as D898V), 900 (such as Y900F), 901 (such as E901K), 904 (such as S904F, S904C), 905 (such as Y905F), 907 (such as K907E, K907M), 908 (such as R908K), 911 (such as G911D), 912 (such as R912P, R912Q), 918 (such as M918T, M918V, M918L, M918R) (such as causing MTC), 919 (such as A919V), 921 (such as E921K), 922 (such as S922P, S922Y), 930 (eg T930M), 961 (eg F961L), 972 (eg R972G), 981 (eg Y981F), 982 (eg R982C), 1009 (eg M1009V), 1015 (eg Y1015F), 1017 (eg D1017N), 1041 ( e.g. V1041G), 1064 (e.g. M1064T), 1096 (e.g. Y1096F), in-frame deletions in exons 6 and 11, 3 bp in-frame deletions in exon 15, nucleotide position 2136+2 (e.g. 2136+ 2T>G), del632-636 ins6, and RET extracellular cysteine mutations (defined as mutations involving at least one of the following cysteine residues: 609, 611, 618, 620, 630, or 634) . Other mutations include D631-liter633delinsE, E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del + D903_S904delinsEP, K666N, T636-V637insCRT, and D378-G385delinsE. Still other mutations include D631-liter633delinsE, E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del+D903_S904delinsEP, K666N, T636-V637insCRT, and D378-G385delinsE. RET kinase protein point mutations, insertions and deletions can be, for example, M918T, M918V, C634W, V804L or V804M. Other RET kinase protein point mutations/insertions/deletions may not be included in the list herein or not yet known; however, compounds of formula (I) and methods and uses as described herein are expected to be effective inhibitors for the prevention of brain metastases.

Dysregulation of the expression or activity or level of the RET gene, RET kinase, or either may also include splicing variations in the RET mRNA that result in an expressed protein that is Alternative splice variants of RET compared to ), resulting in constitutive activity of the RET kinase domain.

The following examples are offered for the purpose of illustrating some of the aspects and embodiments described above and are not intended to limit the scope of the invention as claimed. Examples Example 1 : Clinical Trials

Serpatinib's ability to prevent brain metastases will be evaluated in Study JZJC, a global multicenter, randomized, open-label, controlled Phase 3 study in patients with locally advanced or metastatic RET fusion-positive non-squamous Serpatinib (arm A) was compared with platinum- and pemetrexed-based therapy with or without pembrolizumab (arm B) in patients with NSCLC. Enrolled patients will be based on geography (East Asian vs. non-East Asian), on investigator-assessed brain metastases (presence vs absent or unknown) and investigator's treatment choice (with or without palizumab) in case of randomization to Arm B Antibody and cisplatin versus carboplatin - must declare choice/intention of treatment prior to randomization). Patients will be randomized in a 2:1 ratio: Arm A and Arm B. Following confirmation of disease progression by blinded individual central review, patients will be allowed to crossover from comparative arm B to arm A upon meeting the eligibility criteria for the interchange. The primary endpoint assessed was PFS by BICR according to RECIST 1.1. This study will further characterize the intracranial activity of serpatinib compared to the control group. Specifically, time to CNS progression according to RECIST 1.1 by blinded individual central review was added as a secondary endpoint. other embodiments

From the foregoing description it will be evident that changes and modifications can be made to the invention described herein to adapt it to different uses and conditions. Such embodiments are also within the scope of the following claims.

The recitation of a list of elements in any definition of a variable herein includes definitions of that variable as any single element or combination (or subcombination) of the listed elements. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

         
          <![CDATA[<110> Loxo Oncology, Inc.]]>
          <![CDATA[<120> Compositions and methods for preventing brain metastasis]]>
          <![CDATA[<130> X22898]]>
          <![CDATA[<140> TW 110145376]]>
          <![CDATA[<141> 2021-12-06]]>
          <![CDATA[<150> US 63/125,085]]>
          <![CDATA[<151> 2020-12-14]]>
          <![CDATA[<160> 1 ]]>
          <![CDATA[<170> PatentIn version 3.5]]>
          <![CDATA[<210> 1]]>
          <![CDATA[<211> 1114]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> Homo sapiens]]>
          <![CDATA[<400> 1]]>
          Met Ala Lys Ala Thr Ser Gly Ala Ala Gly Leu Arg Leu Leu Leu Leu
          1 5 10 15
          Leu Leu Leu Pro Leu Leu Gly Lys Val Ala Leu Gly Leu Tyr Phe Ser
                      20 25 30
          Arg Asp Ala Tyr Trp Glu Lys Leu Tyr Val Asp Gln Ala Ala Gly Thr
                  35 40 45
          Pro Leu Leu Tyr Val His Ala Leu Arg Asp Ala Pro Glu Glu Val Pro
              50 55 60
          Ser Phe Arg Leu Gly Gln His Leu Tyr Gly Thr Tyr Arg Thr Arg Leu
          65 70 75 80
          His Glu Asn Asn Trp Ile Cys Ile Gln Glu Asp Thr Gly Leu Leu Tyr
                          85 90 95
          Leu Asn Arg Ser Leu Asp His Ser Ser Trp Glu Lys Leu Ser Val Arg
                      100 105 110
          Asn Arg Gly Phe Pro Leu Leu Thr Val Tyr Leu Lys Val Phe Leu Ser
                  115 120 125
          Pro Thr Ser Leu Arg Glu Gly Glu Cys Gln Trp Pro Gly Cys Ala Arg
              130 135 140
          Val Tyr Phe Ser Phe Phe Asn Thr Ser Phe Pro Ala Cys Ser Ser Leu
          145 150 155 160
          Lys Pro Arg Glu Leu Cys Phe Pro Glu Thr Arg Pro Ser Phe Arg Ile
                          165 170 175
          Arg Glu Asn Arg Pro Pro Gly Thr Phe His Gln Phe Arg Leu Leu Pro
                      180 185 190
          Val Gln Phe Leu Cys Pro Asn Ile Ser Val Ala Tyr Arg Leu Leu Glu
                  195 200 205
          Gly Glu Gly Leu Pro Phe Arg Cys Ala Pro Asp Ser Leu Glu Val Ser
              210 215 220
          Thr Arg Trp Ala Leu Asp Arg Glu Gln Arg Glu Lys Tyr Glu Leu Val
          225 230 235 240
          Ala Val Cys Thr Val His Ala Gly Ala Arg Glu Glu Val Val Met Val
                          245 250 255
          Pro Phe Pro Val Thr Val Tyr Asp Glu Asp Asp Ser Ala Pro Thr Phe
                      260 265 270
          Pro Ala Gly Val Asp Thr Ala Ser Ala Val Val Glu Phe Lys Arg Lys
                  275 280 285
          Glu Asp Thr Val Val Ala Thr Leu Arg Val Phe Asp Ala Asp Val Val
              290 295 300
          Pro Ala Ser Gly Glu Leu Val Arg Arg Tyr Thr Ser Thr Leu Leu Pro
          305 310 315 320
          Gly Asp Thr Trp Ala Gln Gln Thr Phe Arg Val Glu His Trp Pro Asn
                          325 330 335
          Glu Thr Ser Val Gln Ala Asn Gly Ser Phe Val Arg Ala Thr Val His
                      340 345 350
          Asp Tyr Arg Leu Val Leu Asn Arg Asn Leu Ser Ile Ser Glu Asn Arg
                  355 360 365
          Thr Met Gln Leu Ala Val Leu Val Asn Asp Ser Asp Phe Gln Gly Pro
              370 375 380
          Gly Ala Gly Val Leu Leu Leu His Phe Asn Val Ser Val Leu Pro Val
          385 390 395 400
          Ser Leu His Leu Pro Ser Thr Tyr Ser Leu Ser Val Ser Arg Arg Ala
                          405 410 415
          Arg Arg Phe Ala Gln Ile Gly Lys Val Cys Val Glu Asn Cys Gln Ala
                      420 425 430
          Phe Ser Gly Ile Asn Val Gln Tyr Lys Leu His Ser Ser Gly Ala Asn
                  435 440 445
          Cys Ser Thr Leu Gly Val Val Thr Ser Ala Glu Asp Thr Ser Gly Ile
              450 455 460
          Leu Phe Val Asn Asp Thr Lys Ala Leu Arg Arg Pro Lys Cys Ala Glu
          465 470 475 480
          Leu His Tyr Met Val Val Ala Thr Asp Gln Gln Thr Ser Arg Gln Ala
                          485 490 495
          Gln Ala Gln Leu Leu Val Thr Val Glu Gly Ser Tyr Val Ala Glu Glu
                      500 505 510
          Ala Gly Cys Pro Leu Ser Cys Ala Val Ser Lys Arg Arg Leu Glu Cys
                  515 520 525
          Glu Glu Cys Gly Gly Leu Gly Ser Pro Thr Gly Arg Cys Glu Trp Arg
              530 535 540
          Gln Gly Asp Gly Lys Gly Ile Thr Arg Asn Phe Ser Thr Cys Ser Pro
          545 550 555 560
          Ser Thr Lys Thr Cys Pro Asp Gly His Cys Asp Val Val Glu Thr Gln
                          565 570 575
          Asp Ile Asn Ile Cys Pro Gln Asp Cys Leu Arg Gly Ser Ile Val Gly
                      580 585 590
          Gly His Glu Pro Gly Glu Pro Arg Gly Ile Lys Ala Gly Tyr Gly Thr
                  595 600 605
          Cys Asn Cys Phe Pro Glu Glu Glu Lys Cys Phe Cys Glu Pro Glu Asp
              610 615 620
          Ile Gln Asp Pro Leu Cys Asp Glu Leu Cys Arg Thr Val Ile Ala Ala
          625 630 635 640
          Ala Val Leu Phe Ser Phe Ile Val Ser Val Leu Leu Ser Ala Phe Cys
                          645 650 655
          Ile His Cys Tyr His Lys Phe Ala His Lys Pro Pro Ile Ser Ser Ser Ala
                      660 665 670
          Glu Met Thr Phe Arg Arg Pro Ala Gln Ala Phe Pro Val Ser Tyr Ser
                  675 680 685
          Ser Ser Gly Ala Arg Arg Pro Ser Leu Asp Ser Met Glu Asn Gln Val
              690 695 700
          Ser Val Asp Ala Phe Lys Ile Leu Glu Asp Pro Lys Trp Glu Phe Pro
          705 710 715 720
          Arg Lys Asn Leu Val Leu Gly Lys Thr Leu Gly Glu Gly Glu Phe Gly
                          725 730 735
          Lys Val Val Lys Ala Thr Ala Phe His Leu Lys Gly Arg Ala Gly Tyr
                      740 745 750
          Thr Thr Val Ala Val Lys Met Leu Lys Glu Asn Ala Ser Pro Ser Glu
                  755 760 765
          Leu Arg Asp Leu Leu Ser Glu Phe Asn Val Leu Lys Gln Val Asn His
              770 775 780
          Pro His Val Ile Lys Leu Tyr Gly Ala Cys Ser Gln Asp Gly Pro Leu
          785 790 795 800
          Leu Leu Ile Val Glu Tyr Ala Lys Tyr Gly Ser Leu Arg Gly Phe Leu
                          805 810 815
          Arg Glu Ser Arg Lys Val Gly Pro Gly Tyr Leu Gly Ser Gly Gly Ser
                      820 825 830
          Arg Asn Ser Ser Ser Leu Asp His Pro Asp Glu Arg Ala Leu Thr Met
                  835 840 845
          Gly Asp Leu Ile Ser Phe Ala Trp Gln Ile Ser Gln Gly Met Gln Tyr
              850 855 860
          Leu Ala Glu Met Lys Leu Val His Arg Asp Leu Ala Ala Arg Asn Ile
          865 870 875 880
          Leu Val Ala Glu Gly Arg Lys Met Lys Ile Ser Asp Phe Gly Leu Ser
                          885 890 895
          Arg Asp Val Tyr Glu Glu Asp Ser Tyr Val Lys Arg Ser Gln Gly Arg
                      900 905 910
          Ile Pro Val Lys Trp Met Ala Ile Glu Ser Leu Phe Asp His Ile Tyr
                  915 920 925
          Thr Thr Gln Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile
              930 935 940
          Val Thr Leu Gly Gly Asn Pro Tyr Pro Gly Ile Pro Pro Glu Arg Leu
          945 950 955 960
          Phe Asn Leu Leu Lys Thr Gly His Arg Met Glu Arg Pro Asp Asn Cys
                          965 970 975
          Ser Glu Glu Met Tyr Arg Leu Met Leu Gln Cys Trp Lys Gln Glu Pro
                      980 985 990
          Asp Lys Arg Pro Val Phe Ala Asp Ile Ser Lys Asp Leu Glu Lys Met
                  995 1000 1005
          Met Val Lys Arg Arg Asp Tyr Leu Asp Leu Ala Ala Ser Thr Pro
              1010 1015 1020
          Ser Asp Ser Leu Ile Tyr Asp Asp Gly Leu Ser Glu Glu Glu Thr
              1025 1030 1035
          Pro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg Ala Leu Pro
              1040 1045 1050
          Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Met Ser Asp Pro Asn
              1055 1060 1065
          Trp Pro Gly Glu Ser Pro Val Pro Leu Thr Arg Ala Asp Gly Thr
              1070 1075 1080
          Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp Ser Val Tyr Ala Asn
              1085 1090 1095
          Trp Met Leu Ser Pro Ser Ala Ala Lys Leu Met Asp Thr Phe Asp
              1100 1105 1110
          Ser
          
      

Claims (26)

A use of selpercatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing brain metastasis in an individual suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing the risk of developing or developing brain metastases in individuals suffering from cancer. A use of serpatinib, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in an individual suffering from cancer, which medicament reduces the risk of developing detectable metastases of the cancer to the brain. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for delaying the onset of brain metastases in individuals suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing the onset of brain metastases in individuals suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the metastatic progression of cancer in the brain of an individual suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the growth and/or survival of metastatic cancer cells in the brain of an individual suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the progression of cancer to metastatic brain cancer in an individual suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing the risk of detectable brain metastases or the onset of detectable brain metastases in an individual suffering from cancer. A use of serpatinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for prolonging the survival period of an individual suffering from cancer. The use according to any one of claims 1 to 10, wherein the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer and/or RET-related cancers. The use according to any one of claims 1 to 11, wherein one or more cells of the cancer exhibit RET mutations and/or RET fusions associated with the cancer. The use according to any one of claims 1 to 12, wherein the brain metastases comprise undetected or undetectable metastases. The use of any one of claims 1 to 13, wherein the individual has not had a previous transfer. The use according to any one of claims 1 to 13, wherein the individual has previously been treated for previous metastasis. The use according to any one of claims 1 to 15, wherein the individual suffers from advanced primary cancer. The use according to any one of claims 1 to 16, wherein the individual has a primary cancer associated with an increased risk and/or increased likelihood of metastatic progression. The use of any one of claims 1 to 17, wherein the individual is not known to have brain metastases prior to administration of the agent. The use according to any one of claims 1 to 18, wherein the medicament further comprises another anticancer agent or is used in combination with another anticancer agent. The use according to any one of claims 1 to 19, wherein the individual is identified by detecting one or more of RET mutation, RET fusion, RET gene and/or RET protein expression, activity or content disorder. The use according to any one of claims 1 to 20, wherein the medicament is used for daily administration of serpatinib or a pharmaceutically acceptable salt thereof at about 0.1 mg/kg to about 15.0 mg/kg body weight. The use according to any one of claims 1 to 21, wherein when the individual weighs less than 50 kg, the medicament is used to administer 120 mg of serpatinib or a pharmaceutically acceptable salt thereof, and wherein when When the individual weighs more than 50 kg, the agent is used to administer 160 mg of serpatinib or a pharmaceutically acceptable salt thereof. The use according to any one of claims 1 to 22, wherein the medicament is for administration once or twice a day. The use according to any one of claims 1 to 23, wherein the serpatinib or a pharmaceutically acceptable salt thereof is a polymorph. The use according to any one of claims 1 to 23, wherein the serpatinib or a pharmaceutically acceptable salt thereof is amorphous. The use according to any one of claims 1 to 25, wherein the serpatinib is a free amine.