WO2022132683A1 - Polythérapie à base d'inhibiteurs de ret pour le traitement du cancer - Google Patents

Polythérapie à base d'inhibiteurs de ret pour le traitement du cancer Download PDF

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WO2022132683A1
WO2022132683A1 PCT/US2021/063187 US2021063187W WO2022132683A1 WO 2022132683 A1 WO2022132683 A1 WO 2022132683A1 US 2021063187 W US2021063187 W US 2021063187W WO 2022132683 A1 WO2022132683 A1 WO 2022132683A1
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cancer
ret
pharmaceutically acceptable
acceptable salt
selpercatinib
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PCT/US2021/063187
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English (en)
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Louis Frank Stancato
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Loxo Oncology, Inc.
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Priority to AU2021402927A priority Critical patent/AU2021402927A1/en
Publication of WO2022132683A1 publication Critical patent/WO2022132683A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application relates to combination therapy with a RET inhibitor, or a pharmaceutically acceptable salt thereof, and a microtubule-targeting agent, for the treatment of cancer.
  • RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is typically expressed at low levels in normal tissue. RET is required for normal development, 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 that are involved in ligand binding, and a juxtamembrane cysteine-rich region that is necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains.
  • RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN), and persephin (PSPN) (Arighi et al., Cytokine Growth Factor Rev. (2005) 16:441-67).
  • GDNF glial cell line-derived neurotrophic factor
  • NTRN neurturin
  • ARTN artemin
  • PSPN persephin
  • RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF family receptor-a (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage.
  • GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol -rich membrane subdomains
  • RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways.
  • Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions.
  • RET expression and/or activity are associated with different cancers (e.g., lymphoma, thyroid cancer, and lung cancer (NSCLC)), and in gastrointestinal disorders such as irritable bowel syndrome (IBS).
  • cancers e.g., lymphoma, thyroid cancer, and lung cancer (NSCLC)
  • NSCLC lung cancer
  • IBS irritable bowel syndrome
  • Selpercatinib (LOXO-292 or RETEVMOTM) is a specific inhibitor of RET and has regulatory approval for use in the treatment of patients with metastatic RET fusion-positive NSCLC, RET-mutant medullary thyroid cancer, and metastatic RET fusion-positive thyroid cancer.
  • the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a compound of Formula I (i.e., selpercatinib) or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and a microtubule-targeting agent, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula I i.e., selpercatinib
  • a pharmaceutically acceptable salt i.e., selpercatinib
  • amorphous form, or polymorph form thereof
  • a microtubule-targeting agent or a pharmaceutically acceptable salt thereof.
  • the disclosure also provides a method for treating cancer, comprising administering to a subject in need thereof a composition comprising a compound of Formula I (i.e., selpercatinib) or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and a microtubule-targeting agent.
  • a composition comprising a compound of Formula I (i.e., selpercatinib) or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and a microtubule-targeting agent.
  • the composition is a pharmaceutical composition.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.
  • the present invention also provides a compound of Formula (I) (i.e., selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and a microtubule-targeting agent, or a pharmaceutically acceptable salt thereof, for use in treatment of cancer.
  • a compound of Formula (I) i.e., selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and a microtubule-targeting agent, or a pharmaceutically acceptable salt thereof, for use in treatment of cancer.
  • the method further comprises administering to the subject an additional anti -cancer agent.
  • the cancer can include any one or more of lung cancer, breast cancer, melanoma, colon cancer, kidney cancer, renal cell carcinoma, thyroid, mesothelioma, ovarian cancer, pancreatic cancer, sarcoma, leukemia, lymphoma, urothelial cancer, head and neck cancer, osteosarcoma and bladder cancer, glioblastoma and/or astrocytoma.
  • the lung cancer is non-small cell lung cancer.
  • the thyroid cancer is medullary thyroid cancer.
  • the cancer can be one in which the subject has one or more of a RET mutation, RET fusion, RET rearrangement, dysregulation of the expression, activity, or level of a RET gene and/or a RET protein.
  • any of the embodiments relating to the use of compounds of Formula (I) (i.e., selpercatinib) and a microtubule-targeting agent in the treatment of cancer the use of a compound of Formula I can be simultaneous, separate or sequential with the use of a microtubule-targeting agent.
  • the subject is identified by detecting one or more of a RET mutation, RET fusion, RET rearrangement, dysregulation of the expression, activity, or level of a RET gene and/or a RET protein.
  • the subject is administered, or the use comprises, about 0.1 mg/kg to about 15.0 mg/kg of body weight per day of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • the subject when the subject weighs less than 50 kg, the subject is administered, or the use comprises, 120 mg of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • the subject when the subject weighs more than 50 kg, the subject is administered, or the use comprises, 160 mg of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • the microtubuletargeting agent is paclitaxel, docetaxel, vinblastine, vincristine, or vinorelbine, or a pharmaceutically acceptable salt of any one thereof.
  • the microtubuletargeting agent is docetaxel, or a pharmaceutically acceptable salt thereof.
  • the microtubule-targeting agent is docetaxel.
  • the microtubuletargeting agent e.g., docetaxel
  • the method or the use comprises once or twice daily administration of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • the method or use comprises selpercatinib or a pharmaceutically acceptable salt thereof in a polymorph form.
  • the method or use comprises selpercatinib or a pharmaceutically acceptable salt thereof in an amorphous form.
  • the method or use comprises selpercatinib as the free amine.
  • microtubule-targeting agent refers to compounds that bind to the microtubule and contribute to cell arrest, e.g., in the G2/M phase of the cell cycle.
  • microtubule-targeting agents are paclitaxel, docetaxel, vinblastine, vincristine and vinorelbine.
  • polymorph refers to crystals of the same compound having different physical properties as a result of the order of the molecules in the crystal lattice. Different polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic, and/or biological properties from each other.
  • Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in composition and product manufacturing), dissolution rates (an important factor in determining bio-availability), solubility, melting point, chemical stability, physical stability, powder flowability, water sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., crystal changes on storage as a kinetically favored polymorph converts to a thermodynamically more stable polymorph) or both (e.g., one polymorph is more hygroscopic than the other).
  • chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical changes e.g., crystal changes on storage as a kinetically favored poly
  • Crystal does not include amorphous forms of the compound.
  • amorphous refers to a noncrystalline form of a compound which can be a solid state form of the compound or a solubilized form of the compound.
  • amorphous refers to a compound (e.g., a solid form of the compound) without a regularly repeating arrangement of molecules or external face planes.
  • anhydrous refers to a crystal form of the compound of Formula (I) that has 1% or less by weight water. For example, 0.5% or less, 0.25% or less, or 0.1% or less by weight water.
  • solvate refers to a crystalline form of the compound of Formula (I), such as a polymorph form of the compound, where the crystal lattice comprises one or more solvents of crystallization.
  • hydrate or "hydrated polymorph form” refer to a crystalline form of the compound of Formula (I), such as a polymorph form of the compound, where the crystal lattice comprises water.
  • hydrate refers to a "stoichiometric hydrate.”
  • a stoichiometric hydrate contains the water molecules as an integral part of the crystal lattice, where removal of the water molecules will cause instability of the crystal network.
  • a non-stoichiometric hydrate comprises water, but changes in the water content does not cause significant changes to the crystal structure.
  • non-stoichiometric hydrates During drying of non- stoichiometric hydrates, a considerable proportion of water can be removed without significantly disturbing the crystal network, and the crystals can subsequently rehydrate to give the initial non- stoichiometric hydrated crystalline form. Unlike stoichiometric hydrates, the dehydration and rehydration of non-stoichiometric hydrates is not accompanied by a phase transition, and thus all hydration states of a non-stoichiometric hydrate represent the same crystal form.
  • suitable excipients include but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, antiadherants, glidants, dispersing or wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colors, flavors and sweeteners.
  • 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, and the like, which are not biologically or otherwise undesirable.
  • 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, and the like, which are not biologically or otherwise undesirable.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations.
  • various excipients such as are commonly used in the art, can be included.
  • ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence, “about 5 grams” means “about 5 grams” and also “5 grams.” It also is understood that ranges expressed herein include whole numbers within the ranges and fractions thereof. For example, a range of between 5 grams and 20 grams includes whole number values such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 grams, and fractions within the range including, but not limited to, 5.25, 6.5, 8.75 and 11.95 grams. The term "about” preceding a value for DSC, TGA, TG, or DTA, which are reported as degrees Celsius, have an allowable variability of +/-5 °C.
  • Compounds of Formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof, or pharmaceutical composition (e.g., any of the solid or liquid formulations described herein) thereof, can act as a RET inhibitor can be demonstrated by the assays described in, e.g., PCT Publication No. WO2018/071447 and U.S. Patent Application Publication No. US 2018/0134702.
  • a compound of Formula I can exhibit brain and/or central nervous system (CNS) penetrance.
  • the compounds are capable of crossing the blood brain barrier and inhibiting a RET kinase in the brain and/or other CNS structures.
  • the compounds provided herein are capable of crossing the blood brain barrier in an amount effective to treat cancer.
  • the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount.
  • treatment of a patient with cancer can include administration (e.g., oral administration) of the compound to the patient.
  • the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor.
  • Various embodiments and embodiments of the disclosure relate to methods for preventing a brain metastasis.
  • Metalastasis or the plural, “metastases,” as used herein, refers to the presence of one or more cancer cells at a location that is not physically contiguous with the original location of the cancer (e.g., primary cancer).
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the methods described herein can lengthen the survival period of a subject having cancer by, for example, a period of months to years (e.g., about 1 month, about 2 months, about 3 months, about 4 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).
  • a period of months to years e.g., about 1 month, about 2 months, about 3 months, about 4 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.
  • a compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, as described herein may be administered to the patient at a dose of about 0.1 mg/kg to 200 mg/kg (effective dosage sub-ranges are noted herein).
  • the methods and uses described herein can further comprise administering to the subject an additional anti-cancer agent, as is generally known in the art.
  • the methods described herein may comprise administering, to the subject, a therapeutically effective amount of a compound of Formula (I) (i.e., selpercatinib) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition (e.g., any of the solid or liquid formulations described herein) thereof, and an effective amount of an anti-cancer agent that can penetrate the blood brain barrier to achieve therapeutic levels, such as (for example), nimustine (N'-[(4-amino-2-methylpyrimidin-5- yl)methyl]-N-(2-chloroethyl)-N-nitrosourea or ACNU), carmustine (bis-chloroethylnitrosourea, BiCNU, or BCNU), lomustine (l-(2-chloroeth
  • the terms "subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the patient is a human.
  • the subject has experienced and/or exhibited at least one symptom of a disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having a cancer, such as breast cancer, lung cancer, and/or a cancer with a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (a RET-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., an FDA-approved, assay or kit or a lab developed test (LDT)).
  • a RET-associated cancer e.g., as determined using a regulatory agency-approved, e.g., an FDA-approved, assay or kit or a lab developed test (LDT)
  • the subject has a tumor that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit).
  • the subject can be a subject with a tumor(s) that is positive for a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA- approved, assay or kit).
  • the subject can be a subject whose tumors have a dysregulation of a RET gene, a RET protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
  • the subject is suspected of having a RET-associated cancer.
  • the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the patient is a pediatric patient.
  • the primary cancer e.g., a cancer (e.g., a RET-associated cancer) that is being actively treated (or that has been treated) is a hematological cancer.
  • the primary cancer e.g., RET-associated cancer
  • the primary cancer is a solid tumor (e.g., an advanced solid tumor and/or a RET-fusion positive solid tumor).
  • the primary cancer e.g., RET-associated cancer
  • the primary cancer is a lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer (e.g., sporadic medullary thyroid cancer or hereditary medullary thyroid cancer), differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid ademona, endocrine gland neoplasms, lung adenocarcinoma, bronchioles lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytom
  • the primary cancer e.g., RET-associated cancer
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • cancer in adolescents adrenocortical carcinoma
  • anal cancer appendix cancer
  • astrocytoma atypical teratoid/rhabdoid tumor
  • basal cell carcinoma bile duct cancer
  • bladder cancer bone cancer
  • brain stem glioma brain tumor
  • breast cancer bronchial tumor
  • Burkitt lymphoma carcinoid tumor
  • unknown primary carcinoma cardiac tumors, cervical cancer, childhood cancers, chordoma
  • CML chronic myelogenous leukemia
  • chronic myeloproliferative neoplasms neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T
  • a hematological primary cancer is selected from the group consisting of leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • APL acute prom
  • hematological primary cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF/IPF/PMF).
  • MPD myeloproliferative disorders
  • PV polycythemia vera
  • ET essential thrombocytopenia
  • IMF/IPF/PMF idiopathic primary myelofibrosis
  • the hematological primary cancer e.g., the hematological cancer that is a RET-associated cancer
  • AML or CMML.
  • the primary cancer is a solid tumor.
  • solid tumors e.g., solid tumors that are RET-associated cancers
  • 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, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, and cervical cancer.
  • the cancer comprises lung cancer, colon cancer, kidney cancer, melanoma, breast cancer, thyroid, and/or a RET- associated cancer.
  • a subject may be identified as having a risk, including an increased risk, of developing or onset one or more metastatic growths in the brain.
  • a subject may be identified by establishing and/or determining a stage of underlying disease, such as identifying stage of primary (or underlying) cancer disease.
  • a subject may be identified by having an underlying disease, e.g., a type of cancer, with a known risk of progressing to metastatic growth.
  • a subject may be identified by detecting and/or determining that the primary (or underlying) cancer disease is a RET-associated cancer.
  • RET-associated cancers, RET mutations, RET fusions, dysregulated RET genes, and diagnostic methods useful in the detection of such RET-based biomarkers is provided below.
  • the compounds provided herein exhibit potent and selective RET inhibition.
  • the compounds of Formula (I) provided herein exhibit nanomolar potency against wild type RET and a RET kinase encoded by a RET gene including an activating mutation or a RET kinase inhibitor resistance mutation, including, for example, the KIF5B-RET fusion, G810R and G810S ATP cleft front mutations, M918T activating mutation, and V804M, V804L, and V804E gatekeeper mutations, with minimal activity against related kinases.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition selectively target a RET kinase.
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition e.g., any of the solid or liquid formulations described herein
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition e.g., any of the solid or liquid formulations described herein
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition e.g., any of the solid or liquid formulations described herein
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition exhibit nanomolar potency against an altered RET fusion protein encoded by a RET gene encoding the RET fusion protein (e.g.
  • any of the RET fusion proteins described herein including, without limitation, CCDC6-RET or KIF5B-RET) which RET gene includes a RET kinase inhibitor resistance mutation (e.g., any of the RET mutations described herein including, without limitation, V804M, V804L, or V804E) such that the altered RET protein is a RET fusion protein that exhibits RET kinase inhibitor resistance due to the presence of a RET kinase inhibitor resistance amino acid substitution or deletion.
  • Non-limiting examples include CCDC6-RET-V804M and KIF5B-RET-V804M.
  • the compounds provided herein exhibit nanomolar potency against an altered RET protein encoded by a RET gene that that includes a RET mutation (e.g. any of the RET mutations described herein including, without limitation, C634W or M918T) and that includes a RET kinase inhibitor resistance mutation (e.g., any of the RET kinase inhibitor resistance mutations described herein including, without limitation, V804M, V804L, or V804E) such that the altered RET protein includes a RET substitution caused by the RET mutation (e.g., a RET primary mutation) and the altered RET protein exhibits RET kinase resistance due to the presence of a RET kinase inhibitor resistance amino acid substitution or deletion.
  • a RET mutation e.g. any of the RET mutations described herein including, without limitation, C634W or M918T
  • a RET kinase inhibitor resistance mutation e.g., any of the RET
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition e.g., any of the solid or liquid formulations described herein
  • the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, polymorph form, or pharmaceutical composition exhibits at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80- fold selectivity; at least a 90-fold selectivity; at least 100-fold selectivity; at least 200-fold selectivity; at least 300-fold selectivity; at least 400-fold selectivity; at least 500-fold selectivity; at least 600-fold selectivity; at least 700-fold selectivity; at least 800-fold selectivity; at least 900-fold selectivity; or at least 1000-fold selectivity for a RET kinase over another kinase.
  • selectivity for a RET kinase over another kinase is measured in a cellular assay (e.g., a cellular assay).
  • the compounds provided herein can exhibit selectivity for a RET kinase over a KDR kinase (e.g., VEGFR2).
  • the selectivity for a RET kinase over a KDR kinase is observed without loss of potency for a RET kinase encoded by a RET gene including an activating mutation or a RET kinase inhibitor resistance mutation (e.g., a gatekeeper mutant).
  • the selectivity over a KDR kinase is at least 10-fold (e.g., at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 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 selectivity) as compared to the inhibition of KIF5B-RET (e.g., the compounds are more potent against KIF5B-RET than KDR).
  • KIF5B-RET e.g., the compounds are more potent against KIF5B-RET than KDR
  • the selectivity for a RET kinase over a KDR kinase is about 30-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 100-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 150-fold. In some embodiments, the selectivity for a RET kinase over a KDR kinase is at least 400-fold.
  • potent KDR kinase inhibition is believed to be a common feature among multikinase inhibitors (MKIs) that target RET and may be the source of the dose-limiting toxicities observed with such compounds.
  • inhibition of V804M is similar to that observed for wild-type RET.
  • inhibition of V804M is within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibition of wild-type RET (e.g., the compounds were similarly potent against wild-type RET and V804M).
  • selectivity for a wildtype or V804M RET kinase over another kinase is measured in an enzyme assay (e.g., an enzyme assay as provided herein).
  • an enzyme assay e.g., an enzyme assay as provided herein.
  • the compounds provided herein exhibit selective cytotoxicity to RET -mutant cells.
  • inhibition of G810S and/or G810R is similar to that observed for wild-type RET.
  • inhibition of G810S and/or G810R is within about 2-fold (e.g., about 5-fold, about 7-fold, about 10-fold) of inhibition of wild-type RET (e.g., the compounds were similarly potent against wild-type RET and G810S and/or G810R).
  • selectivity for a wildtype or G810S and/or G810R RET kinase over another kinase is measured in an enzyme assay (e.g., an enzyme assay as provided herein).
  • the compounds provided herein exhibit selective cytotoxicity to RET-mutant cells.
  • RET-associated disease or disorder refers to diseases or disorders associated with or having a dysregulation of a RET gene, a RET kinase (also called herein RET kinase protein), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a RET gene, a RET kinase, a RET kinase domain, or the expression or activity or level of any of the same described herein).
  • Non-limiting examples of a RET-associated disease or disorder include, for example, cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).
  • RET-associated cancer refers to cancers associated with or having a dysregulation of a RET gene, a RET kinase (also called herein RET kinase protein), or expression or activity, or level of any of the same.
  • RET-associated cancer is described herein.
  • the phrase "dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a chromosomal translocation that results in the expression of a fusion protein including a RET kinase domain and a fusion partner, a mutation in a RET gene that results in the expression of a RET protein that includes a deletion of at least one amino acid as compared to a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with one or more point mutations as compared to a wildtype RET protein, a mutation in a RET gene that results in the expression of a RET protein with at least one inserted amino acid as compared to a wildtype RET protein, a gene duplication that results in an increased level of RET protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/
  • a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same can be a mutation in a RET gene that encodes a RET protein that is constitutively active or has increased activity as compared to a protein encoded by a RET gene that does not include the mutation.
  • a dysregulation of a RET gene, a RET protein, or expression or activity, or level of any of the same can be the result of a gene or chromosome translocation which results in the expression of a fusion protein that contains a first portion of RET that includes a functional kinase domain, and a second portion of a partner protein (i.e., that is not RET).
  • dysregulation of a RET gene, a RET protein, or expression or activity or level of any of the same can be a result of a gene translocation of one RET gene with another non-RET gene.
  • RET fusion proteins, RET kinase protein mutations e.g., point mutations/insertions/deletions, inhibitor resistance mutations, etc.
  • US Patent 10,786,489 e.g., in Tables 1-4.
  • dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in a RET gene (see, e.g., chromosome translocations that result in the expression of any of the fusion proteins listed herein and/or as listed in Table 1 of US Patent 10,786,489).
  • dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by a genetic mutation that results in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase (see, e.g., amino acid substitutions disclosed herein including at positions: 634 (e.g., C634W), 732 (e.g., E732K), 778, 788 (e.g., I788N), 790 (e.g., L790F), 804 (e.g., V804M, V804L, V804E), 778 and 804, 804 and 805 (e.g., V804M/E805K), 806 (e.g., Y806C, Y806
  • MKI
  • dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be caused by a mutation in a nucleic acid encoding an altered RET protein (e.g., a RET fusion protein or a RET protein having a mutation (e.g., a primary mutation) that results in the expression of an altered RET protein that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET kinase.
  • an altered RET protein e.g., a RET fusion protein or a RET protein having a mutation (e.g., a primary mutation) that results in the expression of an altered RET protein that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype RET
  • Such exemplary RET kinase amino acid substitutions, RET kinase point mutations, insertions, and deletions can be caused by an activating mutation and/or can result in the expression of a RET kinase that has increased resistance to inhibition by a RET kinase inhibitor and/or a multi-kinase inhibitor (MKI).
  • MKI multi-kinase inhibitor
  • activating mutation describes a mutation in a RET kinase gene that results in the expression of a RET kinase that has an increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • an activating mutation can result in the expression of a fusion protein that includes a RET kinase domain and a fusion partner.
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • one or more amino acid substitutions e.g., any combination of any of the amino acid substitutions described herein
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wildtype RET kinase, e.g., when assayed under identical conditions.
  • an activating mutation can be a mutation in a RET kinase gene that results in the expression of a RET kinase that has 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 inserted as compared to a wildtype RET kinase, e.g., the exemplary wildtype RET kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art.
  • wildtype or wild-type describes a nucleic acid (e.g., a RET gene or a RET mRNA) or protein (e.g., a RET protein) that is found in a subject that does not have a RET- associated disease, e.g., a RET-associated cancer (and optionally also does not have an increased risk of developing a RET-associated disease and/or is not suspected of having a RET-associated disease), or is found in a cell or tissue from a subject that does not have a RET-associated disease, e.g., a RET-associated cancer (and optionally also does not have an increased risk of developing a RET-associated disease and/or is not suspected of having a RET-associated disease).
  • a RET-associated disease e.g., a RET-associated cancer
  • the solid formulation including the compound of Formula (I), or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof can be administered by a variety of routes, depending upon the treatment desired and upon the area to be treated.
  • administration is oral.
  • Oral administration can include a dosage form formulated for once-daily or twice-daily (BID) administration.
  • compositions comprising the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof can be formulated in a unit dosage form, each dosage containing from about 1 to about 1,000 mg (1 g), more usually about 5 mg to about 100 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other patients, each unit containing a predetermined quantity of active material (i.e., the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the solid formulation is formulated as a Img, 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 form.
  • the solid formulation is formulated as a 10 mg, 20 mg, 60 mg, 80 mg, 120 mg or 160 mg dosage form.
  • the compositions provided herein contain from about 1 mg to about 50 mg of the active ingredient.
  • the compositions provided herein contain 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 the active ingredient.
  • the compositions provided herein contain about 10 mg of the active ingredient.
  • the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient.
  • the active ingredient contains from about 50 mg to about 500 mg of the active ingredient.
  • One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing 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 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 the active ingredient.
  • the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient.
  • the active ingredient contains from about 500 mg to about 1,000 mg of the active ingredient.
  • this embodies compounds or compositions containing 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 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 the active ingredient.
  • the daily dosage of the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof can be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
  • the compositions can be provided in the form of tablets containing about 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 80, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.1 to about 50.0 mg/kg of body weight per day, or any amount or range therein.
  • the range is from about 0.1 to about 15.0 mg/kg of 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/ to about 8 mg/kg or about 3 mg/kg to 7 mg/kg.
  • the compound of Formula (I) can be administered, for example, in an amount of about 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,
  • the subject is administered about 0.1 mg/kg to about 15.0 mg/kg of body weight per day of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • compositions containing the compound of Formula (I) or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof can be administered on a regimen of 1 to 4 times per day. More preferably, the subject is administered selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form thereof, once or twice daily, or in a single daily dose. Daily administration can be once-daily or in multiple doses, e.g., twice-daily (BID) administration.
  • BID twice-daily
  • dosing can be as follows: when the subject weighs less than 50 kg, the subject is administered 120 mg of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, and wherein when the subject weighs more than 50 kg, the subject is administered 160 mg of selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof, or a composition comprising selpercatinib or a pharmaceutically acceptable salt, amorphous form, or polymorph form, thereof.
  • the selpercatinib or a pharmaceutically acceptable salt thereof is a polymorph.
  • the selpercatinib or a pharmaceutically acceptable salt thereof is amorphous.
  • selpercatinib is the free amine.
  • the active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Optimal dosages to be administered can be readily determined by those skilled in the art. It will be understood, therefore, that the amount of the compound actually administered will usually be determined by a physician, and will vary according to the relevant circumstances, including the mode of administration, the actual compound administered, the strength of the preparation, the condition to be treated, and the advancement 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 the patient's symptoms, will result in the need to adjust dosages.
  • the solid formulation includes a polymorph form of the compound of Formula (I), i.e., selpercatinib.
  • the forms include, e.g., free bases, solvates, hydrates, salts, and non-solvated forms of the compound of Formula (I), including, for example, polymorph Forms 1-8 (e.g., 1, 2, 7, and 8) as disclosed in US Patent 10,786,489.
  • the polymorph form of the compound of Formula (I) is a pharmaceutically acceptable salt.
  • the polymorph of the compound is the free base.
  • the compound of Formula (I) is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of the compound of Formula (I) can include, but are not limited to, sulfate, tosylate, naphthalene-2-sulfonate, oxalate, phosphate, tartrate, and fumarate salts.
  • the compound of Formula (I) is a sulfate salt or a phosphate salt.
  • the sulfate salt is prepared in a mixture of solvents.
  • the solvent is a mixture of isopropyl alcohol (IP A) and water.
  • IP A isopropyl alcohol
  • the water is present in an amount of 10% by weight.
  • the compound of Formula (I) is a tosylate salt.
  • the tosylate salt is prepared in a mixture of solvents.
  • the solvent is a mixture of acetone and water.
  • the water is present in an amount of 10% by weight.
  • the compound of Formula (I) is a naphthalene-2-sulfonate salt.
  • the naphthalene-2-sulfonate salt is prepared in a mixture of solvents.
  • the solvent is a mixture of THF and water.
  • the water is present in an amount of 10% by weight.
  • the compound of Formula (I) is an oxalate salt.
  • the oxalate salt is prepared in a mixture of solvents.
  • the solvent is a mixture of 1,4-di oxane and water.
  • the water is present in an amount of 10% by weight.
  • the oxalate salt is prepared from evaporation from a mixture of solvents.
  • the solvent is a mixture of THF and water.
  • the compound of Formula (I) is a tartrate salt.
  • the tartrate salt is prepared in a mixture of solvents.
  • the solvent is a mixture of IP A and water.
  • the water is present in an amount of 10% by weight.
  • the compound of Formula (I) is a fumarate salt. In some embodiments, the fumarate salt is prepared in a mixture of solvents. 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 salt is prepared in a mixture of solvents. In some embodiments, the solvent is a mixture of acetone and water. In some embodiments, the solvent is a mixture of IP A and water. In some embodiments, the water is present in an amount of 10% by weight. Salts of Formula (I), as well as methods for preparing such salts, are described in US Patents 10,584,124 and 10,786,489.
  • Scheme 1 shows a general scheme for the synthesis of the compound of Formula (I) (shown as compound 12 in scheme 1), where B is -CFb CFh ⁇ OH; X 1 is N; X 2 , X 3 , and X 4 are CH; and D and E are represented by where the wavy line indicates the point of attachment to the ring comprising X 1 , X 2 , X 3 , and X 4 .
  • Compound 2 is obtained by treating commercially available 3-bromo-5- methoxypyridine (compound 1) with O-(mesitylsulfonyl)hydroxylamine.
  • the O- mesityl sulfonylhydroxylamine can be prepared as described in Mendiola et al., Org. Process Res. Dev. (2009) 13(2):263-267.
  • Compound 2 can be reacted with ethyl propiolate to provide a mixture of compounds 3 A and 3B, which typically are obtained in a ratio of approximately 2: 1 to 9: 1, respectively.
  • the mixture of compounds 3 A and 3B can be treated with 48% HBr at elevated temperatures, followed by recrystallization or chromatography purifications, to isolate compound 4A as the minor isomer and compound 4B as the major isomer. After isolation, compound 4A can be treated with POCh to provide compound 5.
  • the formyl group can be converted to an 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 hydroxy group by treating compound 7 with aluminum trichloride to provide compound 8.
  • compound 8 can be reacted with a reagent such as where X is a leaving atom or group (such as a halide or triflate), in the presence of a suitable base (e.g., a metal alkali carbonate, such as potassium carbonate).
  • a suitable base e.g., a metal alkali carbonate, such as potassium carbonate.
  • 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 prepared by coupling compound 9 with the corresponding boronic ester compound 10 (where Ring D is wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X 1 , X 2 , X 3 , and X 4 , and the asterisk indicates the point of attachment to P 1 ; X 1 , X 2 , X 3 , and X 4 are as defined above; 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 the atoms to which they are connected form a 5-6 membered ring optionally substituted with 1-4 substituents selected from (C1-C3 alkyl)) using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in
  • Compound 12 can then be prepared from compound 11 by removing the protecting group P 1 under standard conditions (for example, a Boc group can be removed by treating compound 11 under acidic conditions, e.g., HC1), followed by functionalization (i.e., reacting or treating compound 11 with the appropriate reagent) to introduce the E group under standard conditions.
  • a Boc group can be removed by treating compound 11 under acidic conditions, e.g., HC1
  • functionalization i.e., reacting or treating compound 11 with the appropriate reagent
  • compound 8 can be coupled with the corresponding boronic ester compound 10 to provide compound I la using appropriate palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling reaction conditions (for example, a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and ISfeCCh in dioxane at elevated temperatures).
  • a palladium catalyst and optionally a ligand in the presence of an inorganic base, for example, Pd(PPh3)4 and ISfeCCh in dioxane at elevated temperatures e.g., Pd(PPh3)4 and ISfeCCh in dioxane at elevated temperatures.
  • Compound I la can then be reacted with a reagent such as where X is a leaving atom or group (such as a halide or tritiate), under Mitsunobu reaction conditions (e.g., PPI13 and diisopropyl
  • Scheme 2 shows another general scheme for the synthesis of compound 12 where and B, X 1 , X 2 , X 3 , and X 4 , Ring D, and E are as defined above for Scheme 1.
  • the protecting group P 1 on Ring D of compound 16 can be removed under standard conditions (for example, a Boc group can be removed by treating compound 16 under acidic conditions, e.g., HC1) to provide compound 12 where E is H (i.e., Ring D is deprotected).
  • the deprotected Ring D can then be functionalized (i.e., reacted or treated with an appropriate reagent) to introduce the E group under standard conditions such as described below to provide compound 12 where E is as defined above.
  • amino protecting group refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound.
  • suitable protecting groups for use in any of the processes described herein include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group.
  • Non-limiting examples of amino protecting groups are acetyl, trifluoroacetyl, t-butyloxycarbonyl ("Boc”), benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl ("Fmoc”). Further examples of these groups, and other protecting groups, are found in T. W. Greene et al., Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006.
  • Hydroxy groups can be protected with any convenient 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 ethers, and the like.
  • Nitrogen atoms in compounds described in any of the above methods can be protected with any convenient nitrogen protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis," 2. sup. nd ed. New York; John Wiley & Sons, Inc., 1991.
  • nitrogen protecting groups include acyl and alkoxy carbonyl groups, such as t-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM).
  • the dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same can be the result of one or more chromosome translocations or inversions resulting in a RET gene fusion (i.e., the genetic translocations result in an expressed protein that is a fusion protein containing residues from a non-RET partner protein, and including a minimum of a functional RET kinase domain).
  • Non -limiting examples of RET fusion partners and their associated cancers include ACBD5 (papillary thyroid cancer); AFAP1 (NSCLC); AFAP1L2 (papillary thyroid cancer); AKAP13 (papillary thyroid cancer); BCR (chronic myelomonocytic leukemia); ClOorfl 18 (papillary thyroid cancer); CCDC6 (also called PTCI, D10S170, or H4) (NSCLC, colon cancer, papillary thyroid cancer, adenocarcinomas, lung adenocarcinoma, metastatic colorectal cancer, adenosquamous carcinomas, breast cancer); CCDC88C (NSCLC); CCDC186-RET, CEP55 (diffuse gastric cancer); CGNL1 (pancreatic cancer); CLIP1 (adenocarcinoma); CUX1 (lung a
  • KIAA1217 also called SKT
  • KIAA1468 also called PTC9 and RFG9
  • KIF13A NSCLC
  • KIF5B NSCLC
  • MBD1 also known as PCM1
  • MPRIP NSCLC
  • MYH10 infantile myofibromatosis
  • MYH13 medullary thyroid cancer
  • NCOA4 also called PTC3, ELEI, and RFG
  • PRKAR1 A also called PTC2 (papillary thyroid cancer); PTClex9 (a novel CCDC6 rearrangement) (metastatic papillary thyroid cancer); PTC4 (a novel NCO4/ELE1 rearrangement) (papillary thyroid cancer); RAB61P2 (papillary thyroid cancer); RASAL2 (Sarcoma); RASGEF1A (breast cancer); RBPMS (NSCLC); RFG8 (papillary thyroid cancer); RRBP1 (colon cancer); RUFY1 (colorectal cancer); RUFY2 (NSCLC; papillary thyroid cancer); RUFY3 (papillary thyroid cancer); SLC12A2 (NSCLC); SORBS2 (papillary thyroid cancer); SPECC1L (papillary thyroid cancer; thyroid gland cancer); SQSTM1 (papillary thyroid cancer); TAF3 (pancreatic cancer); TBL1XR1 (papillary thyroid cancer, thyroid gland cancer); TFG (pancreatic cancer
  • the fusion protein can be, for example, KIF5B-RET. Fusions that were identified in single tumors included CCDC186-RET, ERC1-RET, KTN1-RET, and RUFY3- RET. Still other RET fusion proteins may not be included in the listing herein or are not yet known; however, the compounds of Formula (I), and methods and uses comprising the same as described herein, are expected to be effective inhibitors, and also effective in treating cancer.
  • the dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same, can be caused by one or more point mutations, insertions, or deletions in a RET gene (compared to wildtype RET).
  • SEQ ID NO: 1 the sequence of mature human RET protein (SEQ ID NO: 1) is provided here:
  • Non-limiting examples of potentially activating RET kinase protein point mutations, insertions, or deletions as compared to wild-type RET kinase can occur at the following amino acid positions: 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 20, 32 (e.g., S32L), 34 (e.g., D34S), 40 (e.g., L40P), 56 (e.g., L56M), 64 (e.g., P64L), 67 (e.g., R67H), 114 (e.g., 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 (e.g., R330Q), 338 (e.g., T338I), 360 (e.g., R360
  • D631- liter633delinsE E632-liter633del, A883F, D631-liter633delinsV, L790F, D898-E901del, D898_E901del + D903_S904delinsEP, K666 N, T636-V637insCRT, and D378-G385delinsE.
  • Still other mutations include D631-liter633delinsE, E632-liter633del, A883F, D631- liter633delinsV, L790F, D898-E901del, D898_E901del + D903 _S904delinsEP, K666 N, T636- V637insCRT, and D378-G385delinsE.
  • the 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 listing herein or are not yet known; however, the compounds of Formula (I) and methods and uses as described herein for treating cancer.
  • a dysregulation of a RET gene, a RET kinase, or expression or activity or level of any of the same can also include a splice variation in a RET mRNA which results in an expressed protein that is an alternatively spliced variant of RET having at least one residue deleted (as compared to the wild-type RET kinase) resulting in a constitutive activity of a RET kinase domain.
  • Immune compromised female mice between 5-8 weeks of age are housed on irradiated papertwist-enriched 1/8” corncob bedding (Sheperd) in individual HEPA ventilated cages (Innocage® IVC, Innovive USA) on a 12-hour light-dark cycle at 68-74°F (20-23°C) and 30-70% humidity. Animals are fed water ad libitum (reverse osmosis, 2 ppm C12) and an irradiated Test rodent diet (Teklad 2919) consisting of 19% protein, 9% fat, and 4% fiber.
  • Animals are implanted unilaterally in the flank region with tumor fragments harvested from donor animals, each implanted from a specific passage lot. Pre-study tumor volumes are recorded for each experiment beginning approximately one week post implantation. When tumors reach approximately 100-300 mm3, animals are matched by tumor volume into treatment and control groups and dosing initiated (Day 0). Animals in all studies are tagged and followed individually throughout the experiment.
  • CMC carboxymethylcellulose
  • SDS sodium lauryl sulfate
  • SDS sodium dodecyl sulfate
  • Docetaxel alone 5 mg/kg is administered intravenously once a week for four weeks.
  • Combination 5 mg/kg docetaxel is administered intravenously once a week for four weeks, and 5 mg/kg selpercatinib is administered by mouth twice a day for 28 days.
  • the % response to treatment is % delta T/C for tumor volumes above baseline and % regression for tumor volumes below baseline. Data are provided in Table 1.

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Abstract

L'invention concerne un procédé de traitement du cancer, notamment un cancer associé à RET, comprenant l'administration d'un composé de formule I et d'un agent de ciblage de microtubules.
PCT/US2021/063187 2020-12-18 2021-12-14 Polythérapie à base d'inhibiteurs de ret pour le traitement du cancer WO2022132683A1 (fr)

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