TW202237086A

TW202237086A - Method for treating cancer with a ret inhibitor and a platinum agent

Info

Publication number: TW202237086A
Application number: TW110145377A
Authority: TW
Inventors: 路易斯法蘭克斯坦卡托
Original assignee: 美商絡速藥業公司
Priority date: 2020-12-18
Filing date: 2021-12-06
Publication date: 2022-10-01
Also published as: AR124265A1; WO2022132973A1

Abstract

The disclosure provides a method for treating cancer, including a RET-associated cancer, comprising administering a compound of Formula I and a platinum agent.

Description

以RET抑制劑及鉑劑治療癌症之方法Methods of treating cancer with RET inhibitors and platinum agents

本申請案係關於以RET抑制劑或其醫藥學上可接受之鹽及鉑劑治療癌症之組合療法。This application relates to the combination therapy of RET inhibitors or their pharmaceutically acceptable salts and platinum agents for the treatment of cancer.

儘管已在診斷及治療多種類型之癌症，包括RET (轉染重排)相關癌症，中取得進展，但治療仍為一種挑戰。Despite advances in the diagnosis and treatment of many types of cancer, including RET (rearranged transfection)-associated cancers, treatment remains a challenge.

RET為屬於酪胺酸激酶超家族之單程跨膜受體，其典型地以低含量表現於正常組織中。RET為若干組織及細胞類型之正常產生、成熟及維護所需的(Mulligan, L. M., Nature Reviews Cancer (2014) 14:173-186)。RET激酶之胞外部分含有四個參與配位體結合之鈣依賴性鈣黏蛋白樣重複序列及RET胞外域正確摺疊所需之近膜富含半胱胺酸區，而受體之細胞質部分包括兩個酪胺酸激酶子域。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傳信藉由神經膠質細胞株源性神經營養因子(GDNF)家族配位體(GFL)中之一組可溶蛋白質的結合來介導，該蛋白質亦包括神經秩蛋白(neurturin，NTRN)、神經鞘胚素(artemin，ARTN)及珀瑟芬(persephin，PSPN) (Arighi等人, Cytokine Growth Factor Rev. (2005) 16:441-67)。不同於其他受體酪胺酸激酶，RET不直接結合於GFL且需要另一共受體：亦即，四種GDNF家族受體-α (GFRα)家族成員中之一者，其藉由糖基化磷脂醯肌醇鍵聯繫栓至細胞表面。GFL與GFRα家族成員形成二元複合物，該等複合物又結合於RET且將其募集至被稱為脂質筏的富膽固醇膜子域，其中發生RET傳信。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.

在配位體-共-受體複合物結合後，細胞內酪胺酸殘基上之RET二聚化及自體磷酸化募集轉接蛋白及傳信蛋白質以刺激多個下游路徑。轉接蛋白結合於此等對接位點引起Ras-MAPK及PI3K-Akt/mTOR傳信路徑之活化，或引起泛素連接酶之CBL家族之募集，該等連接酶在RET介導之功能之RET下調中起作用。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.

異常RET表現及/或活性(例如由與其他蛋白質之突變或染色體重排/融合引起)與不同癌症(例如淋巴瘤、甲狀腺癌及肺癌(NSCLC))及腸胃疾病，諸如大腸急躁症(IBS)相關。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.

塞爾帕替尼(Selpercatinib) (LOXO-292或RETEVMO ^TM)為RET之特定抑制劑且經法規批准用於治療患有轉移性RET融合陽性NSCLC、RET突變體髓質甲狀腺癌及轉移性RET融合陽性甲狀腺癌之患者。塞爾帕替尼或6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈具有以下化學結構：

(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).

本發明提供一種治療癌症之方法，其包含向有需要之個體投與式I化合物(亦即塞爾帕替尼)或其醫藥學上可接受之鹽、非晶形式或多晶形式，及鉑劑。The present invention provides a method of treating cancer comprising administering to a subject in need thereof a compound of Formula I (ie serpatinib) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, and platinum agent.

本發明亦提供一種治療癌症之方法，其包含向有需要之個體投與包含式I化合物(亦即塞爾帕替尼)或其醫藥學上可接受之鹽、非晶形式或多晶形式及鉑劑的組合物。在另一實施例中，該組合物為醫藥組合物。在另一實施例中，該醫藥組合物進一步包含一或多種醫藥學上可接受之載劑或賦形劑。The present invention also provides a method of treating cancer comprising administering to an individual in need thereof a compound comprising formula I (i.e. serpatinib) or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof and Composition of platinum agents. In another embodiment, the composition is a pharmaceutical composition. In another embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients.

本發明亦提供用於治療癌症之式(I)化合物(亦即塞爾帕替尼)及鉑劑。The present invention also provides a compound of formula (I) (ie serpatinib) and a platinum agent for use in the treatment of cancer.

在任一以上實施例之一些實施例中，該方法進一步包含向個體投與另一抗癌劑。In some of any of the above embodiments, the method further comprises administering to the individual another anticancer agent.

在與使用式(I)化合物(亦即塞爾帕替尼)及鉑劑之治療方法或式(I)化合物(亦即塞爾帕替尼)及鉑劑之用途相關的任一實施例中，癌症可包括以下中之任一者或多者：肺癌、乳癌、黑素瘤、大腸癌、腎癌、腎細胞癌瘤、甲狀腺癌、間皮瘤、卵巢癌、胰臟癌、肉瘤、白血病、淋巴瘤、尿道上皮癌、頭頸癌、骨肉瘤及膀胱癌、膠質母細胞瘤及/或星形細胞瘤。在一實施例中，肺癌為非小細胞肺癌。在另一實施例中，甲狀腺癌為髓質甲狀腺癌。In any embodiment related to the method of treatment using the compound of formula (I) (ie serpatinib) and platinum or the use of the compound of formula (I) (ie serpatinib) and platinum , cancer can include any one or more of the following: lung cancer, breast cancer, melanoma, colorectal cancer, kidney cancer, renal cell carcinoma, thyroid cancer, mesothelioma, ovarian cancer, pancreatic cancer, sarcoma, leukemia , lymphoma, urothelial carcinoma, head and neck cancer, osteosarcoma and bladder cancer, glioblastoma and/or astrocytoma. In one embodiment, the lung cancer is non-small cell lung cancer. In another embodiment, the thyroid cancer is medullary thyroid cancer.

在與使用式(I)化合物(亦即塞爾帕替尼)及鉑劑之治療方法或式(I)化合物(亦即塞爾帕替尼)及鉑劑之用途相關的任一實施例中，癌症可為其中個體具有RET突變、RET融合、RET重排、RET基因及/或RET蛋白質之表現、活性或含量失調中之一或多者的癌症。In any embodiment related to the method of treatment using the compound of formula (I) (ie serpatinib) and platinum or the use of the compound of formula (I) (ie serpatinib) and platinum , the cancer can be a cancer in which the individual has one or more of RET mutations, RET fusions, RET rearrangements, RET gene and/or RET protein expression, activity or content dysregulation.

在與式(I)化合物(亦即塞爾帕替尼)及鉑劑用於治療癌症之用途相關的任一實施例中，式I化合物之使用與鉑劑之使用可為同步的、分開的或依序的。In any of the embodiments relating to the use of a compound of formula (I) (i.e. serpatinib) and a platinum agent for the treatment of cancer, the use of the compound of formula I and the use of the platinum agent may be simultaneous, separate or sequentially.

在任一以上實施例之一些實施例中，藉由偵測RET突變、RET融合體、RET重排、RET基因及/或RET蛋白質之表現、活性或含量失調中之一或多者來鑑別個體。In some embodiments of any of the above embodiments, the individual is identified by detecting one or more of RET mutations, RET fusions, RET rearrangements, RET gene and/or RET protein expression, activity or content dysregulation.

在任一以上實施例之一些實施例中，向個體投與或用途包含每天約0.1 mg/kg至約15.0 mg/kg體重的塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。In some of any of the above embodiments, administering or using cerpatinib or a pharmaceutically acceptable salt thereof, an amorphous form thereof comprising about 0.1 mg/kg to about 15.0 mg/kg body weight per day to the individual or a polymorphic form, or a composition comprising serpatinib or a pharmaceutically acceptable salt thereof, an amorphous form or a polymorphic form.

在任一以上實施例之一些實施例中，當個體體重小於50 kg時，向個體投與或用途包含120 mg塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。在一些其他實施例中，當個體體重超過50 kg時，向個體投與或用途包含160 mg塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。In some embodiments of any of the above embodiments, administering or using to the individual comprises 120 mg of selpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof when the individual weighs less than 50 kg , or a composition comprising serpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof. In some other embodiments, when the individual weighs more than 50 kg, administering or using to the individual comprises 160 mg serpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof, or comprises a plug Compositions of erpatinib or pharmaceutically acceptable salts, amorphous forms or polymorphic forms thereof.

在本發明之方法及用途之另一實施例中，鉑劑為順鉑(cisplatin)、卡鉑(carboplatin)或奧沙利鉑(oxaliplatin)。在另一實施例中，鉑劑為順鉑。In another embodiment of the method and use of the present invention, the platinum agent is cisplatin, carboplatin or oxaliplatin. In another embodiment, the platinum agent is cisplatin.

在本發明之方法及用途之另一實施例中，以約25 mg/m ²之劑量向個體投與鉑劑，例如順鉑。 In another embodiment of the methods and uses of the invention, a platinum agent, such as cisplatin, is administered to the individual at a dose of about ²⁵ mg/m2.

在任一以上實施例之一些實施例中，該方法或用途包含每天一次或兩次投與塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。In some of any of the above embodiments, 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.

在任一以上實施例之一些實施例中，該方法或用途包含呈多晶形式之塞爾帕替尼或其醫藥學上可接受之鹽。In some embodiments of any of the above embodiments, the method or use comprises serpatinib, or a pharmaceutically acceptable salt thereof, in polymorphic form.

在任一以上實施例之一些實施例中，該方法或用途包含呈非晶形式之塞爾帕替尼或其醫藥學上可接受之鹽。In some embodiments of any of the above embodiments, the method or use comprises serpatinib, or a pharmaceutically acceptable salt thereof, in amorphous form.

在任一以上實施例之一些實施例中，該方法或用途包含呈游離胺形式之塞爾帕替尼。In some embodiments of any of the above embodiments, the method or use comprises serpatinib in the free amine form.

由本發明提供之其他特徵、一或多個實施例及優勢將自以下實施方式顯而易見。Other features, one or more embodiments, and advantages provided by the present invention will become apparent from the following description.

本申請案根據35 U.S.C. §119(e)主張2020年12月18日申請之美國臨時申請案系列第63/127,434號之權益；其揭示內容以引用之方式併入本文中。This application claims the benefit of U.S. Provisional Application Serial No. 63/127,434, filed December 18, 2020, under 35 U.S.C. § 119(e); the disclosure of which is incorporated herein by reference.

定義definition

除非另外定義，否則本文所使用之所有技術及科學術語均具有熟習本發明所屬領域者通常理解的意義。如本文所使用，除非另外規定，否則以下術語具有下文歸屬於其之意義。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.

如本文所使用，術語「多晶型物」係指由於分子在晶格中之次序而具有不同物理特性的相同化合物之晶體。單一化合物之不同多晶型具有彼此不同的一或多種化學、物理、機械、電學、熱力學及/或生物學特性。多晶型所展現之物理特性的差異可影響醫藥參數，諸如儲存穩定性、可壓縮性、密度(在組合物及產物製造上具有重要作用)、溶解速率(決定生物可利用性的重要因素)、溶解度、熔點、化學穩定性、物理穩定性、粉末流動性、吸水性、緊密度及粒子形態。穩定性差異可起因於化學反應性之變化(例如差異氧化，使得劑型當由一種多晶型物構成時比由另一多晶型物構成時變色更快)或機械變化(例如晶體在儲存時發生變化，原因為動力學上有利的多晶型物轉化為熱力學上更穩定的多晶型物)或兩者(例如一種多晶型物的吸濕性比另一種更強)。由於溶解度/溶解差異，因此一些轉變影響效能及/或毒性。另外，晶體的物理特性對於處理而言可具有重要作用；例如，一種多晶型物更可能形成溶劑合物或可能難以過濾及洗去雜質(亦即粒子形狀及大小分佈在一種多晶型物相對於另一種之間可為不同的)。如本文所使用，「多晶型物」不包括化合物之非晶形式。如本文所使用，「非晶形」係指化合物之非結晶形式，其可為化合物之固態形式或化合物之溶解形式。舉例而言，「非晶形」係指無分子或外表面平面有規律地重複排列之化合物(例如化合物之固體形式)。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).

如本文所用，術語「無水」係指式(I)化合物的結晶形式，其含有1重量%或更少的水。舉例而言，0.5重量%或更少、0.25重量%或更少或0.1重量%或更少之水。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.

如本文所用，術語「溶劑合物」係指式(I)化合物之結晶形式，諸如化合物之多晶形式，其中晶格包含結晶的一或多種溶劑。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.

術語「水合物」或「水合多晶形式」係指式(I)化合物之結晶形式，諸如化合物之多晶形式，其中晶格包含水。除非另外規定，否則如本文所使用，術語「水合物」係指「化學計量水合物」。化學計量的水合物含有水分子作為晶格的整體部分，其中水分子之移除將造成晶體網路不穩定。相比之下，非化學計量的水合物包含水，但水含量的變化不引起晶體結構發生顯著變化。在非化學計量水合物乾燥期間，可以移除大部分的水而不會顯著擾亂晶體網路，且晶體隨後可以復水而得到非化學計量的初始水合結晶形式。不同於化學計量水合物，非化學計量水合物的脫水及復水不伴隨相轉變，且因此非化學計量水合物的所有水合狀態代表相同結晶形式。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 "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 initially 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.

為了提供更簡潔之描述，本文中之一些定量表述係以約量X至約量Y的範圍敍述。應理解，當敍述範圍時，該範圍不限於所述上限及下限，而係包括約量X至約量Y之全範圍，或其中之任何範圍。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.

如本文所用，術語「賦形劑」係指將組合物調配成所需形式所需要之任何物質。舉例而言，適合之賦形劑包括但不限於稀釋劑或填充劑、黏合劑或成粒劑或黏著劑、崩解劑、潤滑劑、抗黏劑、滑動劑、分散或濕潤劑、溶解阻滯劑或增強劑、吸附劑、緩衝液、螯合劑、防腐劑、顏料、調味劑及甜味劑。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.

術語「醫藥學上可接受之載劑」或「醫藥學上可接受之賦形劑」包括在生物學上或在其他方面無不良作用的任何及所有溶劑、共溶劑、錯合劑、分散介質、包衣、抗細菌劑及抗真菌劑、等張劑及吸收延遲劑等。此類介質及藥劑用於醫藥學上活性之物質的用途為此項技術中已知的。除非任何習知介質或藥劑與活性成分不相容，否則考慮將其用於治療調配物中。調配物中亦可合併補充活性成分。另外，可包括各種賦形劑，諸如此項技術中常用的賦形劑。此等及其他此類化合物描述於文獻中，例如Merck Index, Merck & Company, Rahway, N.J中。在醫藥組合物中包括各種組分之考慮因素描述於例如Gilman等人(編) (2010)；Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 第12版, The McGraw-Hill Companies中。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.

除非上下文另外明確規定，否則如本文所用之單數形式「一(a/an)」及「該(the)」包括複數個參照物。As used herein, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise.

如本文所用，範圍及量可表示為「約」特定值或範圍。約亦包括精確量。因此，「約5公克」意謂「約5公克」亦及「5公克」。亦理解，本文所表示之範圍包括範圍內之整數及其分數。舉例而言，5公克與20公克之間之範圍包括整數值，諸如5、6、7、8、9、10、11、12、13、14、15、16、17、18、19及20公克，及範圍內之分數，包括但不限於5.25、6.5、8.75及11.95公克。DSC、TGA、TG或DTA值(以攝氏度報導)之前的術語「約」具有+/-5℃之可允許變化。As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes exact quantities. Therefore, "about 5 grams" means "about 5 grams" and "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.

應瞭解，為了清楚起見而在單獨實施例之情形中描述的本發明之特定特徵亦可以組合形式提供於單一實施例中。相反，為簡潔起見而描述於單一實施例之上下文中的本發明之各種特徵亦可分別或以任何適合的子組合形式提供。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.

本發明尤其涵蓋屬於本文所述實施例之實施例之所有組合，正如同每一者及每種組合個別地明確敍述一樣，就此而言，此類組合涵蓋可能的實施例。另外，本發明尤其亦涵蓋本文所述之實施例中所含實施例之所有子組合以及本文所述之所有其他實施例中所含之實施例之所有子組合，正如同所有實施例之每一者及每種子組合在本文中明確地敍述一樣。The invention especially encompasses all combinations of embodiments belonging to the embodiments described herein, as if each and each combination were individually and explicitly stated, such combinations encompassing possible embodiments in this respect. In addition, the invention specifically also covers all subcombinations of the embodiments contained in the embodiments described herein and all subcombinations of the embodiments contained in all other embodiments described herein, just as each of the embodiments and each subcombination are expressly recited herein.

方法及用途Method and use

式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或其醫藥組合物(例如本文所描述之固體或液體調配物中之任一者)可充當RET抑制劑，可藉由例如PCT公開案第WO2018/071447號及美國專利申請公開案第US 20180134702號中所描述的分析證實。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 confirmed by assays such as those described in PCT Publication No. WO2018/071447 and US Patent Application Publication No. US 20180134702.

如本文所提供，式I化合物(塞爾帕替尼)可展現腦及/或中樞神經系統(CNS)外顯率。在本文所揭示之方法之一些實施例中，化合物能夠穿越血腦障壁且抑制腦及/或其他CNS結構中之RET激酶。在一些實施例中，本文中所提供之化合物能夠以有效地治療癌症之量穿越血腦障壁。在一些實施例中，本文所提供之化合物能夠以治療有效量穿越血腦障壁。舉例而言，治療患有癌症之患者可包括向患者投與(例如經口投與)化合物。在一些此類實施例中，本文所提供之化合物適用於治療原發性腦瘤或轉移性腦瘤。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 treat cancer. 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 can include administering (eg, orally administering) a compound to the patient. In some such embodiments, the compounds provided herein are useful in the treatment of primary or metastatic brain tumors.

本發明之各種實施例及實施例係關於用於預防腦轉移之方法。如本文所使用，「轉移(Metastasis)」或複數「轉移(metastases)」係指在與癌症(例如原發性癌症)之原始位置不實體相鄰之位置處存在一或多個癌細胞。Various embodiments 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).

如本文所用，術語「治療(treat)」或「治療(treatment)」係指治療性或姑息性措施。有益或所需臨床結果包括(但不限於)與疾病或病症或病狀相關之症狀的完全或部分緩解、疾病程度之減輕、疾病病況穩定(亦即不惡化)、疾病進展延遲或減緩、疾病病況(例如疾病之一或多種症狀)改善或緩和以及緩解(無論部分或全部)，無論可偵測或不可偵測。「治療」亦可意謂與不接受治療情況下之預計存活期相比，存活期延長。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.

在一些實施例中，本文中所描述之方法可將患有癌症之個體之存活時段延長達例如數月至數年時段(例如約1個月、約2個月、約3個月、約4個月、約6個月、約8個月、約10個月、約12個月、約14個月、約18個月、約20個月、約2年、約3年、約4年、約5年、約6年或更長時間)。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).

在此等用途之任何實施例中，可以約0.1 mg/kg至200 mg/kg之劑量(本文中標記有效劑量子範圍)向患者投與如本文中所描述之式(I)化合物或醫藥學上可接受之鹽、非晶形式、多晶形式。In any embodiment of these uses, a compound of formula (I) as described herein or pharmaceutical Acceptable salts, amorphous forms, polymorphic forms.

在一些實施例中，本文所描述之方法及用途可進一步包含向個體投與如此項技術中通常已知之另一抗癌劑。在一些實例實施例中，本文中所描述之方法可包含向個體投與治療有效量之式(I)化合物(亦即塞爾帕替尼)或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之固體或液體調配物中之任一者)及有效量之可穿透血腦障壁以達成治療性水準之抗癌劑，諸如(例如)尼莫司汀(nimustine) (N'-[(4-胺基-2-甲基嘧啶-5-基)甲基]-N-(2-氯乙基)-N-亞硝基脲或ACNU)、卡莫司汀(carmustine) (雙氯乙基亞硝基脲、BiCNU或BCNU)、洛莫司汀(lomustine) (1-(2-氯乙基)-3-環己基-1-亞硝基脲或CCNU)、羥基尿素(hydroxyurea)、拓朴替康(topotecan)、替莫唑胺(temozolomide)、達卡巴嗪(dacarbazine)、甲胺喋呤、阿糖胞苷(cytarabine) (胞嘧啶***糖苷或ara-C)、卡培他濱(capecitabine)、長春瑞賓(vinorelbine)或其組合。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, vinorelbine, or combinations thereof.

如本文所用，術語「個體(subject)」、「個體(individual)」或「患者」可互換使用，係指任何動物，包括哺乳動物，諸如小鼠、大鼠、其他嚙齒動物、兔、犬、貓、豬、牛、綿羊、馬、靈長類動物及人類。在一些實施例中，患者為人類。在一些實施例中，個體已經歷及/或展現待治療及/或預防之疾病或病症之至少一種症狀。在一些實施例中，個體已鑑別或診斷患有癌症，諸如乳癌、肺癌及/或具有RET基因、RET蛋白質或其中任一者之表現或活性或含量之失調之癌症(RET相關癌症) (例如，如使用管理機構批准，例如FDA批准之分析或套組或實驗室研發之測試(LDT)所測定)。在一些實施例中，個體具有對RET基因、RET蛋白質或其中任一者之表現或活性或含量之失調呈陽性之腫瘤(例如使用管理機構批准之分析或套組測定)。個體可為患有腫瘤的個體，該腫瘤對RET基因、RET蛋白質或其任一者之表現或活性或含量之失調呈陽性(例如使用管制機構批准，例如FDA批准的分析或套組鑑別為陽性)。個體可為其腫瘤具有RET基因、RET蛋白質或其表現或活性或含量之失調之個體(例如使用管理機構批准，例如FDA經批准之分析或套組鑑別腫瘤具有此類失調)。在一些實施例中，懷疑個體患有RET相關癌症。在一些實施例中，個體之臨床記錄表明，個體患有其中RET基因、RET蛋白質或其任一者之表現或活性或含量存在失調之腫瘤(且視情況，臨床記錄表明該個體應用本文所提供之組合物中之任一者進行治療)。在一些實施例中，患者為兒科患者。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 level of the RET gene, RET protein, or either is dysregulated (and optionally, the individual's clinical records indicate that the individual uses the any one of the compositions for treatment). In some embodiments, the patient is a pediatric patient.

在本文所描述之方法或用途中之任一者之一些實施例中，原發性癌症(例如經積極地治療(或已經治療的)癌症(例如RET相關癌症))為血液癌。在本文中所描述之方法或用途中之任一者之一些實施例中，原發性癌症(例如RET相關癌症)為實體腫瘤(例如晚期實體腫瘤及/或RET融合體陽性實體腫瘤)。在本文所述之方法或用途中之任一者的一些實施例中，原發性癌症(例如RET相關癌症)為肺癌(例如小細胞肺癌或非小細胞肺癌)、甲狀腺癌(例如乳頭狀甲狀腺癌、髓質甲狀腺癌(例如偶發性髓質甲狀腺癌或遺傳性髓質甲狀腺癌)、分化甲狀腺癌、復發甲狀腺癌或難治性分化甲狀腺癌)、甲狀腺腺瘤、內分泌腺贅生物、肺腺癌、細支氣管肺細胞癌瘤、2A或2B型多發性內分泌瘤(分別為MEN2A或MEN2B)、嗜鉻細胞瘤、副甲狀腺增生、乳癌、乳腺癌、乳腺癌瘤、乳腺贅瘤、大腸直腸癌(例如轉移性大腸直腸癌)、乳頭狀腎細胞癌、胃腸黏膜之神經節瘤病、發炎肌纖維母細胞瘤，或子宮頸癌。在本文所描述之方法或用途中之任一者之一些實施例中，原發性癌症(例如RET相關癌症)係選自以下之群：急性淋巴母細胞白血病(ALL)、急性骨髓性白血病(AML)、青少年癌症、腎上腺皮質癌、肛門癌、闌尾癌、星形細胞瘤、非常型類畸胎/桿狀瘤、基底細胞癌、膽管癌、膀胱癌、骨癌、腦幹神經膠質瘤、腦瘤、乳癌、支氣管腫瘤、伯基特淋巴瘤(Burkitt lymphoma)、類癌瘤、未知原發性癌瘤、心臟腫瘤、子宮頸癌、兒童癌、脊索瘤、慢性淋巴球白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓增生性腫瘤、結腸癌、大腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、乳腺管原位癌(DCIS)、胚胎腫瘤、子宮內膜癌、室管膜母細胞瘤、室管膜瘤、食道癌、敏感性神經胚細胞瘤、尤文氏肉瘤(Ewing Sarcoma)、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、部位腫瘤(neoplasms by site)、腫瘤、大腸癌、大腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、皮膚血管肉瘤、膽管癌、乳腺管原位癌、胚胎腫瘤、子宮內膜癌、室管膜瘤、食道癌、敏感性神經胚細胞瘤、尤文氏肉瘤(Ewing sarcoma)、顱外生殖細胞腫瘤、性腺外生殖細胞腫瘤、肝外膽管癌、眼癌、輸卵管癌、骨骼之纖維性組織細胞瘤、膽囊癌、胃癌、胃腸道類癌瘤、胃腸道基質腫瘤(GIST)、生殖細胞腫瘤、妊娠期滋養病、神經膠質瘤、毛狀細胞腫瘤、毛細胞白血病、頭頸癌、胸腔腫瘤、頭頸腫瘤、CNS腫瘤、原發性CNS腫瘤、心臟癌、肝細胞癌、組織細胞增多病、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、下咽癌、眼內黑素瘤、胰島細胞瘤、胰臟神經內分泌腫瘤、卡堡氏肉瘤(Kaposi sarcoma)、腎癌、蘭格漢氏細胞(Langerhans cell)組織細胞增生症、喉癌、白血病、唇及口腔癌、肝癌、肺癌、淋巴瘤、巨球蛋白血症、骨骼之惡性纖維組織細胞瘤、骨肉瘤、黑素瘤、梅克爾細胞癌(Merkel cell carcinoma)、間皮瘤、轉移性鱗狀頸癌、中線道癌瘤、口腔癌、多發性內分泌瘤症候群、多發性骨髓瘤、蕈樣黴菌病、骨髓發育不良症候群、骨髓發育不良/骨髓增生性腫瘤、部位腫瘤、腫瘤、骨髓性白血病、骨髓白血病、多發性骨髓瘤、骨髓增生性腫瘤、鼻腔及鼻竇癌、鼻咽癌、神經母細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、肺腫瘤、肺癌、肺腫瘤、呼吸道腫瘤、支氣管癌、支氣管腫瘤、口腔癌(oral cancer)、口腔癌(oral cavity cancer)、唇癌、口咽癌、骨肉瘤、卵巢癌、胰臟癌、乳頭狀瘤症、副神經節瘤、副鼻鼻竇及鼻腔癌、副甲狀腺癌、陰莖癌、咽癌、嗜鉻細胞瘤、垂體癌、漿細胞腫瘤、胸膜肺母細胞瘤、懷孕相關乳癌、原發性中樞神經系統淋巴瘤、原發性腹膜癌、***癌、直腸癌、大腸癌、結腸腫瘤、腎細胞癌、視網膜胚細胞瘤、橫紋肌肉瘤、唾液腺癌、肉瘤、塞紮萊症候群(Sezary syndrome)、皮膚癌、施皮茨腫瘤(Spitz tumors)、小細胞肺癌、小腸癌、軟組織肉瘤、鱗狀細胞癌、鱗狀頸癌、胃癌、T細胞淋巴瘤、睪丸癌、咽喉癌、胸腺瘤及胸腺癌、甲狀腺癌、髓質甲狀腺癌、腎盂及尿管之移行細胞癌症、未知的原發性癌瘤、尿道癌、子宮癌、子宮肉瘤、***癌、外陰癌及威耳姆士腫瘤(Wilms'tumor)。In some embodiments of any of the methods or uses described herein, the primary cancer (eg, an actively treated (or has been treated) cancer (eg, 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, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, ventricular Ependymoblastoma, Ependymoma, Esophageal Cancer, Sensitive Neuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, 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, sensitivity 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 Tract 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, primary CNS tumors, heart cancer, hepatocellular carcinoma, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaburger's sarcoma (Kaposi sarcoma), kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and mouth cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous tissue of bone Cell tumor, 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, neoplasms, myeloid leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and sinus cancer, nasopharyngeal carcinoma , 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 (o ral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid 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, colorectal cancer Carcinoma, 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, medullary thyroid cancer, transitional cell cancer of renal pelvis and urinary tract, unknown Primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer and Wilms' tumor.

在一些實施例中，血液原發性癌症(例如作為RET相關癌症之血液癌症)係選自由以下組成之群：白血病、淋巴瘤(非霍奇金氏淋巴瘤)、霍奇金氏病(亦稱為霍奇金氏淋巴瘤)及骨髓瘤，例如急性淋巴球性白血病(ALL)、急性骨髓性白血病(AML)、急性前髓細胞性白血病(APL)、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、慢性骨髓單核球性白血病(CMML)、慢性嗜中性白血球性白血病(CNL)、急性未分化白血病(AUL)、多形性大細胞淋巴瘤(ALCL)、前淋巴球性白血病(PML)、青少年骨髓單核球性白血病(JMML)、成年人T細胞ALL、AML伴三系骨髓發育不良(AML/TMDS)、混合系白血病(MLL)、骨髓發育不良症候群(MDS)、骨髓增生病(MPD)及多發性骨髓瘤(MM)。血液原發性癌症之其他實例包括骨髓增生病(MPD)，諸如真性紅血球增多症(PV)、原發性血小板減少症(ET)及特發性原發性骨髓纖維化(IMF/IPF/PMF)。在一個實施例中，血液原發性癌症(例如作為RET相關癌症之血液癌症)為AML或CMML。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.

在一些實施例中，原發性癌症(例如RET相關癌症)為實體腫瘤。實體腫瘤(例如作為RET相關癌症之實體腫瘤)之實例包括例如甲狀腺癌(例如乳頭狀甲狀腺癌、甲狀腺髓質癌)、肺癌(例如肺腺癌、小細胞肺癌)、胰臟癌、胰管癌、乳癌、大腸癌、大腸直腸癌、***癌、腎細胞癌、頭頸腫瘤、神經母細胞瘤及黑色素瘤。參見例如Nature Reviews Cancer, 2014, 14, 173-186。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.

在一些實施例中，原發性癌症係選自由以下組成之群：肺癌、乳頭狀甲狀腺癌、髓質甲狀腺癌、分化甲狀腺癌、復發性甲狀腺癌、難治性分化甲狀腺癌、2A或2B型多發性內分泌瘤(分別為MEN2A或MEN2B)、嗜鉻細胞瘤、副甲狀腺增生、乳癌、大腸直腸癌、乳頭狀腎細胞癌、胃腸黏膜之神經節瘤病、及子宮頸癌。在一個較佳實施例中，癌症包含肺癌、大腸癌、腎癌、黑素瘤、乳癌、甲狀腺癌及/或RET相關癌症。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.

在與如本文中所描述之預防腦轉移之方法相關的實施例中，個體可經鑑別為具有大腦中出現或發作一或多種轉移性生長之風險，包括增加之風險。在一些實施例中，可藉由建立及/或判定原有疾病之階段，諸如鑑別原發性(或原有)癌症疾病之階段來鑑別個體。在一些實施例中，個體可鑑別為患有具有發展為轉移性生長之已知風險的原有疾病，例如癌症類型。在一些實施例中，個體可藉由偵測及/或判定原發性(或原有)癌症疾病為RET相關癌症來鑑別。下文提供RET相關癌症、RET突變、RET融合體、RET基因失調、及適用於偵測此類基於RET之生物標記物之診斷方法的論述。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, of 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 pre-existing disease, such as identifying the stage of primary (or pre-existing) cancer disease. In some embodiments, an individual can be identified as having a pre-existing disease, such as a type of cancer, with a known risk of developing metastatic growth. In some embodiments, an individual can be identified by detection and/or determination of a primary (or pre-existing) 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.

在一些實施例中，本文所提供之化合物展現強效及選擇性RET抑制。舉例而言，本文所提供之化合物針對野生型RET及RET基因所編碼之RET激酶展現奈莫耳濃度效力，該RET基因包括活化突變或RET激酶抑制劑抗性突變，包括例如KIF5B-RET融合、G810R及G810S ATP裂隙前緣突變、M918T活化突變及V804M、V804L及V804E守門基因突變，同時針對相關激酶的活性最小。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.

在一些實施例中，式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之固體或液體調配物中之任一者)選擇性地靶向RET激酶。舉例而言，式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之固體或液體調配物中之任一者)可以選擇性地靶向RET激酶而非另一激酶或非激酶標靶。在一些實施例中，式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之固體或液體調配物中之任一者)針對由RET基因編碼之變異RET融合蛋白展現奈莫耳濃度效力，該RET基因編碼RET融合蛋白(例如本文所描述之任一種RET融合蛋白，包括(但不限於) CCDC6-RET或KIF5B-RET)，RET基因包括RET激酶抑制劑抗性突變(例如本文所描述之任一種RET突變，包括(但不限於) V804M、V804L或V804E)，使得該變異RET蛋白為RET融合蛋白，其因RET激酶抑制劑抗性胺基酸取代或缺失的存在而展現RET激酶抑制劑抗性。非限制性實例包括CCDC6-RET-V804M及KIF5B-RET-V804M。在一些實施例中，本文所提供之化合物展現針對由RET基因編碼之變異RET蛋白質之奈莫耳濃度效能，該RET基因包括RET突變(例如本文中所描述之RET突變中之任一者，包括(但不限於)C634W或M918T)且包括RET激酶抑制劑抗性突變(例如本文中所描述之RET激酶抑制劑抗性突變中之任一者，包括(但不限於) V804M、V804L或V804E)，使得變異RET蛋白質包括由RET突變(例如RET初始突變)引起的RET取代且變異RET蛋白質由於存在RET激酶抑制劑抗性胺基酸取代或缺失而展現RET激酶抗性。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-resistant 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. Resistance to RET kinase inhibitors 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.

在一些實施例中，式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之任一種固體或液體調配物)針對RET激酶展現的選擇性為另一激酶的至少30倍。舉例而言，式(I)化合物或其醫藥學上可接受之鹽、非晶形式、多晶形式或醫藥組合物(例如本文所描述之任一種固體或液體調配物)針對RET激酶展現的選擇性為另一激酶的至少40倍；至少50倍；至少60倍；至少70倍；至少80倍；至少90倍；至少100倍；至少200倍；至少300倍；至少400倍；至少500倍；至少600倍；至少700倍；至少800倍；至少900倍或至少1000倍。在一些實施例中，在細胞分析(例如，如本文所提供的細胞分析)中，相對於另一激酶量測針對RET激酶的選擇性。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).

在一些實施例中，相對於KDR激酶，本文所提供之化合物可展現針對RET激酶(例如VEGFR2)之選擇性。在一些實施例中，觀測到針對RET激酶的選擇性超過KDR激酶，而對包括活化突變或RET激酶抑制劑抗性突變(例如守門基因突變體)之RET基因所編碼的RET激酶無效力損失。在一些實施例中，與抑制KIF5B-RET相比，選擇性為KDR激酶之至少10倍(例如至少40倍選擇性；至少50倍選擇性；至少60倍選擇性；至少70倍選擇性；至少80倍選擇性；至少90倍選擇性；至少100倍選擇性；至少150倍選擇性；至少200倍選擇性；至少250倍選擇性；至少300倍選擇性；至少350倍選擇性；或至少400倍選擇性) (例如化合物對KIF5B-RET的效能大於KDR)。在一些實施例中，對RET激酶之選擇性為KDR激酶的約30倍。在一些實施例中，對RET激酶之選擇性為KDR激酶的至少100倍。在一些實施例中，對RET激酶的選擇性為KDR激酶的至少150倍。在一些實施例中，對RET激酶之選擇性為KDR激酶的至少400倍。不受任何理論束縛，咸信強效KDR激酶抑制為靶向RET之多重激酶抑制劑(MKI)當中的共同特徵且可為使用此類化合物所觀測到之劑量限制毒性之來源。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.

在一些實施例中，V804M之抑制與關於野生型RET所觀測到之抑制類似。舉例而言，V804M之抑制在野生型RET之抑制的約2倍(例如約5倍、約7倍、約10倍)內(亦即，化合物針對野生型RET及V804M之效能類似)。在一些實施例中，在酶分析(例如本文所提供的酶分析)中，量測到對野生型或V804M RET激酶的選擇性大於另一激酶。在一些實施例中，本文所提供之化合物對RET突變體細胞展現選擇性細胞毒性。In some embodiments, the 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.

在一些實施例中，G810S及/或G810R之抑制與針對野生型RET所觀測到之抑制類似。舉例而言，G810S及/或G810R之抑制在野生型RET之抑制的約2倍(例如約5倍、約7倍、約10倍)內(例如，化合物針對野生型RET及G810S及/或G810R的效能類似)。在一些實施例中，在酶分析(例如本文所提供之酶分析)中，量測到對野生型或G810S及/或G810R RET激酶的選擇性大於另一激酶。在一些實施例中，本文所提供之化合物對RET突變體細胞展現選擇性細胞毒性。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.

如本文所用，術語「RET相關疾病或病症」係指與RET基因、RET激酶(本文亦稱為RET激酶蛋白質)或其任一者(例如一或多者)之表現或活性或含量之失調(例如本文所描述之RET基因、RET激酶、RET激酶域或其任一者之表現或活性或含量的任何類型之失調)相關或具有該失調的疾病或病症。RET相關疾病或病症之非限制性實例包括例如癌症及腸胃疾病，諸如大腸急躁症(IBS)。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).

如本文所用，術語「RET相關癌症」係指與RET基因、RET激酶(本文中亦稱為RET激酶蛋白質)或其中任一者之表現或活性或含量之失調相關或具有該失調的癌症。RET相關癌症之非限制性實例描述於本文中。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.

片語「RET基因、RET激酶或其中任一者之表現或活性或含量之失調」係指基因突變(例如引起包括RET激酶域及融合搭配物之融合蛋白質之表現的染色體易位、引起包括至少一個胺基酸缺失(與野生型RET蛋白質相比)之RET蛋白質之表現的RET基因突變、引起具有一或多個點突變(與野生型RET蛋白質相比)之RET蛋白質之表現的RET基因突變、引起具有至少一個***之胺基酸(與野生型RET蛋白質相比)之RET蛋白質之表現的RET基因突變、引起細胞中之RET蛋白質含量增加的基因複製或引起細胞中之RET蛋白質含量增加的調節序列(例如啟動子及/或強化子)突變)、引起在RET蛋白質中具有至少一個胺基酸缺失(與野生型RET蛋白質相比)之RET蛋白質的RET mRNA之替代剪接形式，或因異常細胞傳信及/或自分泌/旁分泌傳信失調而引起的哺乳動物細胞中之野生型RET激酶之表現增強(例如含量增加) (例如與對照性非癌細胞相比)。作為另一實例，RET基因、RET蛋白質或其中任一者之表現或活性或含量之失調可為編碼RET蛋白質之RET基因中的突變，該RET蛋白質具有組成性活性或與由不包括突變之RET基因編碼的蛋白質相比具有增加之活性。舉例而言，RET基因、RET蛋白質或其中任一者之表現或活性或含量之失調可為基因或染色體易位之結果，該基因或染色體易位引起含有包括功能性激酶域的RET之第一部分及搭配物蛋白質(亦即非RET)之第二部分的融合蛋白質之表現。在一些實例中，RET基因、RET蛋白質或其中任一者之表現或活性或含量之失調可為一種RET基因與另一種非RET基因之基因易位的結果。RET融合蛋白、RET激酶蛋白質突變(例如點突變/***/缺失、抑制劑抗性突變等)之非限制性實例係此項技術中已知的且描述於例如美國專利10,786,489中(例如表1至4中)。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).

在本文所描述之方法及用途之一些實施例中，RET基因、RET激酶或其中任一者之表現或活性或含量之失調可由RET基因之活化突變所導致(參見例如本文所列及/或如美國專利10,786,489之表1中所列之引起任何融合蛋白之表現的染色體易位)。在一些實施例中，RET基因、RET激酶或其中任一者之表現或活性或含量之失調可由基因突變所導致，該基因突變引起例如與野生型RET激酶相比，具有增大對RET激酶抑制劑及/或多激酶抑制劑(MKI)抑制之抗性的RET激酶之表現(參見例如本文中所揭示之胺基酸取代，包括以下位置處之取代：634 (例如C634W)、732 (例如E732K)、778、788 (例如I788N)、790 (例如L790F)、804 (例如V804M、V804L、V804E)、778及804、804及805 (例如V804M/E805K)、806 (例如Y806C、Y806E、Y806S、Y806H、Y806N)、804及806 (例如V804M/Y806C)、810 (例如G810A、G810R、G810S、G810C、G810V及G810D)、865 (例如L865V)、870 (例如L870F)、891 (例如S891A)、904 (例如S904F)、804及904 (例如V804M/S904C)、918 (例如M918T)，以及可誘導位阻及/或活性構形作用之額外例示性突變，包括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及R912P及/或如美國專利10,786,489之表3及4中所列出的)。在一些實施例中，RET基因、RET激酶或其中任一者之表現或活性或含量之失調可由編碼變異RET蛋白質(例如RET融合蛋白質或具有突變(例如初始突變)之RET蛋白質)之核酸中的突變導致，該突變引起例如與野生型RET激酶相比，具有增大對RET激酶抑制劑及/或多激酶抑制劑(MKI)抑制之抗性的變異蛋白質之表現。此類例示性RET激酶胺基酸取代、RET激酶點突變、***及缺失(例如，如美國專利10,786,489中已知且描述)可由活化突變所導致及/或可引起具有增大對RET激酶抑制劑及/或多激酶抑制劑(MKI)抑制之抗性的RET激酶之表現。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 listed in Table 1 of US Patent No. 10,786,489 that result in the expression of any of the fusion proteins). 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 US Patent 10,786,489). 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 (e.g., as known and described in U.S. Patent No. 10,786,489) may result from activating mutations and/or may result in increased resistance to RET kinase inhibitors. and/or expression of RET kinase resistant to multikinase inhibitor (MKI) inhibition.

術語「活化突變」描述RET激酶基因中之突變，其引起例如與野生型RET激酶相比具有增加之激酶活性的RET激酶之表現，例如在相同條件下分析時。舉例而言，活化突變可引起包括RET激酶域及融合搭配物之融合蛋白表現。在另一實例中，活化突變可為RET激酶基因之突變，該突變導致具有一或多個(例如兩個、三個、四個、五個、六個、七個、八個、九個或十個)胺基酸取代之RET激酶表現(例如本文所述之任何胺基酸取代之任何組合)，該RET激酶具有例如與野生型RET激酶相比增加的激酶活性，例如在相同條件下分析時。在另一實例中，活化突變可為RET激酶基因之突變，其引起具有一或多個(例如兩個、三個、四個、五個、六個、七個、八個、九個或十個)胺基酸缺失的RET激酶之表現，例如與野生型RET激酶相比，例如在相同條件下分析時。在另一實例中，活化突變可為RET激酶基因之突變，該突變引起具有至少一個(例如至少2個、至少3個、至少4個、至少5個、至少6個、至少7個、至少8個、至少9個、至少10個、至少12個、至少14個、至少16個、至少18個或至少20個)胺基酸***之RET激酶表現，與野生型RET激酶，例如本文所描述之例示性野生型RET激酶相比，例如在相同條件下分析時。活化突變之其他實例為此項技術中已知的。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.

術語「野生型(wildtype)」或「野生型(wild-type)」描述一種核酸(例如RET基因或RET mRNA)或蛋白質(例如RET蛋白質)，其發現於不患有RET相關疾病(例如RET相關癌症)(且視情況亦不具有罹患RET相關疾病之增加風險及/或未懷疑患有RET相關疾病)的個體中，或發現於細胞或組織中，該細胞或組織來自不患有RET相關疾病(例如RET相關癌症) (且視情況亦不具有罹患RET相關疾病之增加風險及/或未懷疑患有RET相關疾病)的個體。 調配物及劑量 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

在一些實施例中，視所要治療及待治療之區域而定，包括式(I)化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式的固體調配物可藉由多種途徑投與。在一些實施例中，投藥係經口的。經口投藥可包括經調配用於每日一次或每日兩次(BID)投藥之劑型。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.

包含式(I)化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式的組合物可調配成單位劑型，各劑量含有約1至約1,000 mg (1 g)、更通常約5 mg至約100 mg活性成分。術語「單位劑型」係指以單位劑量形式適用於人類個體及其他患者的物理離散單元，各單位含有經計算產生所需治療作用之預定量的活性材料(亦即式(I)化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式)，以及適合的醫藥賦形劑。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.

在一些實施例中，固體調配物經調配為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或250 mg劑型。在一些實施例中，固體調配物經調配為10 mg、20 mg、60 mg、80 mg、120 mg或160 mg劑型。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.

在一些實施例中，本文所提供之組合物含有約1 mg至約50 mg活性成分。一般熟習此項技術者將瞭解，此體現化合物或組合物含有約1 mg至約5 mg、約5 mg至約10 mg、約10 mg至約15 mg、約15 mg至約20 mg、約20 mg至約25 mg、約25 mg至約30 mg、約30 mg至約35 mg、約35 mg至約40 mg、約40 mg至約45 mg或約45 mg至約50 mg活性成分。在一些實施例中，本文提供的組合物含有約10 mg活性成分。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, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg 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 active ingredient. In some embodiments, the compositions provided herein contain about 10 mg of the active ingredient.

在一些實施例中，本文所提供之組合物含有約50 mg至約500 mg活性成分。一般熟習此項技術者將瞭解，此體現化合物或組合物含有約50 mg至約100 mg、約100 mg至約150 mg、約120 mg至約160 mg、約150 mg至約200 mg、約200 mg至約250 mg、約250 mg至約300 mg、約350 mg至約400 mg或約450 mg至約500 mg活性成分。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.

在一些實施例中，本文所提供之組合物含有約500 mg至約1,000 mg活性成分。一般熟習此項技術者將瞭解，此包含化合物或組合物含有約500 mg至約550 mg、約550 mg至約600 mg、約600 mg至約650 mg、約650 mg至約700 mg、約700 mg至約750 mg、約750 mg至約800 mg、約800 mg至約850 mg、約850 mg至約900 mg、約900 mg至約950 mg或約950 mg至約1,000 mg活性成分。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.

式(I)化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式的日劑量可在每個成人每天1.0至10,000 mg或更高的廣泛範圍內或其中的任何範圍內變化。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.

在一些實施例中，對於經口投藥，組合物可以錠劑形式提供，該等錠劑含有約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及500毫克活性成分以便根據待治療之患者的症狀來調整劑量。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, 80, 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.

有效量之藥物通常以每天約0.1 mg/kg至約1000 mg/kg體重的給藥量或其中之任何範圍供應。在一些實施例中，範圍為每天約0.5至約500 mg/kg體重，或其中的任何範圍。在一些實施例中，為每天約1.0至約250 mg/kg體重，或其中的任何範圍。在一些實施例中，為每天約0.1至約100 mg/kg體重，或其中的任何範圍。在一些實施例中，範圍為每天約0.1至約50.0 mg/kg體重，或其中的任何量或範圍。在一些實施例中，範圍為每天約0.1至約15.0 mg/kg體重，或約0.5 mg/kg至約10 mg/kg、或1 mg/kg至約9 mg/kg、或約2 mg/kg至約8 mg/kg或約3 mg/kg至7 mg/kg。另外，式(I)化合物可以例如以下量投與：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、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約55 mg/kg、約60 mg/kg。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 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.

在一個實施例中，向個體投與每天約0.1 mg/kg至約15.0 mg/kg體重的塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。In one embodiment, 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.

含有式(I)化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式之醫藥組合物可按每天1至4次之療程投與。更佳地，每天一次或兩次或以單一日劑量向個體投與塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。每日投藥可為每日一次或呈多次劑量形式，例如每日兩次(BID)投藥。在一實施例中，給藥可如下進行：當個體體重小於50 kg時，向個體投與120 mg塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物，且其中當個體體重超過50 kg時，向個體投與160 mg塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式，或包含塞爾帕替尼或其醫藥學上可接受之鹽、非晶形式或多晶形式之組合物。在一些實施例中，塞爾帕替尼或其醫藥學上可接受之鹽為多晶型物。替代地，自塞爾帕替尼或其醫藥學上可接受之鹽為非晶形。在某些實施例中，塞爾帕替尼為游離胺。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 embodiment, administration may be performed by administering 120 mg of serpatinib, or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof, to the individual when the individual weighs less than 50 kg, or A composition comprising serpatinib or a pharmaceutically acceptable salt thereof, an amorphous form or a polymorphic form thereof, wherein 160 mg of selpatinib or a selpatinib is administered to the individual when the individual weighs more than 50 kg A pharmaceutically acceptable salt, amorphous form or polymorphic form, or a composition comprising serpatinib or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof. In some embodiments, serpatinib or a pharmaceutically acceptable salt thereof is a polymorph. Alternatively, serpatinib or a pharmaceutically acceptable salt thereof is amorphous. In certain embodiments, serpatinib is a free amine.

活性化合物可在寬劑量範圍內有效，且通常以醫藥學有效量投與。待投與的最佳劑量可由熟習此項技術者容易地判定。因此應瞭解，化合物的實際上投與量通常將由醫師判定，且根據相關情形而變，包括投藥模式、所投與的實際化合物、製備強度、待治療之病狀及疾病狀況的進展。另外，與所治療之特定患者相關的因素，包括患者反應、年齡、體重、膳食、投藥時間及患者症狀的嚴重程度，將引起調整劑量的需要。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.

式Mode (I)(I) 化合物之多晶形式Polymorphic Forms of Compounds

在一些實施例中，固體調配物包括式(I)化合物，亦即塞爾帕替尼之多晶形式。形式包括例如式(I)化合物之游離鹼、溶劑合物、水合物、鹽及非溶劑化形式，包括(例如)如美國專利10,786,489中所揭示之多晶形式1至8 (例如1、2、7及8)。在一些實施例中，式(I)化合物之多晶形式為醫藥學上可接受之鹽。在一實施例中，式(I)化合物之多晶型物為游離鹼。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 as disclosed in US Pat. No. 10,786,489 (eg, 1, 2, 7 and 8). In some embodiments, polymorphic forms of compounds of formula (I) are pharmaceutically acceptable salts. In one embodiment, the polymorph of the compound of formula (I) is the free base.

式Mode (I)(I) 之鹽salt of

在一些實施例中，式(I)化合物為醫藥學上可接受之鹽。舉例而言，式(I)化合物之醫藥學上可接受之鹽可包括(但不限於)硫酸鹽、甲苯磺酸鹽、萘-2-磺酸鹽、草酸鹽、磷酸鹽、酒石酸鹽及反丁烯二酸鹽。在一些實施例中，式(I)化合物為硫酸鹽或磷酸鹽。在一些實施例中，硫酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為異丙醇(IPA)及水之混合物。在一些實施例中，水以10重量%之量存在。在一些實施例中，式(I)化合物為甲苯磺酸鹽。在一些實施例中，甲苯磺酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為丙酮及水之混合物。在一些實施例中，水以10重量%之量存在。在一些實施例中，式(I)化合物為萘-2-磺酸鹽。在一些實施例中，萘-2-磺酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為THF及水之混合物。在一些實施例中，水以10重量%之量存在。在一些實施例中，式(I)化合物為草酸鹽。在一些實施例中，草酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為1,4-二㗁烷及水之混合物。在一些實施例中，水以10重量%之量存在。在一些實施例中，草酸鹽係藉由自溶劑混合物蒸發來製備。在一些實施例中，溶劑為THF及水之混合物。在一些實施例中，式(I)化合物為酒石酸鹽。在一些實施例中，酒石酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為IPA及水之混合物。在一些實施例中，水以10重量%之量存在。在一些實施例中，式(I)化合物為反丁烯二酸鹽。在一些實施例中，反丁烯二酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為THF及水之混合物。在一些實施例中，式(I)化合物為磷酸鹽。在一些實施例中，磷酸鹽係於溶劑混合物中製備。在一些實施例中，溶劑為丙酮及水之混合物。在一些實施例中，溶劑為IPA及水之混合物。在一些實施例中，水以10重量%之量存在。式(I)之鹽以及用於製備此類鹽的方法描述於美國專利10,584,124及10,786,489中。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 Patents 10,584,124 and 10,786,489.

用於製備式for preparation (I)(I) 化合物之方法compound method

式(I)化合物可獲自商業來源，或在替代例中，其可藉由合成方法製備，諸如他處所揭示及描述之方法(例如美國專利10,112,942)。僅出於說明之目的，流程1及2展示用於製備本文所提供之化合物以及關鍵中間物的通用方法。個別反應步驟之更詳細描述揭示於美國專利10,112,942及國際專利公開案WO 2018/071447中。熟習此項技術者將瞭解，可以利用其他合成途徑合成化合物。儘管特定起始材料及試劑描述於流程中且在下文論述，但其他起始材料及試劑可容易取代以提供多種衍生物及/或反應條件。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 No. 10,112,942). 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. 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.

流程 1

Process 1

流程1展示用於合成式(I)化合物(流程1中所示之化合物12)的通用流程，其中B為-CH ₂C(CH ₃) ₂OH；X ¹為N；X ²、X ³及X ⁴為CH；且D及E由以下表示：

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) (compound 12 shown in Scheme 1), wherein B is -CH ₂ C(CH ₃ ) ₂ OH; X ¹ is N; X ² , X ³ and X 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 .

化合物2係藉由O-((

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.

在一些實施例中，為製備化合物9，可使化合物8與諸如以下之試劑：

，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。接著製備化合物11，其可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與對應二羥硼酸酯化合物10偶合(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)。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 is then prepared using appropriate palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g. palladium catalyst and optional ligand in the presence of an inorganic base, e.g. containing Pd( In the case of PPh ₃ ) ₄ and Na ₂ CO ₃ dioxane, at high temperature), compound 9 is coupled with the corresponding dihydroxyboronate compound 10 (wherein 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). 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.

替代地，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8與相應二羥硼酸酯化合物10偶合，以提供化合物11a。接著可在光延反應條件(例如PPh ₃及偶氮二甲酸二異丙酯)下，使化合物11a與諸如以下之試劑反應：

，其中X為離去原子或基團(諸如鹵離子或三氟甲磺酸根)，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 dihydroxyboronate 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.

流程 2

Process 2

流程2展示用於合成化合物12之另一通用流程，其中B、X ¹、X ²、X ³及X ⁴、環D及E如上文針對流程1所定義。 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 .

可使用適當的鈀催化之交叉偶合反應條件，例如鈴木偶合反應條件(例如鈀催化劑及視情況存在之配位體，在無機鹼，例如含Pd(PPh ₃) ₄及Na ₂CO ₃)之二㗁烷存在下，在高溫下)，使化合物9 (例如，如流程1中所述製備) (其中B如上文所定義)與相應的二羥硼酸酯13 (其中X ¹、X ²、X ³及X ⁴如上文所定義；L ²為離去基，諸如三氟甲磺酸根或鹵離子；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連同其所連接的原子一起形式視情況經1至4個選自(C1-C3烷基)之取代基取代的5至6員環)偶合，以提供化合物14。化合物16可藉由使化合物14與化合物15 (其中環D如上文所定義且P ¹為胺基保護基)在適當S _NAr條件下(例如視情況在諸如K ₂CO ₃之鹼存在下及在高溫下)偶合來製備。 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) (where B is as defined above) and the corresponding dihydroxyboronate 13 (where X ¹ , X ² , X ³ and X ⁴ are as defined above; L ² is a leaving group such as triflate or halide; 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 attached, are optionally substituted with 1 to 4 substituents selected from (C1-C3 alkyl) substituted 5-6 membered rings) 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.

化合物16之環D上的保護基P ¹可在標準條件下移除(例如，Boc基團可以藉由在例如HCl之酸性條件下處理化合物16來移除)，以提供化合物12，其中E為H (亦即，環D經去保護)。接著可使經去保護環D在諸如下文描述之標準條件下發生官能化(亦即，與適當試劑反應或用適當試劑處理)以引入E基團，以提供化合物12，其中E如上文所定義。 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 .

如本文所用，術語「胺基保護基」係指通常用於阻斷或保護胺基、同時使化合物之其他官能基發生反應的基團衍生物。適用於本文所述任何方法中之保護基團實例包括胺基甲酸酯、醯胺、烷基及芳基、亞胺，以及多種N-雜原子衍生物，其可移除而使所需胺基再生。胺基保護基之非限制性實例為乙醯基、三氟乙醯基、三級丁氧羰基(「Boc」)、苯甲氧羰基(「CBz」)及9-茀基亞甲基氧基羰基(「Fmoc」)。此等基團及其他保護基之其他實例見於T. W. Greene等人，Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006中。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.

羥基可用例如如以下文獻中所描述之任何適宜羥基保護基保護：T. W. Greene等人，Greene's Protective Groups in Organic Synthesis. New York: Wiley Interscience, 2006。實例包括苯甲基、三苯甲基、矽基醚及其類似基團。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.

任何上述方法中所描述的化合物中之氮原子可用例如如以下文獻中所描述之任何適宜氮保護基保護：Greene及Wuts編,「Protecting Groups in Organic Synthesis」, 補充第2版, New York; John Wiley & Sons, Inc., 1991。氮保護基之實例包括醯基及烷氧基羰基，諸如三級丁氧基羰基(BOC)、苯氧基羰基及[2-(三甲基矽基)乙氧基]甲基(SEM)。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).

其他途徑可用於合成式I化合物，包括(例如)美國專利10,786 489中所揭示的合成途徑(例如流程3至6)。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).

鑑別處於風險下之個體及identify individuals at risk and RETRET 序列之伴隨診斷companion diagnostics

RET基因、RET激酶或其任一者之表現或活性或含量之失調可為一或多種染色體易位或倒位之結果，從而產生RET基因融合體(亦即，基因易位產生表現之蛋白質，該表現之蛋白質為含有來自非RET搭配物蛋白質之殘基且包括最小的功能性RET激酶域之融合蛋白)。RET融合體搭配物及其相關癌症(例如可與腦轉移及/或出現腦轉移之風險增大相關的彼等癌症)之非限制性實例包括ACBD5 (乳頭狀甲狀腺癌)；AFAP1 (NSCLC)；AFAP1L2 (乳頭狀甲狀腺癌)；AKAP13 (乳頭狀甲狀腺癌)；BCR (慢性骨髓單核球性白血病)；C10orf118 (乳頭狀甲狀腺癌)；CCDC6 (亦稱為PTC1、D10S170或H4) (NSCLC、大腸癌、乳頭狀甲狀腺癌、腺癌、肺腺癌、轉移性大腸直腸癌、腺鱗癌瘤、乳癌)；CCDC88C (NSCLC)；CCDC186-RET, CEP55 (彌漫性胃癌)；CGNL1 (胰臟癌)；CLIP1 (腺癌)；CUX1 (肺腺癌)；DLG5 (非退行性甲狀腺癌)；DOCK1 (NSCLC)；EML4 (乳頭狀甲狀腺癌)；ERC1 (亦稱為ELKS) (乳頭狀甲狀腺癌、乳癌)；ETV6 (唾腺癌症)；FGFR1OP (CMML，原發性骨髓纖維化伴有繼發性急性骨髓性白血病)；FKBP15 (乳頭狀甲狀腺癌)；FOXP4 (肺腺癌)；FRMD4A (NSCLC)；GOLGA5 (亦稱為PTC5) (乳頭狀甲狀腺癌，類施皮茨腫瘤(spitzoid neoplasms))；H4L (各種)；HOOK3 (乳頭狀甲狀腺癌)；HRH4-RET (甲狀腺癌及/或乳頭狀甲狀腺癌)；HTIF1 (各種)；KIAA1217 (亦稱為SKT) (乳頭狀甲狀腺癌、肺腺癌、NSCLC)；KIAA1468 (亦稱為PTC9及RFG9) (乳頭狀甲狀腺癌、肺腺癌)；KIF13A (NSCLC)；KIF5B (NSCLC、卵巢癌、類施皮茨腫瘤、肺腺癌、腺鱗癌瘤)；KTN1 (亦稱為PTC8) (乳頭狀甲狀腺癌)；MBD1 (亦稱為PCM1) (乳頭狀甲狀腺癌)；MPRIP (NSCLC)；MYH10 (嬰兒肌纖維瘤病)；MYH13 (髓質甲狀腺癌)；NCOA4 (亦稱為PTC3、ELE1及RFG) (乳頭狀甲狀腺癌、NSCLC、大腸癌、唾液腺癌、轉移性大腸直腸癌、肺腺癌、乳頭狀甲狀腺癌之腺鱗癌瘤彌漫性硬化變異體、乳癌、腺泡細胞癌症、***類似物分泌癌症)；OLFM4 (小腸癌)；PARD3 (NSCLC)；PCM1 (乳頭狀甲狀腺癌)；PIBF1 (細支氣管肺細胞癌症)；PICALM (NSCLC)；PPFIBP2 (乳頭狀甲狀腺癌)；PRKAR1A (亦稱為PTC2) (乳頭狀甲狀腺癌)；PTC1ex9 (新穎CCDC6重排) (轉移性乳頭狀甲狀腺癌)；PTC4 (新穎NCO4/ELE1重排) (乳頭狀甲狀腺癌)；RAB61P2 (乳頭狀甲狀腺癌)；RASAL2 (肉瘤)；RASGEF1A (乳癌)；RBPMS (NSCLC)；RFG8 (乳頭狀甲狀腺癌)；RRBP1 (大腸癌)；RUFY1 (大腸直腸癌)；RUFY2 (NSCLC；乳頭狀甲狀腺癌)；RUFY3 (乳頭狀甲狀腺癌)；SLC12A2 (NSCLC)；SORBS2 (乳頭狀甲狀腺癌)；SPECC1L (乳頭狀甲狀腺癌；甲狀腺癌症)；SQSTM1 (乳頭狀甲狀腺癌)；TAF3 (胰臟癌)；TBL1XR1 (乳頭狀甲狀腺癌、甲狀腺癌症)；TFG (胰臟癌)；TIF1G (各種)；TRIM24 (亦稱為PTC6) (乳頭狀甲狀腺癌)；TRIM27 (亦稱為RFP) (乳頭狀甲狀腺癌)；AKAP13 (乳頭狀甲狀腺癌)；TRIM33 (亦稱為PTC7及RFG7) (NSCLC，乳頭狀甲狀腺癌)；以及UEVLD (乳頭狀甲狀腺癌)。融合蛋白可為例如KIF5B-RET。單一腫瘤中鑑別出的融合體包括 CCDC186-RET 、 ERC1-RET 、 KTN1-RET及 RUFY3-RET。又其他RET融合蛋白可不包括於本文中之清單中或尚未已知；然而，預期包含與本文所描述相同之式(I)化合物及方法及用途為預防腦轉移之有效抑制劑，且亦有效治療癌症。RET基因、RET激酶或其任一者之表現或活性或含量之失調可由RET基因中之一或多個點突變、***或缺失(與野生型RET相比)引起。為了參考，本文提供成熟人類RET蛋白之序列(SEQ ID NO: 1)：

Dysregulation of the expression or activity or level of the RET gene, RET kinase, or any of them 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, such as those cancers that may be associated with brain metastases and/or an increased risk of developing brain metastases, include ACBD5 (papillary thyroid cancer); AFAP1 (NSCLC); AFAP1L2 (papillary thyroid carcinoma); AKAP13 (papillary thyroid carcinoma); BCR (chronic myelomonocytic leukemia); C10orf118 (papillary thyroid carcinoma); CCDC6 (also known as PTC1, D10S170, or H4) (NSCLC, colorectal carcinoma, papillary thyroid carcinoma, adenocarcinoma, lung adenocarcinoma, metastatic colorectal carcinoma, adenosquamous carcinoma, breast carcinoma); CCDC88C (NSCLC); CCDC186-RET, CEP55 (diffuse gastric carcinoma); CGNL1 (pancreatic carcinoma) ; CLIP1 (adenocarcinoma); CUX1 (lung adenocarcinoma); DLG5 (nondegenerative thyroid cancer); DOCK1 (NSCLC); EML4 (papillary thyroid carcinoma); ERC1 (also known as 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 carcinoma, lung adenocarcinoma, adenosquamous carcinoma diffuse sclerosing variant of papillary thyroid carcinoma, breast carcinoma, acinar cell carcinoma, breast analog secreting carcinoma); OLFM4 (small bowel carcinoma); PARD3 (NSCLC); PCM1 (papillary thyroid carcinoma); PIBF1 (bronchiolopulmonary cell carcinoma); PICALM (NSCLC); PPFIBP2 (papillary thyroid carcinoma ); PRKAR1A (also known as PTC2) (papillary thyroid cancer); PTC1ex9 (novel CCDC6 rearrangement) (metastatic papillary thyroid cancer); PTC4 (novel NCO4/ELE1 rearrangement) (papillary thyroid cancer); RAB61P2 ( papillary 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); 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 effective for the treatment of cancer. 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:

與野生型RET激酶相比，潛在地活化RET激酶蛋白質點突變、***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***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、***及缺失可為例如M918T、M918V、C634W、V804L或V804M。其他RET激酶蛋白質點突變/***/缺失可不包括於本文中之清單中或尚未已知；然而，式(I)化合物及方法及用途如本文所描述用於治療癌症。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 deletion in exons 6 and 11, 3 bp in-frame deletion 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 are as described herein for the treatment of cancer.

RET基因、RET激酶或其任一者之表現或活性或含量的失調亦可包括RET mRNA中之剪接變異，該剪接變異產生經表現蛋白質，其為具有至少一個殘基缺失(與野生型RET激酶相比)的RET之替代剪接變異體，從而產生RET激酶域之構成性活性。Dysregulation of the expression or activity or level of the RET gene, RET kinase, or either of these 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.

實例example 11 組合在活體內模型中之作用Role of combinations in in vivo models

將5至8週齡之間的雌性免疫功能不全小鼠(Taconic；NCr)收容在12小時亮-暗循環、68至74℉ (20至23℃)及30%至70%濕度下之單獨的HEPA通風籠(Innocage® IVC, Innovive USA)中的經輻射之富含紙撚的1/8"玉米芯鋪墊(Sheperd)上。動物任意飲用水(逆滲透，2 ppm Cl2)及由19%蛋白質、9%脂肪及4%纖維組成之經輻射測試嚙齒動物膳食(Teklad 2919)。Female immunocompromised mice (Taconic; NCr) between 5 and 8 weeks of age were housed in individual rooms with a 12-h light-dark cycle, 68 to 74°F (20 to 23°C) and 30% to 70% humidity. On irradiated paper-twisted 1/8" corncob bedding (Sheperd) in HEPA ventilated cages (Innocage® IVC, Innovive USA). Animals had ad libitum access to drinking water (reverse osmosis, 2 ppm Cl) and 19% protein , 9% fat and 4% fiber radiation tested rodent diet (Teklad 2919).

在動物之側腹區域的單側移植自供體動物採集之腫瘤片段，每一者自特定通道批次移植。在移植後大致一週開始記錄各實驗之研究前腫瘤體積。當腫瘤達到約100至300 mm3時，藉由腫瘤體積將動物匹配至處理組及對照組且開始給藥(第0天)。所有研究中之動物經標記且在整個實驗中進行個別地跟蹤。Unilateral grafts in the flank region of the animals were tumor fragments harvested from donor animals, each grafted from a specific passage batch. Pre-study tumor volumes were recorded for each experiment approximately one week after implantation. When tumors reached approximately 100 to 300 mm3, animals were matched by tumor volume to treatment and control groups and dosing began (Day 0). All study animals were tagged and followed individually throughout the experiment.

一週量測腫瘤體積兩次且在達到終點之研究日或發現動物垂死之當天取得最終腫瘤體積。藉由數位卡尺量測腫瘤體積且記錄各組之資料，包括個別及平均估計腫瘤體積(平均TV±SEM)。可使用公式：TV=寬度2×長度×0.52計算腫瘤體積。在研究完成時，使用公式：%TGI = 1-(Tf-Ti)/(Cf-Ci)之初始(i)及最終(f)腫瘤量測計算且報導各處理組(T)對比對照組(C)之腫瘤生長抑制百分比(TGI%)值。Tumor volumes were measured twice a week and final tumor volumes were obtained on the study day when endpoint was reached or on the day animals were found moribund. Tumor volumes were measured by digital calipers and the data of each group were recorded, including individual and mean estimated tumor volumes (mean TV±SEM). The tumor volume can be calculated using the formula: TV=width2×length×0.52. At the completion of the study, the initial (i) and final (f) tumor measurements were calculated and reported for each treatment group (T) versus the control group ( C) Percent Tumor Growth Inhibition (TGI%) values.

在第0天開始藥劑之初始給藥。各處理組中給藥4個動物，如下：媒劑對照：藉由口服一天投與含1%羧基甲基纖維素(CMC)、0.02%月桂基硫酸鈉(十二烷基硫酸鈉；SDS)之無菌水兩次，持續28天。僅塞爾帕替尼：藉由口服一天投與5 mg/kg兩次，持續28天。僅順鉑：一週靜脈內投與5 mg/kg一次，持續四週。組合：一週靜脈內投與5 mg/kg順鉑一次，持續四週，且藉由口服一天投與5 mg/kg塞爾帕替尼兩次，持續28天。 Initial dosing of the drug was initiated on Day 0. Four animals were dosed in each treatment group as follows: Vehicle Control: Sterile water containing 1% carboxymethylcellulose (CMC) and 0.02% sodium lauryl sulfate (sodium dodecyl sulfate; SDS) was administered orally twice a day for 28 days. Serpatinib only: 5 mg/kg administered orally twice a day for 28 days. Cisplatin only: 5 mg/kg administered intravenously once a week for four weeks. Combination: 5 mg/kg cisplatin administered intravenously once a week for four weeks and 5 mg/kg selpatinib administered orally twice a day for 28 days.

對治療之反應%為高於基線之腫瘤體積△T/C%且低於基線之腫瘤體積消退%。資料提供於表1中。表 1 處理組 天數 塞爾帕替尼之反應 % 順鉑之反應 % 塞爾帕替尼及順鉑之反應 % 預期的附加反應 % 3 -1.5 99.0 -12.8 -1.8 6 -11.0 74.3 -25.3 -21.9 10 -14.5 60.4 -28.7 -34.4 13 -17.2 50.2 -31.8 -44.5 17 -3.2 50.7 -39.1 -36.4 20 -9.0 51.0 -41.3 -41.9 24 5.2 50.5 -19.8 -27.3 27 11.8 49.4 -5.9 -12.6 31 25.4 49.9 4.1 6.3 34 36.0 49.5 7.6 12.9 The % Response to Treatment is the % tumor volume ΔT/C above baseline and the % tumor volume regression below baseline. Data are provided in Table 1. Table 1 treatment group number of days Serpatinib Response % Cisplatin Response % % Response to Serpatinib and Cisplatin Expected additional response % 3 -1.5 99.0 -12.8 -1.8 6 -11.0 74.3 -25.3 -21.9 10 -14.5 60.4 -28.7 -34.4 13 -17.2 50.2 -31.8 -44.5 17 -3.2 50.7 -39.1 -36.4 20 -9.0 51.0 -41.3 -41.9 twenty four 5.2 50.5 -19.8 -27.3 27 11.8 49.4 -5.9 -12.6 31 25.4 49.9 4.1 6.3 34 36.0 49.5 7.6 12.9

         
          <![CDATA[<110>  美商絡速藥業公司(Loxo Oncology, Inc.)]]>
          <![CDATA[<120>  以RET抑制劑及鉑劑治療癌症之方法]]>
          <![CDATA[<130>  X22947]]>
          <![CDATA[<150>  US 63/127,434]]>
          <![CDATA[<151>  2020-12-18]]>
          <![CDATA[<160>  1     ]]>
          <![CDATA[<170>  PatentIn version 3.5]]>
          <![CDATA[<210>  1]]>
          <![CDATA[<211>  1114]]>
          <![CDATA[<212>  PRT]]>
          <![CDATA[<213>  智人]]>
          <![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 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 
          
          <![CDATA[<110> Loxo Oncology, Inc.]]>
          <![CDATA[<120> Methods of treating cancer with RET inhibitors and platinum agents]]>
          <![CDATA[<130> X22947]]>
          <![CDATA[<150> US 63/127,434]]>
          <![CDATA[<151> 2020-12-18]]>
          <![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

一種式I化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式的用途，其用於製造用於治療個體之癌症之藥劑，

(式I) 其中該藥劑進一步包含鉑劑或與鉑劑組合使用。 Use of a compound of formula I or a pharmaceutically acceptable salt, amorphous or polymorphic form thereof for the manufacture of a medicament for treating cancer in an individual,

(Formula I) wherein the agent further comprises a platinum agent or is used in combination with a platinum agent.

如請求項1之用途，其中該癌症包含肺癌、大腸癌、腎癌、黑素瘤、乳癌、甲狀腺癌及/或RET相關癌症。The use according to claim 1, wherein the cancer comprises lung cancer, colorectal cancer, kidney cancer, melanoma, breast cancer, thyroid cancer and/or RET-related cancers.

如請求項2之用途，其中該肺癌為非小細胞肺癌。The use according to claim 2, wherein the lung cancer is non-small cell lung cancer.

如請求項1至3中任一項之用途，其中該鉑劑為順鉑(cisplatin)、卡鉑(carboplatin)或奧沙利鉑(oxaliplatin)。The use according to any one of claims 1 to 3, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.

如請求項4之用途，其中該鉑劑為順鉑。As the application of claim 4, wherein the platinum agent is cisplatin.

如請求項1至5中任一項之用途，其中該癌症之一或多個細胞表現與該癌症相關之RET突變及/或RET融合。The use according to any one of claims 1 to 5, wherein one or more cells of the cancer exhibit RET mutations and/or RET fusions associated with the cancer.

如請求項1至6中任一項之用途，其中該藥劑進一步包含另一抗癌劑或與另一抗癌劑組合使用。The use according to any one of claims 1 to 6, wherein the medicament further comprises another anticancer agent or is used in combination with another anticancer agent.

如請求項1至7中任一項之用途，其中藉由偵測RET突變、RET融合、RET基因及/或RET蛋白質之表現、活性或含量失調中之一或多者來鑑別該個體。The use according to any one of claims 1 to 7, 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 imbalance.

如請求項1至7中任一項之用途，其中該藥劑係用於以每天投與約0.1 mg/kg至約15.0 mg/kg體重的該式I化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式。The use according to any one of claims 1 to 7, wherein the medicament is used to administer the compound of formula I or a pharmaceutically acceptable salt thereof of about 0.1 mg/kg to about 15.0 mg/kg body weight per day, Amorphous or polycrystalline forms.

如請求項1至9中任一項之用途，其中當該個體體重小於50 kg時，該藥劑係投與120 mg式I化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式，且其中當該個體體重超過50 kg時，該藥劑係投與160 mg該式I化合物或其醫藥學上可接受之鹽、非晶形式或多晶形式。The use of any one of claims 1 to 9, wherein when the body weight of the individual is less than 50 kg, the medicament is administered with 120 mg of the compound of formula I or its pharmaceutically acceptable salt, amorphous form or polymorphic form , and wherein when the body weight of the individual exceeds 50 kg, the medicament is administered with 160 mg of the compound of formula I or a pharmaceutically acceptable salt, amorphous form or polymorphic form thereof.

如請求項1至10中任一項之用途，其中該藥劑係每天投與一次或兩次。The use according to any one of claims 1 to 10, wherein the medicament is administered once or twice a day.

如請求項1至11中任一項之用途，其中該式I化合物或其醫藥學上可接受之鹽為多晶型物。The use according to any one of claims 1 to 11, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is a polymorph.

如請求項1至11中任一項之用途，其中該式I化合物或其醫藥學上可接受之鹽為非晶形。The use according to any one of claims 1 to 11, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is amorphous.

如請求項1至11中任一項之用途，其中該式I化合物為游離胺。The use according to any one of claims 1 to 11, wherein the compound of formula I is a free amine.