TWI863667B - Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease - Google Patents
Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease Download PDFInfo
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Abstract
Description
本發明係針對2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸(「化合物A」)、其醫藥學上可接受之鹽及其視情況與一或多種額外治療劑組合用於治療疾病之用途。The present invention is directed to the use of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid ("Compound A"), its pharmaceutically acceptable salts and optionally in combination with one or more additional therapeutic agents for treating diseases.
編碼磷酸肌醇3-激酶(PI3K)催化同功異型物p110α之PIK3CA基因係實體腫瘤中最常突變之基因且亦係PI3K路徑內最常發生基因改變之位點。PIK3CA突變最常見於子宮內膜癌、乳癌及頭頸癌中。大約40% HR+/HER2乳癌患者在PIK3CA中具有活化突變，此活化p110α及PI3K/AKT/mTOR信號傳導網路。H1047R係PIK3CA中最常見之誤義突變。 The PIK3CA gene, encoding the catalytic isoform of phosphoinositide 3-kinase (PI3K), p110α, is the most commonly mutated gene in solid tumors and is also the most common site of genetic alteration within the PI3K pathway. PIK3CA mutations are most commonly seen in endometrial cancer, breast cancer, and head and neck cancer. Approximately 40% of HR+/HER2 breast cancer patients have activating mutations in PIK3CA, which activate p110α and the PI3K/AKT/mTOR signaling network. H1047R is the most common missense mutation in PIK3CA.
PIK3CA中之活化突變引起對內分泌療法之抗性及疾病進展。PIK3CA中新驅動突變之出現亦可能為對CDK4/6抑制劑療法之抗性的機制。臨床前模型中對太平洋紫杉醇(paclitaxel)之抗性亦與PI3K/mTOR路徑活化相關。 Activating mutations in PIK3CA cause resistance to endocrine therapy and disease progression. The emergence of new driver mutations in PIK3CA may also be a mechanism of resistance to CDK4/6 inhibitor therapy. Resistance to paclitaxel in preclinical models is also associated with activation of the PI3K/mTOR pathway.
已在乳癌患者中測試了若干PI3K靶向藥劑。在隨機3期研究(SOLAR-1；NCT02437318)中，PI3Kα特異性抑制劑阿培利司(alpelisib)與氟維司群(fulvestrant)之組合將無進展存活期延長至11.0個月，而單獨使用氟維司群只延長至5.7個月，因此FDA批准阿培利司與氟維司群之組合用於治療HR+/HER2-PIK3CA突變型晚期或轉移性乳癌患者。雖然此批准代表了PIK3CA突變型乳癌之重大治療進展，但阿培利司以及其他臨床研究性PI3Kα抑制劑對野生型(WT)及突變型PI3Kα之抑制效力大致相同。因此，該等抑制劑之功效可能受靶上WT PI3Kα介導之毒性(包括劑量限制性高血糖症以及皮膚及GI毒性)限制，該毒性某種程度上限制PI3Kα抑制劑之廣泛臨床效用。例如，在SOLAR-1試驗中，在阿培利司/氟維司群或安慰劑/氟維司群組之至少35%參與者中出現的不良事件分別包括高血糖症(63.7%對比9.8%)、腹瀉(57.7%對比15.7%)、噁心(44.7%對比22.3%)、食慾減退(35.6%對比10.5%)及皮疹(35.6%對比5.9%) (André F, Ciruelos E, Rubovszky G等人, SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019年5月16日; 380(20):1929-1940)。此外，高血糖症及皮疹為導致阿培利司中止之最頻繁AE。歸因於AE而中止阿培利司及安慰劑之參與者百分比分別為25.0%及4.2% (Andre等人2019)。Several PI3K-targeted agents have been tested in patients with breast cancer. In a randomized phase 3 study (SOLAR-1; NCT02437318), the combination of the PI3Kα-specific inhibitor alpelisib and fulvestrant prolonged progression-free survival to 11.0 months compared with 5.7 months with fulvestrant alone, leading to FDA approval of the combination of alpelisib and fulvestrant for the treatment of patients with HR+/HER2- PIK3CA-mutant advanced or metastatic breast cancer. Although this approval represents a major advance in the treatment of PIK3CA-mutant breast cancer, alpelisib and other investigational PI3Kα inhibitors are roughly equally effective against wild-type (WT) and mutant PI3Kα. Therefore, the efficacy of these inhibitors may be limited by on-target WT PI3Kα-mediated toxicities, including dose-limiting hyperglycemia and skin and GI toxicities, which to some extent limit the broad clinical utility of PI3Kα inhibitors. For example, in the SOLAR-1 trial, adverse events that occurred in at least 35% of participants in the apelisib/fulvestrant or placebo/fulvestrant groups included hyperglycemia (63.7% vs. 9.8%), diarrhea (57.7% vs. 15.7%), nausea (44.7% vs. 22.3%), decreased appetite (35.6% vs. 10.5%), and rash (35.6% vs. 5.9%), respectively (André F, Ciruelos E, Rubovszky G, et al., SOLAR-1 Study Group. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019 May 16;380(20):1929-1940). In addition, hyperglycemia and rash were the most frequent AEs leading to discontinuation of apelisib. The percentage of participants who discontinued apellis and placebo due to AEs were 25.0% and 4.2%, respectively (Andre et al. 2019).
需要具有改良之治療指數之PI3Kα抑制劑，及包括此類PI3Kα抑制劑之組合療法，用於治療與突變PI3K相關之疾病，包括PIK3CA突變型癌症。亦需要克服對經批准之療法之抗性的PI3Kα抑制劑及組合療法。亦需要劑量及給藥方案以達成有效疾病治療，使患者順應性、便利性及耐受性最大化，同時限制劑量中斷及中止，且使不良事件(諸如高血糖症、腹瀉、噁心、食慾減退及皮疹)之風險最小化。亦需要具有有利的物理穩定性、化學穩定性、溶解性或藥物動力學特性的PI3Kα抑制劑之固體形式。There is a need for PI3Kα inhibitors with improved therapeutic indexes, and combination therapies including such PI3Kα inhibitors, for the treatment of diseases associated with mutant PI3K, including PIK3CA mutant cancers. There is also a need for PI3Kα inhibitors and combination therapies that overcome resistance to approved therapies. There is also a need for dosages and dosing regimens to achieve effective disease treatment, maximize patient compliance, convenience, and tolerability, while limiting dose interruptions and discontinuations, and minimize the risk of adverse events such as hyperglycemia, diarrhea, nausea, anorexia, and rash. There is also a need for solid forms of PI3Kα inhibitors with favorable physical stability, chemical stability, solubility, or pharmacokinetic properties.
在一個態樣中，提供化合物A之固體形式。 In one embodiment, a solid form of Compound A is provided.
在另一態樣中，提供化合物A之醫藥學上可接受之鹽及其固體形式。 In another embodiment, a pharmaceutically acceptable salt of Compound A and its solid form are provided.
在另一態樣中，提供包括化合物A或其醫藥學上可接受之鹽之療法，用於治療諸如PIK3CA突變癌症之疾病。 In another embodiment, a therapy comprising Compound A or a pharmaceutically acceptable salt thereof is provided for treating diseases such as PIK3CA mutant cancers.
在另一態樣中，提供包括化合物A或其醫藥學上可接受之鹽之劑量及給藥方案，用於治療諸如PIK3CA突變癌症之疾病。In another aspect, dosages and dosing regimens comprising Compound A or a pharmaceutically acceptable salt thereof are provided for treating diseases such as PIK3CA mutant cancers.
相關申請案之交叉參考 Cross-references to related applications
本申請案主張以下各案之優先權：於2022年11月2日申請之美國臨時申請案63/421,716 (代理人案號30461_US_PRI)；於2022年11月9日申請之美國臨時申請案63/382,999 (代理人案號30461A_US_PRI)；於2022年11月10日申請之美國臨時申請案63/383,206 (代理人案號30461B_US_PRI)；及於2023年3月7日申請之美國臨時申請案63/488,875 (代理人案號30461C_US_PRI)；該等案中之各者之內容以全文引用之方式併入本文中。This application claims priority to U.S. Provisional Application No. 63/421,716 filed on November 2, 2022 (Attorney Docket No. 30461_US_PRI); U.S. Provisional Application No. 63/382,999 filed on November 9, 2022 (Attorney Docket No. 30461A_US_PRI); U.S. Provisional Application No. 63/383,206 filed on November 10, 2022 (Attorney Docket No. 30461B_US_PRI); and U.S. Provisional Application No. 63/488,875 filed on March 7, 2023 (Attorney Docket No. 30461C_US_PRI); the contents of each of which are incorporated herein by reference in their entirety.
化合物2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸(「化合物A」)係強效及突變選擇性PI3Kα H1047R抑制劑。 化合物A The compound 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid ("Compound A") is a potent and mutant-selective PI3Kα H1047R inhibitor. Compound A
在一個態樣中，本文提供化合物A之固體形式。 化合物 A 形式 A In one aspect, provided herein is a solid form of Compound A. Compound A Form A
在一個態樣中，提供結晶2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸形式A，亦稱為化合物A形式A。在一個實施例中，化合物A形式A之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.8° ± 0.2°、12.1° ± 0.2°、13.7° ± 0.2°、14.1° ± 0.2°、16.8° ± 0.2°、17.5° ± 0.2°、18.2° ± 0.2°、18.9° ± 0.2°、19.5° ± 0.2°、20.7° ± 0.2°、21.2° ± 0.2°及24.1° ± 0.2°。在另一實施例中，化合物A形式A之特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式A之特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式A之特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式A之特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。在另一實施例中，化合物A形式A之特徵在於，使用CuKa輻射在7.8° ± 0.2°、12.1° ± 0.2°、13.7° ± 0.2°、14.1° ± 0.2°、16.8° ± 0.2°、17.5° ± 0.2°、18.2° ± 0.2°、18.9° ± 0.2°、19.5° ± 0.2°、20.7° ± 0.2°、21.2° ± 0.2°及24.1° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。 化合物 A 形式 B In one embodiment, crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form A, also referred to as Compound A Form A, is provided. In one embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.8° ± 0.2°, 12.1° ± 0.2°, 13.7° ± 0.2°, 14.1° ± 0.2°, 16.8° ± 0.2°, 17.5° ± 0.2°, 18.2° ± 0.2°, 18.9° ± 0.2°, 19.5° ± 0.2°, 20.7° ± 0.2°, 21.2° ± 0.2°, and 24.1° ± 0.2° using CuKα radiation. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2° using CuKα radiation and at least one peak at a diffraction angle 2-θ selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2° and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1°±0.2° using CuKα radiation and at least two peaks at diffraction angles 2-θ selected from 14.1°±0.2°, 16.8°±0.2°, 18.9°±0.2°, and 20.7°±0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2°, and 20.7° ± 0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2°, and 20.7° ± 0.2°. In another embodiment, Compound A Form A is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.8° ± 0.2°, 12.1° ± 0.2°, 13.7° ± 0.2°, 14.1° ± 0.2°, 16.8° ± 0.2°, 17.5° ± 0.2°, 18.2° ± 0.2°, 18.9° ± 0.2°, 19.5° ± 0.2°, 20.7° ± 0.2°, 21.2° ± 0.2°, and 24.1° ± 0.2° using CuKa radiation. Compound A Form B
在另一態樣中，提供結晶2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸形式B，亦稱為化合物A形式B。在一個實施例中，化合物A形式B之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.0° ± 0.2°、9.7° ± 0.2°、11.9° ± 0.2°、14.9° ± 0.2°及17.4° ± 0.2°。在另一實施例中，化合物A形式B之特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式B之特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式B之特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式B之特徵在於，使用CuKa輻射在7.0° ± 0.2°、9.7° ± 0.2°、11.9° ± 0.2°、14.9° ± 0.2°及17.4° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。 化合物 A 形式 C In another aspect, crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form B is provided, also referred to as Compound A Form B. In one embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 7.0°±0.2°, 9.7°±0.2°, 11.9°±0.2°, 14.9°±0.2°, and 17.4°±0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2°, and 7.0° ± 0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least two peaks at a diffraction angle 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2°, and 7.0° ± 0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2°, and 7.0° ± 0.2°. In another embodiment, Compound A Form B is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2°, and 17.4° ± 0.2° using CuKa radiation. Compound A Form C
在另一態樣中，提供結晶2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸形式C，亦稱為化合物A形式C。在一個實施例中，化合物A形式C之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.4° ± 0.2°、8.5° ± 0.2°、10.6° ± 0.2°、13.4° ± 0.2°及15.7° ± 0.2°。在另一實施例中，化合物A形式C之特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式C之特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式C之特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在另一實施例中，化合物A形式C之特徵在於，使用CuKa輻射在7.4° ± 0.2°、8.5° ± 0.2°、10.6° ± 0.2°、13.4° ± 0.2°及15.7° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。In another aspect, crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid Form C is provided, also referred to as Compound A Form C. In one embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 13.4° ± 0.2° and at least one peak at a diffraction angle 2-θ selected from 8.5° ± 0.2°, 15.7° ± 0.2°, 10.6° ± 0.2°, and 7.4° ± 0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 13.4° ± 0.2° and at least two peaks at a diffraction angle 2-θ selected from 8.5° ± 0.2°, 15.7° ± 0.2°, 10.6° ± 0.2°, and 7.4° ± 0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 8.5°±0.2°, 15.7°±0.2°, 10.6°±0.2°, and 7.4°±0.2°. In another embodiment, Compound A Form C is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.4°±0.2°, 8.5°±0.2°, 10.6°±0.2°, 13.4°±0.2°, and 15.7°±0.2° using CuKa radiation.
在另一態樣中，本文提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之緩血酸胺鹽。化合物A之某些緩血酸胺鹽可具有有利的物理穩定性、化學穩定性、溶解性或藥物動力學特性。化合物A之某些緩血酸胺鹽可具有可加工性或其他製造優點。化合物A之某些緩血酸胺鹽在緩血酸胺鹽結晶後可增強化合物A之對掌性。 化合物 A 緩血酸胺鹽形式 A In another aspect, provided herein is a succinate salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain succinate salts of Compound A may have advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain succinate salts of Compound A may have processability or other manufacturing advantages. Certain succinate salts of Compound A may enhance the chirality of Compound A after crystallization of the succinate salt. Compound A succinate salt Form A
在另一態樣中，提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之結晶緩血酸胺鹽，稱為化合物A緩血酸胺鹽形式A。在一個實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.4° ± 0.2°、8.4° ± 0.2°、10.9° ± 0.2°、11.8° ± 0.2°、13.0° ± 0.2°、16.5° ± 0.2°、16.9° ± 0.2°、22.1° ± 0.2°、23.0° ± 0.2°及24.9° ± 0.2°。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，使用CuKa輻射在6.4° ± 0.2°、8.4° ± 0.2°、10.9° ± 0.2°、11.8° ± 0.2°、13.0° ± 0.2°、16.5° ± 0.2°、16.9° ± 0.2°、22.1° ± 0.2°、23.0° ± 0.2°及24.9° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。In another aspect, a crystalline sulphate amine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, referred to as Compound A sulphate amine salt Form A. In one embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.4° ± 0.2°, 8.4° ± 0.2°, 10.9° ± 0.2°, 11.8° ± 0.2°, 13.0° ± 0.2°, 16.5° ± 0.2°, 16.9° ± 0.2°, 22.1° ± 0.2°, 23.0° ± 0.2° and 24.9° ± 0.2°. In another embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°. In another embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°. In another embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°. In another embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 6.4°±0.2° using CuKa radiation and peaks at diffraction angles 2-θ of 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°. In another embodiment, Compound A sulphate amine salt Form A is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.4° ± 0.2°, 8.4° ± 0.2°, 10.9° ± 0.2°, 11.8° ± 0.2°, 13.0° ± 0.2°, 16.5° ± 0.2°, 16.9° ± 0.2°, 22.1° ± 0.2°, 23.0° ± 0.2°, and 24.9° ± 0.2° using CuKa radiation.
在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、158.7、151.7、149.7、136.3、134.7、132.9、129.3、127.4、125.2、121.7、117.0、115.5、115.2、110.4、64.1、63.2、45.3、22.6、20.3及11.6 ppm (分別± 0.2 ppm)。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、129.3、63.2、20.3及11.6 ppm (分別± 0.2 ppm)。在另一實施例中，化合物A緩血酸胺鹽形式A之特徵在於，包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、158.7、151.7、149.7、136.3、134.7、132.9、129.3、127.4、125.2、121.7、117.0、115.5、115.2、110.4、64.1、63.2、45.3、22.6、20.3及11.6 ppm (分別± 0.2 ppm)。 化合物 A 緩血酸胺鹽形式 C In another embodiment, Compound A sulphatide salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (each ± 0.2 ppm) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A sulphatide amine salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 179.0, 129.3, 63.2, 20.3 and 11.6 ppm (± 0.2 ppm each) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A sulphatide salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, and 11.6 ppm (± 0.2 ppm each). Compound A sulphatide salt Form C
在另一態樣中，提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之結晶緩血酸胺鹽，稱為化合物A緩血酸胺鹽形式C。在一個實施例中，化合物A緩血酸胺鹽形式C之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：10.6° ± 0.2°、13.2° ± 0.2°、14.5° ± 0.2°、15.9° ± 0.2°及17.4° ± 0.2°。在另一實施例中，化合物A緩血酸胺鹽形式C之特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式C之特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式C之特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在一個實施例中，化合物A緩血酸胺鹽形式C之特徵在於，使用CuKa輻射在10.6° ± 0.2°、13.2° ± 0.2°、14.5° ± 0.2°、15.9° ± 0.2°及17.4° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。 化合物 A 緩血酸胺鹽形式 D In another aspect, a crystalline sulphate salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, referred to as Compound A sulphate salt Form C. In one embodiment, Compound A sulphate salt Form C is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 10.6°±0.2°, 13.2°±0.2°, 14.5°±0.2°, 15.9°±0.2°, and 17.4°±0.2°. In another embodiment, Compound A sulphate amine salt Form C is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°. In another embodiment, Compound A sulphate amine salt Form C is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°. In another embodiment, Compound A sulphate amine salt Form C is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 15.9°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°. In one embodiment, Compound A sulphonic acid amine salt Form C is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2°, and 17.4° ± 0.2° using CuKa radiation. Compound A sulphonic acid amine salt Form D
在另一態樣中，提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之結晶緩血酸胺鹽，稱為化合物A緩血酸胺鹽形式D。在一個實施例中，化合物A緩血酸胺鹽形式D之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.3° ± 0.2°、11.1° ± 0.2°、12.6° ± 0.2°、17.1° ± 0.2°及18.9° ± 0.2°。在另一實施例中，化合物A緩血酸胺鹽形式D之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式D之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A緩血酸胺鹽形式D之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在一個實施例中，化合物A緩血酸胺鹽形式D之特徵在於，使用CuKa輻射在6.3° ± 0.2°、11.1° ± 0.2°、12.6° ± 0.2°、17.1° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。In another aspect, a crystalline sulphate amine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, referred to as Compound A sulphate amine salt Form D. In one embodiment, Compound A sulphate amine salt Form D is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.3°±0.2°, 11.1°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 18.9°±0.2°. In another embodiment, Compound A sulphate amine salt Form D is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°. In another embodiment, Compound A sulphonic acid amine salt Form D is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°. In another embodiment, Compound A sulphate amine salt Form D is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°. In one embodiment, Compound A sulphonate amine salt Form D is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2° and 18.9° ± 0.2° using CuKa radiation.
在另一態樣中，本文提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之特丁胺鹽。化合物A之某些特丁胺鹽可具有有利的物理穩定性、化學穩定性、溶解性或藥物動力學特性。化合物A之某些特丁胺鹽可具有可加工性或其他製造優點。 化合物 A 特丁胺鹽形式 A In another aspect, provided herein is the tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid. Certain tert-butylamine salts of Compound A may have advantageous physical stability, chemical stability, solubility, or pharmacokinetic properties. Certain tert-butylamine salts of Compound A may have processability or other manufacturing advantages. Compound A tert-butylamine salt Form A
在另一態樣中，提供2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之結晶特丁胺鹽，稱為化合物A特丁胺鹽形式A。在一個實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.5° ± 0.2°、10.5° ± 0.2°、11.1° ± 0.2°、15.2° ± 0.2°、15.9° ± 0.2°、17.6° ± 0.2°、18.0° ± 0.2°、19.3° ± 0.2°、21.5° ± 0.2°、22.2° ± 0.2°、22.7° ± 0.2°及26.3° ± 0.2°。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。在一個實施例中，化合物A特丁胺鹽形式A之特徵在於，使用CuKa輻射在66.5° ± 0.2°、10.5° ± 0.2°、11.1° ± 0.2°、15.2° ± 0.2°、15.9° ± 0.2°、17.6° ± 0.2°、18.0° ± 0.2°、19.3° ± 0.2°、21.5° ± 0.2°、22.2° ± 0.2°、22.7° ± 0.2°及26.3° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。In another aspect, a crystalline tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid is provided, referred to as Compound A tert-butylamine Salt Form A. In one embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the group consisting of 6.5° ± 0.2°, 10.5° ± 0.2°, 11.1° ± 0.2°, 15.2° ± 0.2°, 15.9° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, 19.3° ± 0.2°, 21.5° ± 0.2°, 22.2° ± 0.2°, 22.7° ± 0.2°, and 26.3° ± 0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1° ± 0.2° using CuKa radiation and at least two peaks at a diffraction angle 2-θ selected from 10.5° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2° and 19.3° ± 0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°. In another embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1° ± 0.2° using CuKa radiation and peaks at diffraction angles 2-θ of 10.5° ± 0.2°, 15.2° ± 0.2°, 18.0° ± 0.2°, and 19.3° ± 0.2°. In one embodiment, Compound A tert-butylamine salt Form A is characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 66.5° ± 0.2°, 10.5° ± 0.2°, 11.1° ± 0.2°, 15.2° ± 0.2°, 15.9° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, 19.3° ± 0.2°, 21.5° ± 0.2°, 22.2° ± 0.2°, 22.7° ± 0.2°, and 26.3° ± 0.2° using CuKa irradiation.
在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、174.8、159.8、151.7、149.5、134.0、132.6、130.7、130.3、129.0、128.1、123.1、122.4、119.4、116.8、115.9、112.3、53.0、47.5、27.4、23.3、21.3及11.3 ppm (分別± 0.2 ppm)。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、132.6、27.4、21.3及11.3 ppm (分別± 0.2 ppm)。在另一實施例中，化合物A特丁胺鹽形式A之特徵在於包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、174.8、159.8、151.7、149.5、134.0、132.6、130.7、130.3、129.0、128.1、123.1、122.4、119.4、116.8、115.9、112.3、53.0、47.5、27.4、23.3、21.3及11.3 ppm (分別± 0.2 ppm)。 治療用途 In another embodiment, Compound A tert-butylamine salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (each ± 0.2 ppm) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A tert-butylamine salt Form A is characterized by a13C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 177.4, 132.6, 27.4, 21.3 and 11.3 ppm (± 0.2 ppm each) referenced to glycine (external reference at 176.5 ppm). In another embodiment, Compound A tert-butylamine salt Form A is characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, and 11.3 ppm (± 0.2 ppm each). Therapeutic Uses
本文亦提供包括化合物A或其醫藥學上可接受之鹽的療法，其用於治療患有疾病之患者，該疾病包括PIK3CA突變癌症(諸如PIK3CA突變晚期或轉移性乳癌)或具有PIK3CA突變之其他實體腫瘤。化合物A或其醫藥學上可接受之鹽可以單藥療法使用或與一或多種額外治療劑組合使用。該等療法可為患者提供新的治療選項，且在一些患者中可提供優於已知療法之增強及/或出人意料的有益治療效果。 Also provided herein are treatments comprising Compound A or a pharmaceutically acceptable salt thereof for treating a patient with a disease including a PIK3CA mutant cancer (such as PIK3CA mutant advanced or metastatic breast cancer) or other solid tumors with a PIK3CA mutation. Compound A or a pharmaceutically acceptable salt thereof can be used as a monotherapy or in combination with one or more additional therapeutic agents. Such treatments can provide new treatment options for patients and can provide enhanced and/or unexpected beneficial therapeutic effects over known treatments in some patients.
癌症治療之功效可藉由常用於評估癌症治療之各種終點量測，包括(但不限於)腫瘤消退、腫瘤重量或尺寸縮小、進展時間、總存活期、無進展存活期、總反應率、反應持續時間、最佳總體反應、疾病控制率、臨床效益率、反應時間及生活品質。治療劑可在原發性腫瘤不縮小之情況下抑制轉移性擴散、可誘導原發性腫瘤縮小或可簡單地發揮腫瘤穩定作用。可視情況採用新穎方法以測定本發明之任何特定單藥療法或組合療法之功效，該等新穎方法包括例如量測血管生成及/或細胞週期活性之血漿或尿液標記物、血管生成及/或細胞週期活性之基於組織之生物標記物，及經由放射學成像量測反應。 The efficacy of cancer treatments can be measured by various endpoints commonly used to evaluate cancer treatments, including, but not limited to, tumor regression, reduction in tumor weight or size, time to progression, overall survival, progression-free survival, overall response rate, duration of response, best overall response, disease control rate, clinical efficacy rate, duration of response, and quality of life. Therapeutics may inhibit metastatic spread without shrinking the primary tumor, may induce shrinkage of the primary tumor, or may simply exert a tumor stabilizing effect. Novel methods may be employed, as appropriate, to determine the efficacy of any particular monotherapy or combination therapy of the invention, including, for example, measuring plasma or urine markers of angiogenesis and/or cell cycle activity, tissue-based biomarkers of angiogenesis and/or cell cycle activity, and measuring responses via radiological imaging.
在一個態樣中，提供一種治療患有與突變型磷酸肌醇3-激酶(PI3K)相關之疾病之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In one aspect, a method for treating a patient suffering from a disease associated with mutant phosphoinositide 3-kinase (PI3K) is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之一或多種治療劑。在一些實施例中，有效量之化合物A或其醫藥學上可接受之鹽與有效量之一或多種治療劑的組合可在PIK3CA突變癌症之治療中提供累加或協同作用。在一些實施例中，組合療法中治療劑中之一或多者(例如紫杉烷(taxane)，諸如太平洋紫杉醇)之有效量可少於化合物A或其醫藥學上可接受之鹽不與一或多種藥劑組合投與的情況下藥劑治療PIK3CA突變癌症之有效量。In another aspect, a method for treating a patient with a PIK3CA mutation cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of one or more therapeutic agents. In some embodiments, the combination of an effective amount of Compound A or a pharmaceutically acceptable salt thereof and an effective amount of one or more therapeutic agents can provide an additive or synergistic effect in the treatment of PIK3CA mutation cancer. In some embodiments, the effective amount of one or more of the therapeutic agents (e.g., taxanes, such as paclitaxel) in the combination therapy may be less than the effective amount of the agent for treating PIK3CA mutation cancer when Compound A or a pharmaceutically acceptable salt thereof is not administered in combination with one or more agents.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之：CDK4及6抑制劑或其醫藥學上可接受之鹽；SERD或其醫藥學上可接受之鹽；芳香酶抑制劑或其醫藥學上可接受之鹽；紫杉烷或其醫藥學上可接受之鹽；mTOR抑制劑或其醫藥學上可接受之鹽；酪胺酸激酶抑制劑或其醫藥學上可接受之鹽；鉑劑；蒽環黴素(anthracycline)或其醫藥學上可接受之鹽；免疫檢查點抑制劑或其醫藥學上可接受之鹽；抗雄激素或其醫藥學上可接受之鹽；抗HER2單株抗體；抗HER2抗體-藥物結合物；KRAS抑制劑或其醫藥學上可接受之鹽；MEK抑制劑或其醫藥學上可接受之鹽；ERK抑制劑或其醫藥學上可接受之鹽；拓樸異構酶抑制劑或其醫藥學上可接受之鹽；SERM或其醫藥學上可接受之鹽；或PARP抑制劑或其醫藥學上可接受之鹽；或其組合。In another embodiment, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline; cline) or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an antiandrogen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERD或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERD或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERD或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERD或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群(imlunestrant)。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of imlunestrant.
在另一態樣中，提供一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。In another embodiment, a method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之紫杉烷或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之紫杉烷或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之紫杉烷或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with PIK3CA mutant breast cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之紫杉烷或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之mTOR抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之mTOR抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之酪胺酸激酶抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之酪胺酸激酶抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之鉑劑。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a platinum agent.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之鉑劑。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of platinum.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之蒽環黴素或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之蒽環黴素或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之抗雄激素或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之抗雄激素或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之抗HER2單株抗體或抗HER2抗體-藥物結合物。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之抗HER2單株抗體或抗HER2抗體-藥物結合物。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之KRAS抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之KRAS抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之MEK抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之MEK抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之ERK抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之ERK抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之SERD或其醫藥學上可接受之鹽；及(ii)有效量之mTOR抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之SERD或其醫藥學上可接受之鹽；及(ii)有效量之mTOR抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERM或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERM or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之SERM或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a SERM or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之PARP抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之PARP抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之鉑劑；及(ii)有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及(i)有效量之鉑劑；及(ii)有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。In another aspect, a method for treating a patient suffering from a PIK3CA mutant cancer is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。 In another embodiment, a method for treating a patient with a PIK3CA mutant solid tumor is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供一種治療患有CLOVES症候群(先天性脂瘤性過度生長、血管畸形、表皮痣、脊柱側凸/骨骼及脊髓症候群)或PIK3CA相關之過度生長症候群(PROS)之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽。 In another embodiment, a method for treating a patient suffering from CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal cord syndrome) or PIK3CA-related hypergrowth syndrome (PROS) is provided, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療與突變型磷酸肌醇3-激酶(PI3K)相關之疾病。 In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in treating diseases associated with mutant phosphoinositide 3-kinase (PI3K).
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in treating advanced or metastatic breast cancer with PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer previously treated with endocrine therapy.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：CDK4及6抑制劑或其醫藥學上可接受之鹽；SERD或其醫藥學上可接受之鹽；芳香酶抑制劑或其醫藥學上可接受之鹽；紫杉烷或其醫藥學上可接受之鹽；mTOR抑制劑或其醫藥學上可接受之鹽；酪胺酸激酶抑制劑或其醫藥學上可接受之鹽；鉑劑；蒽環黴素或其醫藥學上可接受之鹽；免疫檢查點抑制劑或其醫藥學上可接受之鹽；抗雄激素或其醫藥學上可接受之鹽；抗HER2單株抗體；抗HER2抗體-藥物結合物；KRAS抑制劑或其醫藥學上可接受之鹽；MEK抑制劑或其醫藥學上可接受之鹽；ERK抑制劑或其醫藥學上可接受之鹽；拓樸異構酶抑制劑或其醫藥學上可接受之鹽；SERM或其醫藥學上可接受之鹽；或PARP抑制劑或其醫藥學上可接受之鹽；或其組合；用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with the following simultaneously, separately or sequentially: CDK4 and 6 inhibitors or pharmaceutically acceptable salts thereof; SERD or pharmaceutically acceptable salts thereof; aromatase inhibitors or pharmaceutically acceptable salts thereof; taxanes or pharmaceutically acceptable salts thereof; mTOR inhibitors or pharmaceutically acceptable salts thereof; tyrosine kinase inhibitors or pharmaceutically acceptable salts thereof; platinum agents; anthracyclines or pharmaceutically acceptable salts thereof; immune checkpoint inhibitors or pharmaceutically acceptable salts thereof; A pharmaceutically acceptable salt thereof; an anti-androgen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof; for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for the treatment of PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for the treatment of advanced or metastatic breast cancer with PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating advanced or metastatic breast cancer with PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with Fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for treating advanced or metastatic breast cancer with a PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for treating advanced or metastatic breast cancer with a PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating advanced or metastatic breast cancer with PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與鉑劑同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a platinum agent simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與鉑劑同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a platinum agent simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with anthracycline or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with anthracycline or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant solid tumors.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof, for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof, for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof, for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERM或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與SERM或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與以下同時、分開或依序組合使用：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。In another embodiment, compound A or a pharmaceutically acceptable salt thereof is provided for use in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽，其用於治療CLOVES症候群(先天性脂瘤性過度生長、血管畸形、表皮痣、脊柱側凸/骨骼及脊髓症候群)或PIK3CA相關之過度生長症候群(PROS)。In another embodiment, Compound A or a pharmaceutically acceptable salt thereof is provided for use in treating CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal cord syndrome) or PIK3CA-related hypergrowth syndrome (PROS).
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療與突變型磷酸肌醇3-激酶(PI3K)相關之疾病用的藥劑。In another embodiment, there is provided a use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療PIK3CA突變癌症用的藥劑。In another embodiment, a use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑。In another embodiment, a use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑。In another embodiment, a use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑。In another embodiment, there is provided a use of Compound A or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑。In another embodiment, a use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑。In another embodiment, a use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與；SERD或其醫藥學上可接受之鹽；芳香酶抑制劑或其醫藥學上可接受之鹽；紫杉烷或其醫藥學上可接受之鹽；mTOR抑制劑或其醫藥學上可接受之鹽；酪胺酸激酶抑制劑或其醫藥學上可接受之鹽；鉑劑；蒽環黴素或其醫藥學上可接受之鹽；免疫檢查點抑制劑或其醫藥學上可接受之鹽；抗雄激素或其醫藥學上可接受之鹽；抗HER2單株抗體；抗HER2抗體-藥物結合物；KRAS抑制劑或其醫藥學上可接受之鹽；MEK抑制劑或其醫藥學上可接受之鹽；ERK抑制劑或其醫藥學上可接受之鹽；拓樸異構酶抑制劑或其醫藥學上可接受之鹽；SERM或其醫藥學上可接受之鹽；或PARP抑制劑或其醫藥學上可接受之鹽；或其組合。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline; mycin or a pharmaceutically acceptable salt thereof; immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; antiandrogen or a pharmaceutically acceptable salt thereof; anti-HER2 monoclonal antibody; anti-HER2 antibody-drug conjugate; KRAS inhibitor or a pharmaceutically acceptable salt thereof; MEK inhibitor or a pharmaceutically acceptable salt thereof; ERK inhibitor or a pharmaceutically acceptable salt thereof; topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; SERM or a pharmaceutically acceptable salt thereof; or PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating advanced or metastatic breast cancer with PIK3CA mutation, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating advanced or metastatic breast cancer with PIK3CA mutation, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERD or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與氟維司群同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with Fulvestrant simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與氟維司群同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with Fulvestrant simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與伊魯司群同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with ilustrant simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與伊魯司群同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with ilustrant simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating advanced or metastatic breast cancer with PIK3CA mutation, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating advanced or metastatic breast cancer with PIK3CA mutation, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating advanced or metastatic breast cancer with PIK3CA mutation, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an mTOR inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與鉑劑同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a platinum agent simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與鉑劑同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a platinum agent simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with anthracycline or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with anthracycline or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a KRAS inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an ERK inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERM或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與SERM或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a SERM or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與以下同時、分開或依序組合投與：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered simultaneously, separately or sequentially in combination with: (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其藥用鹽之用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中化合物A或其醫藥學上可接受之鹽將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。In another embodiment, the use of Compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein Compound A or a pharmaceutically acceptable salt thereof is administered in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof simultaneously, separately or sequentially.
在另一態樣中，提供化合物A或其醫藥學上可接受之鹽的用途，其用於製造供治療CLOVES症候群(先天性脂瘤性過度生長、血管畸形、表皮痣、脊柱側凸/骨骼及脊髓症候群)或PIK3CA相關之過度生長症候群(PROS)用的藥劑。 In another embodiment, the use of compound A or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for treating CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformation, epidermal nevus, scoliosis/skeletal and spinal cord syndrome) or PIK3CA-related hypergrowth syndrome (PROS).
在一個實施例中，PIK3CA突變癌症係選自急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、腎上腺皮質癌、愛滋病(aids)相關癌症、愛滋病相關淋巴瘤、肛門癌、星形細胞瘤、基底細胞癌、膽管癌、膀胱癌、骨癌、骨肉瘤、惡性纖維組織細胞瘤、腦瘤、乳癌、支氣管腫瘤、伯基特淋巴瘤(Burkitt lymphoma)、類癌瘤、原發灶不明癌、心(心臟)腫瘤、非典型畸胎樣/橫紋肌樣瘤、原發CNS淋巴瘤、子宮頸癌、膽管癌瘤、脊索瘤、慢性淋巴球性白血病(CLL)、慢性骨髓性白血病(CML)、大腸直腸癌、顱咽管瘤、皮膚T細胞淋巴瘤、蕈樣黴菌病、塞紮里症候群(Sézary syndrome)、乳腺管原位癌(DCIS)、胚胎腫瘤、神經管胚細胞瘤、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、輸卵管癌、膽囊癌、胃癌、胃腸類癌瘤、惡性胃腸道基質腫瘤(GIST)、生殖細胞腫瘤、妊娠期滋養細胞疾病、毛細胞白血病、頭頸癌、肝細胞癌、蘭格漢氏細胞(Langerhans cell)組織細胞增多症、霍奇金氏淋巴瘤(Hodgkin lymphoma)、胰島細胞瘤、胰臟神經內分泌腫瘤、卡波西肉瘤(Kaposi sarcoma)、腎臟癌、喉癌、白血病、肝癌、肺癌、淋巴瘤、雄性乳癌、眼內黑色素瘤、梅克爾細胞癌(Merkel cell carcinoma)、惡性間皮瘤、轉移癌、轉移性鱗狀頸癌、nut基因變化的中線束癌、口腔癌、多發性內分泌瘤症候群、多發性骨髓瘤/漿細胞贅瘤、骨髓發育不良症候群、骨髓發育不良贅瘤、骨髓增生性腫瘤、慢性骨髓增生性腫瘤、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、口腔癌、唇及口腔癌、口咽癌、骨惡性纖維組織細胞瘤、卵巢癌、胰臟癌、胰臟神經內分泌腫瘤(胰島細胞瘤)、乳頭狀瘤症、副神經節瘤、副鼻竇及鼻腔癌、副甲狀腺癌、陰莖癌、咽癌、嗜鉻細胞瘤、腦垂體腫瘤、漿細胞贅瘤、多發性骨髓瘤、胸膜肺母細胞瘤、原發中樞神經系統(CNS)淋巴瘤、原發腹膜癌、前列腺癌、直腸癌、復發癌、腎細胞(腎臟)癌症、視網膜母細胞瘤、橫紋肌肉瘤、唾液腺癌、肉瘤、幼年期血管腫瘤、皮膚癌、小細胞肺癌、小腸癌、軟組織肉瘤、皮膚鱗狀細胞癌、睪丸癌、口咽癌、下咽癌、胸腺瘤、胸腺癌、甲狀腺癌、氣管支氣管腫瘤、腎盂及輸尿管之移行細胞癌、尿道癌、子宮肉瘤、陰道癌、血管腫瘤、外陰癌及威爾姆斯腫瘤(Wilms tumor)。 In one embodiment, the PIK3CA mutant cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, AIDS-related cancer, AIDS-related lymphoma, anal cancer, astrocytoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, osteosarcoma, malignant fibroblastic tumor, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, lymphoma), carcinoid tumor, cancer of unknown primary site, cardiac tumor, atypical teratoid/rhabdoid tumor, primary CNS lymphoma, cervical cancer, bile duct carcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), colorectal cancer, cranio-pharyngioma, cutaneous T-cell lymphoma, mycosis fungoides, Sézary syndrome, ductal carcinoma in situ (DCIS), embryonal tumor, medulloblastoma, endometrial cancer, ependymoma, esophageal cancer, sensitive neuroblastoma, Ewing sarcoma, sarcoma), extracranial germ cell tumor, extragonadal germ cell tumor, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, malignant gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophotrophic cell disease, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Langerhans cell histiocytosis, Hodgkin lymphoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymphoma, male breast cancer, intraocular melanoma, Merkel cell carcinoma carcinoma), malignant mesothelioma, metastatic cancer, metastatic squamous cell carcinoma, midline cancer with nut gene mutation, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma/plasmacytic adenomas, myelodysplastic syndrome, myelodysplastic adenomas, myeloproliferative neoplasms, chronic myeloproliferative neoplasms, nasal and sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, malignant fibroblastic tumor of bone, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumor (islet cell tumor), papilloma, paraganglioma, paranasal sinus and nasal cancer, parathyroid cancer, penile cancer , pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell adenocarcinoma, multiple myeloma, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, recurrent cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, juvenile vascular Tumors, skin cancer, small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, testicular cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma, thymic carcinoma, thyroid cancer, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine sarcoma, vaginal cancer, hemangioma, vulvar cancer and Wilms tumor.
在一個實施例中，PIK3CA突變癌症為子宮內膜癌、乳癌、食道鱗狀細胞癌、子宮頸鱗狀細胞癌、子宮頸腺癌、大腸直腸腺癌、膀胱尿道上皮癌、神經膠質母細胞瘤、卵巢癌、非小細胞肺癌、食道胃癌、神經鞘腫瘤、頭頸部鱗狀細胞癌、黑色素瘤、食道胃腺癌、軟組織肉瘤、前列腺癌、纖維板層癌瘤、肝細胞癌、瀰漫性神經膠質瘤、大腸直腸癌、胰臟癌、膽管癌瘤、B細胞淋巴瘤、間皮瘤、腎上腺皮質癌、腎非透明細胞癌、腎透明細胞癌、生殖細胞癌、胸腺腫瘤、嗜鉻細胞瘤、混雜型神經上皮腫瘤、甲狀腺癌、白血病或包封型神經膠質瘤。 In one embodiment, the PIK3CA mutation cancer is endometrial cancer, breast cancer, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, bladder urothelial carcinoma, neuroglioblastoma, ovarian cancer, non-small cell lung cancer, esophageal gastric cancer, neural sheath tumor, head and neck squamous cell carcinoma, melanoma, esophageal gastric adenocarcinoma, soft tissue flesh Tumor, prostate cancer, lamina propria carcinoma, hepatocellular carcinoma, diffuse neuroglioma, colorectal cancer, pancreatic cancer, bile duct carcinoma, B-cell lymphoma, mesothelioma, adrenocortical carcinoma, non-clear cell carcinoma, clear cell carcinoma, germ cell carcinoma, thymic tumor, pheochromocytoma, mixed neuroepithelial tumor, thyroid carcinoma, leukemia or encapsulated neuroglioma.
在一個實施例中，PIK3CA突變癌症係乳癌、腦癌、前列腺癌、子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、大腸直腸癌、肺癌、卵巢癌、皮膚癌或頭頸癌。In one embodiment, the PIK3CA mutant cancer is breast cancer, brain cancer, prostate cancer, endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer or head and neck cancer.
在一個實施例中，PIK3CA突變癌症係乳癌、前列腺癌或腦癌。在一個實施例中，PIK3CA突變癌症為乳癌。在一個實施例中，PIK3CA突變癌症為前列腺癌。在一個實施例中，PIK3CA突變癌症為腦癌。 In one embodiment, the PIK3CA mutation cancer is breast cancer, prostate cancer, or brain cancer. In one embodiment, the PIK3CA mutation cancer is breast cancer. In one embodiment, the PIK3CA mutation cancer is prostate cancer. In one embodiment, the PIK3CA mutation cancer is brain cancer.
在一個實施例中，PIK3CA突變癌症係乳房贅瘤、甲狀腺贅瘤、卵巢贅瘤、非小細胞肺癌、子宮內膜贅瘤或胰臟贅瘤。在一個實施例中，PIK3CA突變癌症係乳房贅瘤。在一個實施例中，PIK3CA突變癌症係甲狀腺贅瘤。在一個實施例中，PIK3CA突變癌症係卵巢贅瘤。在一個實施例中，PIK3CA突變癌症係非小細胞肺癌。在一個實施例中，PIK3CA突變癌症係子宮內膜贅瘤。在一個實施例中，PIK3CA突變癌症係胰臟贅瘤。In one embodiment, the PIK3CA mutation cancer is a breast tumor, a thyroid tumor, an ovarian tumor, a non-small cell lung cancer, an endometrial tumor, or a pancreatic tumor. In one embodiment, the PIK3CA mutation cancer is a breast tumor. In one embodiment, the PIK3CA mutation cancer is a thyroid tumor. In one embodiment, the PIK3CA mutation cancer is an ovarian tumor. In one embodiment, the PIK3CA mutation cancer is a non-small cell lung cancer. In one embodiment, the PIK3CA mutation cancer is an endometrial tumor. In one embodiment, the PIK3CA mutation cancer is a pancreatic tumor.
在一個實施例中，PIK3CA突變晚期或轉移性乳癌係PIK3CA H1047突變型晚期或轉移性乳癌。在一個實施例中，PIK3CA突變晚期或轉移性乳癌係激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌。在一個實施例中，PIK3CA突變晚期或轉移性乳癌係雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌。在一個實施例中，PIK3CA突變晚期或轉移性乳癌係激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌。在一個實施例中，PIK3CA突變晚期或轉移性乳癌係雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌。 In one embodiment, PIK3CA mutation advanced or metastatic breast cancer is PIK3CA H1047 mutation advanced or metastatic breast cancer. In one embodiment, PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer. In one embodiment, PIK3CA mutation advanced or metastatic breast cancer is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer. In one embodiment, PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer. In one embodiment, the PIK3CA mutation advanced or metastatic breast cancer is estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
在一個實施例中，PIK3CA突變實體腫瘤係PIK3CA突變晚期實體腫瘤。在一個實施例中，PIK3CA突變晚期實體腫瘤係選自婦科癌症、頭頸癌及三陰性乳癌。在一個實施例中，PIK3CA突變晚期實體腫瘤為婦科癌症。在一個實施例中，PIK3CA突變晚期實體腫瘤係頭頸癌。在一個實施例中，PIK3CA突變晚期實體腫瘤係三陰性乳癌。 In one embodiment, the PIK3CA mutation solid tumor is a PIK3CA mutation advanced solid tumor. In one embodiment, the PIK3CA mutation advanced solid tumor is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer. In one embodiment, the PIK3CA mutation advanced solid tumor is a gynecological cancer. In one embodiment, the PIK3CA mutation advanced solid tumor is head and neck cancer. In one embodiment, the PIK3CA mutation advanced solid tumor is triple-negative breast cancer.
在一個實施例中，患者為雌性。 In one embodiment, the patient is female.
在一個實施例中，患者為停經後女性。 In one embodiment, the patient is a postmenopausal female.
在一個實施例中，患者患有I型糖尿病。在一個實施例中，患者患有II型糖尿病。 In one embodiment, the patient has type 1 diabetes. In one embodiment, the patient has type 2 diabetes.
在一個實施例中，患者先前未接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。In one embodiment, the patient has not been previously treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在一個實施例中，患者先前接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。In one embodiment, the patient has previously been treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
在一個實施例中，患者先前未接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。In one embodiment, the patient has not been previously treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在一個實施例中，患者先前接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。 In one embodiment, the patient has previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
在一個實施例中，患者已在進行單獨或與CDK4/6抑制劑組合之內分泌療法時或之後進展或復發。 劑量 In one embodiment , the patient has progressed or relapsed during or following endocrine therapy, alone or in combination with a CDK4/6 inhibitor.
化合物A或其醫藥學上可接受之鹽及一或多種額外治療劑及其各別醫藥學上可接受之鹽一般在寬劑量範圍內有效。應理解，實際上投與之化合物的量將由醫師根據相關情況，包括所治療之病況、所選投藥途徑、實際投與之一或多種化合物、個別患者之年齡、體重及反應，以及患者症狀之嚴重程度來確定。 Compound A or its pharmaceutically acceptable salt and one or more additional therapeutic agents and their respective pharmaceutically acceptable salts are generally effective within a wide dosage range. It should be understood that the actual amount of compound administered will be determined by the physician based on relevant circumstances, including the condition being treated, the selected route of administration, the actual administration of one or more compounds, the age, weight and response of the individual patient, and the severity of the patient's symptoms.
應理解，化合物A可以非鹽游離酸形式或其醫藥學上可接受之鹽形式投與；然而除非另外指示，否則化合物A或其醫藥學上可接受之鹽之投與量在本文中基於化合物A之非鹽游離酸形式之重量表示。 It should be understood that Compound A can be administered in a non-salt free acid form or in a pharmaceutically acceptable salt form; however, unless otherwise indicated, the amount of Compound A or its pharmaceutically acceptable salt administered is expressed herein based on the weight of the non-salt free acid form of Compound A.
在一個實施例中，化合物A或其藥用鹽以200 mg至2400 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以400 mg至2000 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以600 mg至1200 mg之總日劑量投與。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 200 mg to 2400 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 400 mg to 2000 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 600 mg to 1200 mg.
在一個實施例中，化合物A或其藥用鹽以200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以400 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以500 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以600 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以700 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以800 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以900 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1000 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1100 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1400 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1500 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1600 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1700 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1800 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以1900 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以2000 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以2100 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以2200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以2300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽以2400 mg之總日劑量投與。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 200 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 300 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 400 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 500 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 600 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 700 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 800 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 900 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1000 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1100 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1200 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1300 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1400 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1500 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1600 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1700 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1800 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1900 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2000 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2100 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2200 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2300 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2400 mg.
在一個實施例中，化合物A或其藥用鹽在28天週期內以200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以400 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以500 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以600 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以700 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以800 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以900 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1000 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1100 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1400 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1500 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1600 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1700 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1800 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1900 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以2000 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以2100 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以2200 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以2300 mg之總日劑量投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以2400 mg之總日劑量投與在28天週期內。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 200 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 300 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 400 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 500 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 600 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 700 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 800 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 900 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1000 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1100 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1200 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1300 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1400 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1500 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1600 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1700 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1800 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 1900 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2000 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2100 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2200 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2300 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a total daily dose of 2400 mg in a 28-day cycle.
在一個實施例中，化合物A或其藥用鹽以100 mg至1200 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以200 mg至1000 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以300 mg至600 mg之劑量一天兩次投與。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 100 mg to 1200 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg to 1000 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 300 mg to 600 mg.
在一個實施例中，化合物A或其藥用鹽以100 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以150 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以200 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以250 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以300 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以350 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以400 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以450 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以500 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以550 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以600 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以650 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以700 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以750 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以800 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以850 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以900 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以950 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以1000 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以1050 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以1100 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以1150 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽以1200 mg之劑量一天兩次投與。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 100 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 150 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 250 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 300 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 350 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 400 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 450 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 500 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 550 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 600 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 650 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 700 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 750 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 800 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 850 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 900 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 950 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1000 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1050 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1100 mg. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of 1150 mg twice a day. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered at a dose of 1200 mg twice a day.
在一個實施例中，化合物A或其藥用鹽在28天週期內以100 mg至1200 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以200 mg至1000 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以100 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以200 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以150 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以200 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以250 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以300 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以350 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以400 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以450 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以500 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以550 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以600 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以650 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以700 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以750 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以800 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以850 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以900 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以950 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1000 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1050 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1100 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1150 mg之劑量一天兩次投與。在一個實施例中，化合物A或其藥用鹽在28天週期內以1200 mg之劑量一天兩次投與在28天週期內。In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 100 mg to 1200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg to 1000 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 100 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 150 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 250 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 300 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 350 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 400 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 450 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 500 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 550 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 600 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 650 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 700 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 750 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 800 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 850 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 900 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 950 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1000 mg over a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1050 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1100 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1150 mg in a 28-day cycle. In one embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1200 mg in a 28-day cycle.
在一較佳實施例中，化合物A或其藥用鹽在28天週期內以200 mg之劑量一天兩次投與。在另一較佳實施例中，化合物A或其藥用鹽在28天週期內以400 mg之劑量一天兩次投與。在另一較佳實施例中，化合物A或其藥用鹽在28天週期內以600 mg之劑量一天兩次投與。在另一較佳實施例中，化合物A或其藥用鹽在28天週期內以800 mg之劑量一天兩次投與。在另一較佳實施例中，化合物A或其藥用鹽在28天週期內以1000 mg之劑量一天兩次投與。In a preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 200 mg over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 400 mg over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 600 mg over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 800 mg over a 28-day cycle. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered twice a day at a dose of 1000 mg over a 28-day cycle.
在一較佳實施例中，化合物A或其藥用鹽以200 mg至800 mg，更佳地300 mg至600 mg之總日劑量投與。在另一較佳實施例中，化合物A或其藥用鹽以300 mg一天兩次、300 mg一天一次或600 mg一天一次之劑量投與。在另一較佳實施例中，化合物A或其藥用鹽以300 mg之劑量一天兩次投與。在另一較佳實施例中，化合物A或其藥用鹽以300 mg之劑量一天一次投與。在另一較佳實施例中，化合物A或其藥用鹽以600 mg之劑量一天一次投與。 醫藥組合物 In a preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a total daily dose of 200 mg to 800 mg, more preferably 300 mg to 600 mg. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a dose of 300 mg twice a day, 300 mg once a day, or 600 mg once a day. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a dose of 300 mg twice a day. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a dose of 300 mg once a day. In another preferred embodiment, Compound A or a pharmaceutically acceptable salt thereof is administered in a dose of 600 mg once a day. Pharmaceutical Compositions
化合物A或其藥用鹽可以諸如錠劑、膠囊(其各者包括持續釋放或定時釋放調配物)、丸劑、散劑、顆粒劑、酏劑、酊劑、懸浮液、糖漿及乳液之形式調配用於經口投與。化合物A或其藥用鹽亦可調配用於靜脈內(推注或輸注)、腹膜內、局部、皮下、肌肉內或經皮(例如貼片)投與，均使用醫藥領域中一般技術者所熟知之形式。 Compound A or its pharmaceutically acceptable salt can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. Compound A or its pharmaceutically acceptable salt can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical field.
化合物A或其藥用鹽或其醫藥組合物可藉由任何方便的投藥途徑，無論全身性/周邊亦或局部(亦即，在所需作用之部位處)向個體投與。 Compound A or its pharmaceutically acceptable salt or its pharmaceutical composition can be administered to a subject by any convenient route of administration, whether systemically/peripherally or locally (i.e., at the site of desired action).
投與途徑包括(但不限於)經口(例如，藉由攝取)；經頰；舌下；經皮(包括例如藉由貼片、膏藥等)；經黏膜(包括例如藉由貼片、膏藥等)；鼻內(例如，藉由經鼻噴霧)；經眼(例如，藉由滴眼劑)；經肺(例如，藉由使用，例如經由氣霧劑，例如經由口腔或鼻之吸入或吹入療法)；經直腸(例如，藉由栓劑或灌腸)；經陰道(例如，藉由子宮托)；非經腸，例如藉由注射，包括皮下、皮內、肌肉內、靜脈內、動脈內、心內、鞘內、脊柱內、囊內、囊下、眶內、腹膜內、氣管內、表皮下、關節內、蛛膜下及胸骨內；藉由例如皮下或肌肉內植入儲槽或儲集囊。 合成方法 Administration routes include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patch, plaster, etc.); transmucosal (including, for example, by patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by use, for example, by aerosol, such as inhalation or insufflation through the mouth or nose); Methods of administration: The invention can be administered intraperitoneally, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or pouch, for example, subcutaneous or intramuscular.
化合物A可使用下文所描述之方法以及有機合成化學技術中已知之合成方法或熟習此項技術者所瞭解之其變化形式合成。較佳方法包括但不限於以下所描述之彼等方法。化合物A可根據通用流程1及2中所概述之步驟合成。起始材料係可商購的或藉由所報導文獻中之已知程序或如下文所說明來製得。 流程1 Compound A can be synthesized using the methods described below and synthetic methods known in the art of organic synthetic chemistry or variations thereof known to those skilled in the art. Preferred methods include but are not limited to those described below. Compound A can be synthesized according to the steps outlined in General Schemes 1 and 2. The starting materials are commercially available or prepared by known procedures reported in the literature or as described below. Scheme 1
流程1描繪化合物A之例示性製備。經取代之酚(1)進行醯化，可得到酯(2)。酯(2)可在路易斯酸(Lewis acid) (例如AlCl 3)或布朗斯特酸(Brønsted acid) (例如三氟甲磺酸)條件下經歷重排，得到羥基芳基酮(3)。芳基醛與羥基芳基酮(3)進行酸性縮合，可得到酮-烯烴(4)，其可環化得到2-經取代之色烯-4-酮(5)。或者，在鹼(例如吡啶或雙(三甲基矽烷基)胺基鋰)存在下用芳基鹵化物將羥基芳基酮(3)烷化，接著在酸性條件(例如HCl)下環化，得到2-經取代之色烯-4-酮(5)。 Scheme 1 depicts an exemplary preparation of compound A. Acylation of substituted phenol (1) can provide ester (2). Ester (2) can undergo rearrangement under Lewis acid (e.g., AlCl 3 ) or Brønsted acid (e.g., trifluoromethanesulfonic acid) conditions to provide hydroxy aryl ketone (3). Acidic condensation of aryl aldehyde with hydroxy aryl ketone (3) can provide keto-olefin (4), which can be cyclized to provide 2-substituted chromen-4-one (5). Alternatively, alkylation of hydroxy aryl ketone (3) with aryl halide in the presence of base (e.g., pyridine or lithium bis(trimethylsilyl)amide) followed by cyclization under acidic conditions (e.g., HCl) can provide 2-substituted chromen-4-one (5).
可經由鈀催化將苯基溴化物(5)醯化，產生醯基色烯-4-酮(6)。例示性鈀催化條件包括苯基溴化物(5)、約5-10莫耳% PdCl 2(Ph 3) 2及約1.2莫耳%三丁基(1-乙氧基乙烯基)錫烷，於約30-35當量二㗁烷中在95℃下持續約16小時；或苯基溴化物(5)、約1莫耳% Pd(OAc) 2、約2莫耳% 1,3-雙(二苯基膦基)丙烷、約5當量丁基乙烯基醚、約3當量三乙胺及約10體積乙二醇，在約100℃下持續約16小時。使用路易斯酸性脫水劑，諸如烷醇鈦(IV)將酮(6)與三級丁烷亞磺醯胺縮合，可得到酮亞胺(7)。可藉由硼氫化物試劑在過渡金屬催化劑(諸如氯化鈰(III))存在下實現亞磺醯亞胺(7)之不對稱還原，得到對掌性增濃之亞磺醯胺(8)。在酸性條件下移除亞磺醯基可用於將亞磺醯胺(8)轉化為苯甲胺(9)，該苯甲胺可在芬科斯坦(Finkelstein)或烏爾曼(Ullmann)類型條件下用芳基鹵化物(10)進行烷化，得到化合物A。 流程2 Phenyl bromide (5) can be acylated via palladium catalysis to produce acylchromen-4-one (6). Exemplary palladium catalytic conditions include phenyl bromide (5), about 5-10 mol% PdCl2 ( Ph3 ) 2 , and about 1.2 mol% tributyl(1-ethoxyvinyl)tinane in about 30-35 equivalents of dioxane at 95°C for about 16 hours; or phenyl bromide (5), about 1 mol% Pd(OAc) 2 , about 2 mol% 1,3-bis(diphenylphosphino)propane, about 5 equivalents of butyl vinyl ether, about 3 equivalents of triethylamine, and about 10 volumes of ethylene glycol at about 100°C for about 16 hours. Condensation of ketone (6) with tert-butanesulfenamide using a Lewis acidic dehydrating agent such as titanium(IV) alkoxide can provide ketimine (7). Asymmetric reduction of sulfenimine (7) can be achieved by borohydride reagents in the presence of transition metal catalysts such as titanium(III) chloride to provide chiral-enriched sulfenamide (8). Removal of the sulfenyl group under acidic conditions can be used to convert sulfenamide (8) to benzylamine (9), which can be alkylated with aryl halide (10) under Finkelstein or Ullmann type conditions to provide compound A. Scheme 2
流程2描繪化合物A之另一例示性製備。酮(6)可用諸如野依(Noyori)催化劑之對掌性催化劑還原成羥基化合物(11)。可用甲烷磺酸酐或甲烷磺醯氯將羥基轉化成離去基，得到甲磺酸鹽(12)。甲磺酸鹽(12)可用於使芳胺(13)烷化，得到化合物A。或者，可用諸如野依催化劑之對掌性催化劑將酮(6)還原成羥基化合物(14)。可藉由諸如2,4,6-三氯-1,3,5-三𠯤之氯化劑將羥基轉化為氯化物(15)。接著氯化物(15)可用於使芳胺(13)烷化，得到化合物A。 定義 Scheme 2 depicts another exemplary preparation of compound A. Ketone (6) can be reduced to hydroxy compound (11) using a chiral catalyst such as Noyori's catalyst. The hydroxy group can be converted to a leaving group using methanesulfonic anhydride or methanesulfonyl chloride to give mesylate (12). Mesylate (12) can be used to alkylate aromatic amine (13) to give compound A. Alternatively, ketone (6) can be reduced to hydroxy compound (14) using a chiral catalyst such as Noyori's catalyst. The hydroxy group can be converted to chloride (15) using a chlorinating agent such as 2,4,6-trichloro-1,3,5-trioxane. Chloride (15) can then be used to alkylate aromatic amine (13) to give compound A. Definition
「CDK4及6抑制劑」或替代地「CDK4/6抑制劑」係指抑制D型週期蛋白(例如，週期蛋白D3)及週期蛋白依賴型激酶(CDK4及6)蛋白複合物(例如，週期蛋白D:CDK4及6複合物)之活性的分子，且通常用以經由抑制激酶活性來阻斷細胞週期自G1至S期之過渡。在一些實施例中，CDK4及6抑制劑為哌柏西利(palbociclib)、瑞博西利(ribociclib)或阿貝西利(abemaciclib)，或其醫藥學上可接受之鹽。在一些實施例中，CDK4及6抑制劑為哌柏西利或其醫藥學上可接受之鹽。在一些實施例中，CDK4及6抑制劑為瑞博西利或其醫藥學上可接受之鹽。在一些實施例中，CDK4及6抑制劑為阿貝西利或其醫藥學上可接受之鹽。在一較佳實施例中，CDK4及6抑制劑為阿貝西利。 "CDK4 and 6 inhibitors" or alternatively "CDK4/6 inhibitors" refers to molecules that inhibit the activity of D-type cyclins (e.g., cyclin D3) and cyclin-dependent kinase (CDK4 and 6) protein complexes (e.g., cyclin D:CDK4 and 6 complexes), and are generally used to block the transition of the cell cycle from G1 to S phase by inhibiting kinase activity. In some embodiments, the CDK4 and 6 inhibitor is palbociclib, ribociclib, or abemaciclib, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is palbociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is ribociclib or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK4 and 6 inhibitor is abemaciclib or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the CDK4 and 6 inhibitor is abemaciclib.
哌柏西利[6-乙醯基-8-環戊基-5-甲基-2-{[5-(哌𠯤-1-基)吡啶-2-基]胺基}吡啶并[2,3,- d]嘧啶-7(8 H)-酮]經指示用於治療HR+、HER2-之晚期或轉移性乳癌：(i)與芳香酶抑制劑組合作為基於內分泌之初始療法用於停經後女性中或男性中，或(ii)與氟維司群組合用於在內分泌療法之後具有疾病進展之患者。 Palbociclib [6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperidin-1-yl)pyridin-2-yl]amino}pyrido[2,3,- d ]pyrimidin-7(8 H )-one] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer: (i) in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men, or (ii) in combination with fulvestrant for patients with disease progression following endocrine therapy.
哌柏西利係經口服用且可作為膠囊(125 mg、100 mg及75 mg)使用，推薦起始劑量的為125 mg，每天一次持續21天，隨後停藥治療7天。哌柏西利可製備為游離鹼或醫藥學上可接受之鹽，包括單酸及二酸加成鹽，諸如單羥乙磺酸鹽、羥乙磺酸鹽之多晶型形式或鹽酸鹽(參見例如WO 2003/062236、WO 2005/005426、WO 2008/032157、美國專利第6,936,612號；第7,208,489號；第7,345,171號；第7,456,168號；第7,781,583號；及第7,863,278號)。呈游離鹼形式之哌柏西利可為無水的或可含有不同量之水或一或多種溶劑(參見例如美國專利第10,723,730號)。 Palbociclib is taken orally and is available as capsules (125 mg, 100 mg, and 75 mg). The recommended starting dose is 125 mg once daily for 21 days, followed by a 7-day break. Palbociclib can be prepared as a free base or a pharmaceutically acceptable salt, including mono- and di-acid addition salts, such as monohydroxyethanesulfonate, polymorphic forms of the hydroxyethanesulfonate, or hydrochloride (see, e.g., WO 2003/062236, WO 2005/005426, WO 2008/032157, U.S. Patent Nos. 6,936,612; 7,208,489; 7,345,171; 7,456,168; 7,781,583; and 7,863,278). Palbociclib in free base form may be anhydrous or may contain varying amounts of water or one or more solvents (see, e.g., U.S. Patent No. 10,723,730).
瑞博西利[7-環戊基- N, N-二甲基-2-{[5-(哌𠯤-1-基)吡啶-2-基]胺基}-7H-吡咯并[2,3- d]嘧啶-6-甲醯胺]經指示用於治療HR+、HER2-之晚期或轉移性乳癌：(i)與芳香酶抑制劑組合作為基於內分泌之初始療法用於停經前/圍停經期或停經後女性中，或(ii)與氟維司群組合作為基於內分泌之初始療法或在進行內分泌療法後疾病進展之後用於絕經後女性中。 Ribociclib [7-cyclopentyl- N , N -dimethyl-2-{[5-(piperidin-1-yl)pyridin-2-yl]amino}-7H-pyrrolo[2,3- d ]pyrimidine-6-carboxamide] is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer: (i) in combination with an aromatase inhibitor as initial endocrine-based therapy in pre-/perimenopausal or postmenopausal women, or (ii) in combination with fulvestrant as initial endocrine-based therapy or after disease progression on endocrine therapy in postmenopausal women.
瑞博西利係經口服用且可作為錠劑(200 mg，等效於254.40 mg丁二酸瑞博西利)使用，推薦起始劑量為600 mg (3×200 mg錠劑)，每日一次持續服用21天，隨後停藥治療7天。瑞博西利可製備為游離鹼或醫藥學上可接受之鹽，諸如丁二酸瑞博西利(參見例如美國專利第9,868,739號；第9,193,732號)。 Ribociclib is taken orally and is available as tablets (200 mg, equivalent to 254.40 mg ribociclib succinate), with a recommended starting dose of 600 mg (3×200 mg tablets), taken once daily for 21 days, followed by a 7-day break. Ribociclib can be prepared as a free base or a pharmaceutically acceptable salt, such as ribociclib succinate (see, e.g., U.S. Patent Nos. 9,868,739; 9,193,732).
阿貝西利[5-(4-乙基-哌𠯤-l-基甲基)-吡啶-2-基]-[5-氟-4-(7-氟-3-異丙基-2-甲基-3H-苯并咪唑-5-基)-嘧啶-2-基]-胺，其鹽形式，包括鹽酸鹽及甲磺酸鹽，以及製備及使用該化合物之方法(包括用於治療癌症，尤其乳癌)係揭示於WO2010/075074中。 Abemaciclib [5-(4-ethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-amine, its salt forms, including hydrochloride and methanesulfonate, and methods of preparing and using the compound (including for the treatment of cancer, especially breast cancer) are disclosed in WO2010/075074.
阿貝西利經批准用於治療若干種乳癌適應症，包括(i)與內分泌療法(他莫昔芬(tamoxifen)或芳香酶抑制劑)組合，用於輔助治療具有高復發風險之患有HR+、HER2-淋巴結陽性之早期乳癌之成年患者；(ii)與芳香酶抑制劑組合作為基於內分泌之初始療法，用於治療患有HR+、HER2-之晚期或轉移性乳癌之停經後女性及男性；(iii)與氟維司群組合，用於治療在內分泌療法之後具有疾病進展的患有HR+、HER2-之晚期或轉移性乳癌之成年患者；以及(iv)作為單藥療法，用於在轉移性情形中治療在內分泌療法及先前化學療法之後具有疾病進展的患有HR+、HER2-之晚期或轉移性乳癌之成年患者。較佳地，如批准標籤上所描述投與阿貝西利。在一些較佳實施例中，阿貝西利或其醫藥學上可接受之鹽以50 mg至200 mg之劑量一天兩次投與。亦較佳地，阿貝西利或其醫藥學上可接受之鹽以100 mg至150 mg之劑量一天兩次投與。亦較佳地，阿貝西利或其醫藥學上可接受之鹽以150 mg之劑量一天兩次投與。亦較佳地，阿貝西利或其醫藥學上可接受之鹽在28天週期內以150 mg之劑量一天兩次投與。較佳地，阿貝西利係經口投與。較佳地，阿貝西利係藉由膠囊投與。亦較佳地，阿貝西利係藉由錠劑投與。 Abemaciclib is approved for the treatment of several breast cancer indications, including (i) in combination with endocrine therapy (tamoxifen or aromatase inhibitors) for the adjuvant treatment of adult patients with HR+, HER2- node-positive early breast cancer who are at high risk of recurrence; and (ii) in combination with aromatase inhibitors as initial endocrine-based therapy for the treatment of adult patients with HR+, HER2- advanced or (iii) in combination with fulvestrant for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy; and (iv) as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Preferably, abemaciclib is administered as described on the approved label. In some preferred embodiments, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg to 200 mg twice a day. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered in a dose of 100 mg to 150 mg twice a day. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg twice a day. Also preferably, abemaciclib or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg twice a day over a 28-day cycle. Preferably, abemaciclib is administered orally. Preferably, abemaciclib is administered by capsule. Also preferably, abemaciclib is administered by tablet.
選擇性雌激素受體降解劑(「SERD」)係指結合於雌激素受體(ER)且下調ER介導之轉錄活性的分子。在一些實施例中，SERD為氟維司群、伊魯司群、吉雷司群(giredestrant)、安森司群(amcenestrant)、瑞妥司群(rintodestrant)、AZD9833或LSZ102或其醫藥學上可接受之鹽。在一些實施例中，SERD為氟維司群或伊魯司群或其醫藥學上可接受之鹽。在一些實施例中，SERD為氟維司群。在一些實施例中，SERD為伊魯司群。 Selective estrogen receptor degraders ("SERDs") refer to molecules that bind to estrogen receptors (ERs) and downregulate ER-mediated transcriptional activity. In some embodiments, the SERD is fulvestrant, iludestrant, giredestrant, amcenestrant, rintodestrant, AZD9833, or LSZ102, or a pharmaceutically acceptable salt thereof. In some embodiments, the SERD is fulvestrant or iludestrant, or a pharmaceutically acceptable salt thereof. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is iludestrant.
氟維司群係經批准，作為單藥療法或作為與經批准之CDK4/6抑制劑之組合療法用於治療HR+轉移性乳癌的SERD。氟維司群亦經批准與特異性針對PIK3CA突變HR+HER2-晚期乳癌之阿培利司(alpelisib)組合。氟維司群調配為可注射劑(靜脈內(IV)或肌肉內(IM))。較佳地，如批准標籤上所描述投與氟維司群，例如，建議劑量為500 mg，在第1天、第15天、第29天呈兩個5 mL注射液經肌肉內緩慢(每次注射1-2分鐘)投與至臀部中，各臀一個，且此後每月一次。 Fulvestrant is a SERD approved for the treatment of HR+ metastatic breast cancer as a monotherapy or as a combination therapy with an approved CDK4/6 inhibitor. Fulvestrant is also approved in combination with alpelisib, which specifically targets PIK3CA mutant HR+HER2- advanced breast cancer. Fulvestrant is formulated as an injectable (intravenous (IV) or intramuscular (IM)). Preferably, fulvestrant is administered as described on the approved label, e.g., the recommended dose is 500 mg, administered slowly (1-2 minutes per injection) intramuscularly into one buttock on Days 1, 15, 29, and monthly thereafter as two 5 mL injections.
伊魯司群(5R)-5-[4-[2-[3-(氟甲基)氮雜環丁烷-1-基]乙氧基]苯基]-8-(三氟甲基)-5H-色烯并[4,3-c]喹啉-2-醇係一種研究性口服SERD。使用WO20/014435或US10,654,866中描述之合成步驟，此化合物可製備為游離鹼或其醫藥學上可接受之鹽。在1期研究中，伊魯司群單藥療法在患有經大量預處理之ER+ HER2-晚期乳癌之患者中具有良好的安全概況且展示令人鼓舞的抗腫瘤活性。伊魯司群仍然在伊魯司群之1b期劑量擴增中進行評估(作為單藥療法且與依維莫司(everolimus)、阿貝西利、阿培利司(alpelisib)或曲妥珠單抗(trastuzumab)組合)。另外，伊魯司群之關鍵3期研究正在進行中。較佳地，伊魯司群以之劑量投與200 mg至400 mg一天一次，更佳地伊魯司群以400 mg之劑量一天一次投與。較佳地，伊魯司群在28天週期內以200 mg至400 mg之劑量一天一次投與，更佳地伊魯司群在28天週期內以400 mg之劑量一天一次投與。較佳地，伊魯司群係經口投與。較佳地，伊魯司群係藉由膠囊投與。亦較佳地，伊魯司群係藉由錠劑投與。 Ilustarant (5R)-5-[4-[2-[3-(fluoromethyl)azepanobutan-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol is an investigational oral SERD. This compound can be prepared as a free base or a pharmaceutically acceptable salt thereof using the synthetic procedures described in WO20/014435 or US10,654,866. In a Phase 1 study, ilusstarant monotherapy had a favorable safety profile and demonstrated encouraging antitumor activity in patients with heavily pretreated ER+ HER2- advanced breast cancer. Iludestrant is still being evaluated in a Phase 1b dose expansion of Iludestrant (as monotherapy and in combination with everolimus, abemaciclib, alpelisib, or trastuzumab). In addition, a pivotal Phase 3 study of Iludestrant is ongoing. Preferably, Iludestrant is administered at a dose of 200 mg to 400 mg once a day, more preferably Iludestrant is administered at a dose of 400 mg once a day. Preferably, Iludestrant is administered at a dose of 200 mg to 400 mg once a day in a 28-day cycle, more preferably Iludestrant is administered at a dose of 400 mg once a day in a 28-day cycle. Preferably, ilustrant is administered orally. Preferably, ilustrant is administered by capsule. Also preferably, ilustrant is administered by tablet.
「芳香酶抑制劑」係指抑制引起雄激素(女性在腎上腺中產生)轉化成雌激素之芳香酶的分子。在一些實施例中，芳香酶抑制劑為阿那曲唑(anastrozole)、來曲唑(letrozole)或依西美坦(exemestane)或其醫藥學上可接受之鹽。在一些實施例中，芳香酶抑制劑為阿那曲唑。較佳地，阿那曲唑以1 mg口服劑量每天一次投與。在一些實施例中，芳香酶抑制劑為來曲唑。較佳地，來曲唑以2.5 mg口服劑量每天一次投與，或對於患有肝硬化或嚴重肝損傷之患者，以2.5 mg口服劑量每隔一天一次投與。在一些實施例中，芳香酶抑制劑為依西美坦。較佳地，依西美坦以25 mg口服劑量每天一次投與。 "Aromatase inhibitor" refers to a molecule that inhibits the aromatase enzyme that causes the conversion of androgens (produced in females in the adrenal glands) into estrogens. In some embodiments, the aromatase inhibitor is anastrozole, letrozole, or exemestane, or a pharmaceutically acceptable salt thereof. In some embodiments, the aromatase inhibitor is anastrozole. Preferably, anastrozole is administered as a 1 mg oral dose once daily. In some embodiments, the aromatase inhibitor is letrozole. Preferably, letrozole is administered as a 2.5 mg oral dose once daily, or for patients with cirrhosis or severe liver damage, as a 2.5 mg oral dose once every other day. In some embodiments, the aromatase inhibitor is exemestane. Preferably, exemestane is administered in a 25 mg oral dose once daily.
「紫杉烷」係指藉由使參與細胞分裂之微管蛋白穩定而發揮抗癌作用的二萜類分子。在一些實施例中，紫杉烷為太平洋紫杉醇或多西紫杉醇(docetaxel)或其醫藥學上可接受之鹽。在一些實施例中，紫杉烷為太平洋紫杉醇。太平洋紫杉醇為遏制微管動力學之紫杉烷，且經批准用於治療轉移性乳癌。太平洋紫杉醇調配成可注射劑(靜脈內(IV))。較佳地，如批准標籤上所描述投與太平洋紫杉醇，例如在第一個劑量週期之第8天、第15天及第22天注射80 mg/m 2，且接著在所有後續劑量週期之第1天、第8天、第15天及第22天注射。在第一個劑量週期以外，可視情況選用第22天劑量。 "Taxane" refers to a diterpenoid molecule that exerts an anticancer effect by stabilizing microtubules involved in cell division. In some embodiments, the taxane is paclitaxel or docetaxel, or a pharmaceutically acceptable salt thereof. In some embodiments, the taxane is paclitaxel. Paclitaxel is a taxane that inhibits microtubule dynamics and is approved for the treatment of metastatic breast cancer. Paclitaxel is formulated as an injectable (intravenous (IV)). Preferably, paclitaxel is administered as described on the approved label, e.g., 80 mg/ m2 on Days 8, 15, and 22 of the first dosing cycle, and then on Days 1, 8, 15, and 22 of all subsequent dosing cycles. Outside of the first dosing cycle, a 22-day dose may be used as appropriate.
「免疫檢查點抑制劑」係指抑制免疫檢查點蛋白質之功能之分子。在一些實施例中，免疫檢查點抑制劑為CTLA-4抑制劑、PD-1抑制劑或PD-L1抑制劑。在一些實施例中，CTLA-4抑制劑為伊匹單抗(ipilimumab)或曲美單抗(tremelimumab)。在一些實施例中，PD-1抑制劑為帕博利珠單抗(pembrolizumab)、納武利尤單抗(nivolumab)、信迪利單抗(sintilimab)、西米普利單抗(cemiplimab)或替雷利珠單抗(tislelizumab)。在一些實施例中，PD-L1抑制劑為阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)或度伐魯單抗(durvalumab)。 "Immune checkpoint inhibitors" refer to molecules that inhibit the function of immune checkpoint proteins. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor, a PD-1 inhibitor, or a PD-L1 inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In some embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplimab, or tislelizumab. In some embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.
「mTOR抑制劑」係指抑制哺乳動物雷帕黴素目標蛋白之分子。在一些實施例中，mTOR抑制劑為西羅莫司(sirolimus)、坦羅莫司(temsirolimus)、依維莫司(everolimus)或RMC-5552。在一些實施例中，mTOR抑制劑為西羅莫司。在一些實施例中，mTOR抑制劑為坦羅莫司。在一些實施例中，mTOR抑制劑為依維莫司。在一些實施例中，mTOR抑制劑為RMC-5552。 "mTOR inhibitor" refers to a molecule that inhibits the mammalian target protein of rapamycin. In some embodiments, the mTOR inhibitor is sirolimus, temsirolimus, everolimus, or RMC-5552. In some embodiments, the mTOR inhibitor is sirolimus. In some embodiments, the mTOR inhibitor is temsirolimus. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the mTOR inhibitor is RMC-5552.
「酪胺酸激酶抑制劑」係指抑制酪胺酸激酶之分子。在一些實施例中，酪胺酸激酶抑制劑為來那替尼(neratinib)或阿法替尼(afatinib)。在一些實施例中，酪胺酸激酶抑制劑為來那替尼。在一些實施例中，酪胺酸激酶抑制劑為阿法替尼。"Tyrosine kinase inhibitor" refers to a molecule that inhibits tyrosine kinase. In some embodiments, the tyrosine kinase inhibitor is neratinib or afatinib. In some embodiments, the tyrosine kinase inhibitor is neratinib. In some embodiments, the tyrosine kinase inhibitor is afatinib.
「鉑劑」係指順鉑(cisplatin)、卡鉑(carboplatin)或奧沙利鉑(oxaliplatin)。在一些實施例中，鉑劑為順鉑。在一些實施例中，鉑劑為卡鉑。在一些實施例中，鉑劑為奧沙利鉑。"Platinum" refers to cisplatin, carboplatin or oxaliplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the platinum agent is carboplatin. In some embodiments, the platinum agent is oxaliplatin.
「抗雄激素」係指抑制雄激素或雄激素調控之分子的分子。在一些實施例中，抗雄激素為阿比特龍(abiraterone)、恩雜魯胺(enzalutamide)、尼魯米特(nilutamide)或氟他胺(flutamide)。在一些實施例中，抗雄激素為阿比特龍。在一些實施例中，抗雄激素為恩雜魯胺。在一些實施例中，抗雄激素為尼魯米特。在一些實施例中，抗雄激素為氟他胺。"Antiandrogen" refers to a molecule that inhibits androgens or androgen-regulated molecules. In some embodiments, the antiandrogen is abiraterone, enzalutamide, nilutamide, or flutamide. In some embodiments, the antiandrogen is abiraterone. In some embodiments, the antiandrogen is enzalutamide. In some embodiments, the antiandrogen is nilutamide. In some embodiments, the antiandrogen is flutamide.
「抗HER2單株抗體」係指用於治療HER2陽性癌症之重組人類化抗HER2單株抗體。在一些實施例中，抗HER2單株抗體為曲妥珠單抗、馬戈妥昔單抗(margetuximab)或帕妥珠單抗(pertuzumab)。在一些實施例中，抗HER2單株抗體為曲妥珠單抗。在一些實施例中，抗HER2單株抗體為馬戈妥昔單抗。在一些實施例中，抗HER2單株抗體為帕妥珠單抗。"Anti-HER2 monoclonal antibody" refers to a recombinant humanized anti-HER2 monoclonal antibody used to treat HER2-positive cancer. In some embodiments, the anti-HER2 monoclonal antibody is trastuzumab, margetuximab, or pertuzumab. In some embodiments, the anti-HER2 monoclonal antibody is trastuzumab. In some embodiments, the anti-HER2 monoclonal antibody is margetuximab. In some embodiments, the anti-HER2 monoclonal antibody is pertuzumab.
「抗HER2抗體-藥物結合物」係指連接至生物活性有效負載或藥物之重組人類化HER2單株抗體，其中抗HER2抗體-藥物結合物用於治療HER2陽性癌症。在一些實施例中，抗HER2抗體-藥物結合物為德曲妥珠單抗(trastuzumab deruxtecan)。在一些實施例中，抗HER2抗體-藥物結合物為恩美曲妥珠單抗(trastuzumab emtansine)。"Anti-HER2 antibody-drug conjugate" refers to a recombinant humanized HER2 monoclonal antibody linked to a biologically active payload or drug, wherein the anti-HER2 antibody-drug conjugate is used to treat HER2-positive cancer. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab deruxtecan. In some embodiments, the anti-HER2 antibody-drug conjugate is trastuzumab emtansine.
「蒽環黴素」一般係指來自某些類型鏈黴菌屬細菌之一種類型抗贅生性抗生素。在一些實施例中，蒽環黴素為多柔比星(doxorubicin)、道諾黴素(daunorubicin)、表柔比星(epirubicin)或艾達黴素(idarubicin)。在一些實施例中，蒽環黴素為多柔比星。在一些實施例中，蒽環黴素為道諾黴素。在一些實施例中，蒽環黴素為表柔比星。在一些實施例中，蒽環黴素為艾達黴素。"Anthracycline" generally refers to a type of antimicrobial antibiotic from certain types of Streptomyces bacteria. In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, or idarubicin. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the anthracycline is daunorubicin. In some embodiments, the anthracycline is epirubicin. In some embodiments, the anthracycline is idarubicin.
「KRAS抑制劑」係指抑制「基爾斯滕大鼠肉瘤(Kirsten Rat Sarcoma)」蛋白之分子。在一些實施例中，KRAS抑制劑為索托拉西布(sotorasib)或阿達格拉西布(adagrasib) 在一些實施例中，KRAS抑制劑為索托拉西布。在一些實施例中，KRAS抑制劑為阿達格拉西布。"KRAS inhibitor" refers to a molecule that inhibits the "Kirsten Rat Sarcoma" protein. In some embodiments, the KRAS inhibitor is sotorasib or adagrasib. In some embodiments, the KRAS inhibitor is sotorasib. In some embodiments, the KRAS inhibitor is adagrasib.
「MEK抑制劑」係指抑制促分裂原活化蛋白激酶之分子。在一些實施例中，MEK抑制劑為曲美替尼(trametinib)。"MEK inhibitor" refers to a molecule that inhibits mitogen-activated protein kinase. In some embodiments, the MEK inhibitor is trametinib.
「ERK抑制劑」係指抑制胞外信號調控激酶之分子。"ERK inhibitor" refers to a molecule that inhibits extracellular signal-regulated kinase.
「拓樸異構酶抑制劑」係指抑制拓樸異構酶、諸如I型拓樸異構酶或II型拓樸異構酶之分子。在一些實施例中，拓樸異構酶抑制劑為依託泊苷。"Topoisomerase inhibitor" refers to a molecule that inhibits a topoisomerase, such as a type I topoisomerase or a type II topoisomerase. In some embodiments, the topoisomerase inhibitor is etoposide.
「SERM」係指阻斷雌激素附接至激素受體之選擇性雌激素受體調節劑。在一些實施例中，SERM為他莫昔芬或托瑞米芬(toremifene)。在一些實施例中，SERM為他莫昔芬。在一些實施例中，SERM為托瑞米芬。"SERM" refers to a selective estrogen receptor modulator that blocks estrogen from attaching to hormone receptors. In some embodiments, the SERM is tamoxifen or toremifene. In some embodiments, the SERM is tamoxifen. In some embodiments, the SERM is toremifene.
「PARP抑制劑」係指抑制聚ADP核糖聚合酶之分子。在一些實施例中，PARP抑制劑為奧拉帕尼(olaparib)或他拉唑帕尼(talazoparib)。在一些實施例中，PARP抑制劑為奧拉帕尼。在一些實施例中，PARP抑制劑為他拉唑帕尼。"PARP inhibitor" refers to a molecule that inhibits poly (ADP ribose) polymerase. In some embodiments, the PARP inhibitor is olaparib or talazoparib. In some embodiments, the PARP inhibitor is olaparib. In some embodiments, the PARP inhibitor is talazoparib.
如本文所使用，術語「治療(treating)」、「治療(to treat)」或「治療(treatment)」係指抑制、減緩、阻止、減輕、縮小、維持疾病穩定，或逆轉現有症狀、病症、病況或疾病之進展或嚴重性。 As used herein, the terms "treating," "to treat," or "treatment" refer to inhibiting, slowing down, arresting, alleviating, reducing, maintaining disease stability, or reversing the progression or severity of an existing symptom, disorder, condition, or disease.
如本文所使用，術語「患者」係指哺乳動物，較佳為人類。 As used herein, the term "patient" refers to a mammal, preferably a human.
如本文所使用，術語「癌症」及「癌性」係指或描述患者中通常特徵為不受調控之細胞增殖之生理病況。此定義中包括良性及惡性癌症。 As used herein, the terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is generally characterized by unregulated cell proliferation. Included within this definition are both benign and malignant cancers.
如本文所使用，術語「晚期」或「轉移性」意謂已擴散至身體之一或多個部分的癌症，該等部分並非原始癌組織部位。 As used herein, the term "advanced" or "metastatic" means cancer that has spread to one or more parts of the body other than the original cancer tissue site.
如本文所使用，術語「有效量」係指視情況與一或多種額外藥劑或其醫藥學上可接受之鹽組合，治療劑或其醫藥學上可接受之鹽(例如化合物A或其醫藥學上可接受之鹽)在接受診斷或治療之患者中提供有效反應的量或劑量。 As used herein, the term "effective amount" refers to the amount or dosage of a therapeutic agent or a pharmaceutically acceptable salt thereof (e.g., Compound A or a pharmaceutically acceptable salt thereof) that provides an effective response in a patient undergoing diagnosis or treatment, optionally in combination with one or more additional agents or a pharmaceutically acceptable salt thereof.
如本文所使用，患者之「有效反應」或患者對使用治療劑或其醫藥學上可接受之鹽治療的「反應」係指在治療劑或其醫藥學上可接受之鹽視情況與一或多種額外藥劑或其醫藥學上可接受之鹽組合投與後賦予患者的臨床或治療效益。 As used herein, an "effective response" of a patient or a patient's "response" to treatment with a therapeutic agent or a pharmaceutically acceptable salt thereof refers to the clinical or therapeutic benefit conferred upon the patient following administration of the therapeutic agent or a pharmaceutically acceptable salt thereof, in combination with one or more additional agents or pharmaceutically acceptable salts thereof, as appropriate.
如本文所使用，術語「與……組合」係指單獨、同時或以任何次序依序，諸如在單個週期或超過一個週期之標準療程期間以重複時間間隔投與治療劑或其醫藥學上可接受之鹽及一或多種額外治療劑或其醫藥學上可接受之鹽，使得一種藥劑可在其他藥劑或其任何組合投與之前、同時或之後投與。 As used herein, the term "in combination with" refers to administering a therapeutic agent or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents or pharmaceutically acceptable salts thereof separately, simultaneously or sequentially in any order, such as at repeated time intervals during a single cycle or more than one cycle of standard treatment, such that one agent may be administered before, simultaneously with or after the other agent or any combination thereof.
如本文所使用，「先前療法」係指先前投與或用於致力於治療癌症之治療(例如用治療癌症之藥物、手術或放射線預先治療)。在一些實施例中，患者先前已用內分泌療法治療癌症。 As used herein, "prior therapy" refers to a therapy previously administered or used in an effort to treat cancer (e.g., prior treatment with drugs, surgery, or radiation to treat cancer). In some embodiments, the patient has previously been treated with endocrine therapy for cancer.
如本文所使用，術語「緩血酸胺」可另外稱為參(羥基甲基)胺基甲烷或tris。 As used herein, the term "aminobenzylamine" may also be referred to as tris(hydroxymethyl)aminomethane or tris.
如本文所使用，術語「特丁胺」可另外稱為三級丁胺。 As used herein, the term "tert-butylamine" may also be referred to as tert-butylamine.
如本文所使用，術語「內分泌療法」係指用於治療癌症之激素療法。例示性內分泌療法包括他莫昔芬或其醫藥學上可接受之鹽及芳香酶抑制劑(例如阿那曲唑、來曲唑或依西美坦)。 例示性態樣 As used herein, the term "endocrine therapy" refers to hormone therapy used to treat cancer. Exemplary endocrine therapies include tamoxifen or a pharmaceutically acceptable salt thereof and aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane). Exemplary Aspects
在以下編號條項中闡述本發明之各種態樣。 Various aspects of the invention are described in the following numbered clauses.
條款1. 一種化合物，其為2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸；或其醫藥學上可接受之鹽。Clause 1. A compound which is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid; or a pharmaceutically acceptable salt thereof.
條款2. 一種化合物，其為2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸。Clause 2. A compound which is 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.
條款3. 一種化合物，其為結晶2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸。Clause 3. A compound which is crystalline 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.
條款4. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.8° ± 0.2°、12.1° ± 0.2°、13.7° ± 0.2°、14.1° ± 0.2°、16.8° ± 0.2°、17.5° ± 0.2°、18.2° ± 0.2°、18.9° ± 0.2°、19.5° ± 0.2°、20.7° ± 0.2°、21.2° ± 0.2°及24.1° ± 0.2°。Clause 4. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 7.8° ± 0.2°, 12.1° ± 0.2°, 13.7° ± 0.2°, 14.1° ± 0.2°, 16.8° ± 0.2°, 17.5° ± 0.2°, 18.2° ± 0.2°, 18.9° ± 0.2°, 19.5° ± 0.2°, 20.7° ± 0.2°, 21.2° ± 0.2° and 24.1° ± 0.2°.
條款5. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 5. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2° and 20.7° ± 0.2°.
條款6. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 6. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2° and 20.7° ± 0.2°.
條款7. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在選自14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 7. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2° and 20.7° ± 0.2°.
條款8. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在12.1° ± 0.2°之繞射角2-θ處具有峰以及在14.1° ± 0.2°、16.8° ± 0.2°、18.9° ± 0.2°及20.7° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 8. A compound according to any one of clauses 1 to 3, characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 12.1° ± 0.2° using CuKa radiation and peaks at diffraction angles 2-θ of 14.1° ± 0.2°, 16.8° ± 0.2°, 18.9° ± 0.2° and 20.7° ± 0.2°.
條款9. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在7.8° ± 0.2°、12.1° ± 0.2°、13.7° ± 0.2°、14.1° ± 0.2°、16.8° ± 0.2°、17.5° ± 0.2°、18.2° ± 0.2°、18.9° ± 0.2°、19.5° ± 0.2°、20.7° ± 0.2°、21.2° ± 0.2°及24.1° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 9. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.8° ± 0.2°, 12.1° ± 0.2°, 13.7° ± 0.2°, 14.1° ± 0.2°, 16.8° ± 0.2°, 17.5° ± 0.2°, 18.2° ± 0.2°, 18.9° ± 0.2°, 19.5° ± 0.2°, 20.7° ± 0.2°, 21.2° ± 0.2° and 24.1° ± 0.2° using CuKa radiation.
條款10. 條款1-3中任一項之化合物，其具有實質上如圖1中所示之X射線粉末繞射圖。Clause 10. A compound of any one of Clauses 1-3, which has an X-ray powder diffraction pattern substantially as shown in Figure 1.
條款11. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.0° ± 0.2°、9.7° ± 0.2°、11.9° ± 0.2°、14.9° ± 0.2°及17.4° ± 0.2°。Clause 11. A compound of any one of clauses 1-3, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2° and 17.4° ± 0.2°.
條款12. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 12. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2° and 7.0° ± 0.2°.
條款13. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 13. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2° and 7.0° ± 0.2°.
條款14. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在9.7° ± 0.2°之繞射角2-θ處具有峰以及在選自14.9° ± 0.2°、11.9° ± 0.2°、17.4° ± 0.2°及7.0° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 14. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 9.7° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 14.9° ± 0.2°, 11.9° ± 0.2°, 17.4° ± 0.2° and 7.0° ± 0.2°.
條款15. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在7.0° ± 0.2°、9.7° ± 0.2°、11.9° ± 0.2°、14.9° ± 0.2°及17.4° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 15. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.0° ± 0.2°, 9.7° ± 0.2°, 11.9° ± 0.2°, 14.9° ± 0.2° and 17.4° ± 0.2° using CuKa radiation.
條款16. 條款1-3中任一項之化合物，其具有實質上如圖2中所示之X射線粉末繞射圖。Clause 16. A compound of any one of Clauses 1-3, which has an X-ray powder diffraction pattern substantially as shown in Figure 2.
條款17. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：7.4° ± 0.2°、8.5° ± 0.2°、10.6° ± 0.2°、13.4° ± 0.2°及15.7° ± 0.2°。Clause 17. A compound of any one of clauses 1-3, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 7.4° ± 0.2°, 8.5° ± 0.2°, 10.6° ± 0.2°, 13.4° ± 0.2° and 15.7° ± 0.2°.
條款18. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 18. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4° ± 0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 8.5° ± 0.2°, 15.7° ± 0.2°, 10.6° ± 0.2° and 7.4° ± 0.2°.
條款19. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 19. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4° ± 0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 8.5° ± 0.2°, 15.7° ± 0.2°, 10.6° ± 0.2° and 7.4° ± 0.2°.
條款20. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在13.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.5° ± 0.2°、15.7° ± 0.2°、10.6° ± 0.2°及7.4° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 20. A compound according to any one of clauses 1 to 3, characterized in that it has an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 13.4° ± 0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 8.5° ± 0.2°, 15.7° ± 0.2°, 10.6° ± 0.2° and 7.4° ± 0.2°.
條款21. 條款1-3中任一項之化合物，其特徵在於，使用CuKa輻射在7.4° ± 0.2°、8.5° ± 0.2°、10.6° ± 0.2°、13.4° ± 0.2°及15.7° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 21. A compound according to any one of clauses 1 to 3, characterized by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 7.4° ± 0.2°, 8.5° ± 0.2°, 10.6° ± 0.2°, 13.4° ± 0.2° and 15.7° ± 0.2° using CuKa radiation.
條款22. 條款1-3中任一項之化合物，其具有實質上如圖3中所示之X射線粉末繞射圖。Clause 22. A compound of any one of Clauses 1-3, which has an X-ray powder diffraction pattern substantially as shown in Figure 3.
條款23. 一種2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之緩血酸胺鹽。Clause 23. A succinate salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.
條款24. 條款23之緩血酸胺鹽，其為結晶。Clause 24. The amine salt of sulphuric acid as defined in Clause 23, which is crystalline.
條款25. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.4° ± 0.2°、8.4° ± 0.2°、10.9° ± 0.2°、11.8° ± 0.2°、13.0° ± 0.2°、16.5° ± 0.2°、16.9° ± 0.2°、22.1° ± 0.2°、23.0° ± 0.2°及24.9° ± 0.2°。Clause 25. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 6.4° ± 0.2°, 8.4° ± 0.2°, 10.9° ± 0.2°, 11.8° ± 0.2°, 13.0° ± 0.2°, 16.5° ± 0.2°, 16.9° ± 0.2°, 22.1° ± 0.2°, 23.0° ± 0.2° and 24.9° ± 0.2°.
條款26. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Item 26. The amine salt of sulphuric acid of Item 23 or Item 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 6.4°±0.2° and at least one peak at a diffraction angle 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°.
條款27. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 27. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 6.4°±0.2° and at least two peaks at diffraction angles 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°.
條款28. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在選自8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 28. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 6.4°±0.2° and at least three peaks at diffraction angles 2-θ selected from 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°.
條款29. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.4° ± 0.2°之繞射角2-θ處具有峰以及在8.4° ± 0.2°、10.9° ± 0.2°、16.9° ± 0.2°及22.1° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 29. The amine salt of sulphuric acid of clause 23 or clause 24, characterised in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 6.4°±0.2° and peaks at diffraction angles 2-θ of 8.4°±0.2°, 10.9°±0.2°, 16.9°±0.2° and 22.1°±0.2°.
條款30. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.4° ± 0.2°、8.4° ± 0.2°、10.9° ± 0.2°、11.8° ± 0.2°、13.0° ± 0.2°、16.5° ± 0.2°、16.9° ± 0.2°、22.1° ± 0.2°、23.0° ± 0.2°及24.9° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 30. The amine salt of sulphuric acid of clause 23 or clause 24, characterised in that it has an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.4° ± 0.2°, 8.4° ± 0.2°, 10.9° ± 0.2°, 11.8° ± 0.2°, 13.0° ± 0.2°, 16.5° ± 0.2°, 16.9° ± 0.2°, 22.1° ± 0.2°, 23.0° ± 0.2° and 24.9° ± 0.2° using CuKa radiation.
條款31. 條款23或條款24之緩血酸胺鹽，其具有實質上如圖4中所示之X射線粉末繞射圖。Clause 31. The sulphonamide salt of Clause 23 or Clause 24, which has an X-ray powder diffraction pattern substantially as shown in Figure 4.
條款32. 條款23-31中任一項之緩血酸胺鹽，其特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、158.7、151.7、149.7、136.3、134.7、132.9、129.3、127.4、125.2、121.7、117.0、115.5、115.2、110.4、64.1、63.2、45.3、22.6、20.3及11.6 ppm (分別± 0.2 ppm)。 Clause 32. The amine salt of any of clauses 23-31, characterized in that it has a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3 and 11.6 ppm (each ± 0.2 ppm) referenced to glycine (external reference at 176.5 ppm).
條款33. 條款23-31中任一項之緩血酸胺鹽，其特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、129.3、63.2、20.3及11.6 ppm (分別± 0.2 ppm)。 Clause 33. The amine salt of any of clauses 23-31, characterized in that it has a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the following: 179.0, 129.3, 63.2, 20.3 and 11.6 ppm (± 0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).
條款34. 條款23-31中任一項之緩血酸胺鹽，其特徵在於，包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、129.3、63.2、20.3及11.6 ppm (分別± 0.2 ppm)。 Clause 34. The amine salt of any of clauses 23-31, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 129.3, 63.2, 20.3 and 11.6 ppm (± 0.2 ppm each).
條款35. 條款23-31中任一項之緩血酸胺鹽，其特徵在於，包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：179.0、158.7、151.7、149.7、136.3、134.7、132.9、129.3、127.4、125.2、121.7、117.0、115.5、115.2、110.4、64.1、63.2、45.3、22.6、20.3及11.6 ppm (分別± 0.2 ppm)。 Clause 35. The amine salt of any of clauses 23-31, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3 and 11.6 ppm (± 0.2 ppm each).
條款36. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：10.6° ± 0.2°、13.2° ± 0.2°、14.5° ± 0.2°、15.9° ± 0.2°及17.4° ± 0.2°。Clause 36. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2° and 17.4° ± 0.2°.
條款37. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 37. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 15.9°±0.2° and at least one peak at a diffraction angle 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°.
條款38. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 38. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 15.9°±0.2° and at least two peaks at diffraction angles 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°.
條款39. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在15.9° ± 0.2°之繞射角2-θ處具有峰以及在選自10.6° ± 0.2°、17.4° ± 0.2°、13.2° ± 0.2°及14.5° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 39. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 15.9°±0.2° and at least three peaks at diffraction angles 2-θ selected from 10.6°±0.2°, 17.4°±0.2°, 13.2°±0.2° and 14.5°±0.2°.
條款40. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在10.6° ± 0.2°、13.2° ± 0.2°、14.5° ± 0.2°、15.9° ± 0.2°及17.4° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 40. The amine salt of sulphuric acid of clause 23 or clause 24, characterised in that it has an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 10.6° ± 0.2°, 13.2° ± 0.2°, 14.5° ± 0.2°, 15.9° ± 0.2° and 17.4° ± 0.2° using CuKa radiation.
條款41. 條款23或條款24之緩血酸胺鹽，其具有實質上如圖5中所示之X射線粉末繞射圖。Clause 41. The sulphonamide salt of Clause 23 or Clause 24, which has an X-ray powder diffraction pattern substantially as shown in Figure 5.
條款42. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.3° ± 0.2°、11.1° ± 0.2°、12.6° ± 0.2°、17.1° ± 0.2°及18.9° ± 0.2°。Clause 42. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2° and 18.9° ± 0.2°.
條款43. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 43. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 11.1°±0.2° and at least one peak at a diffraction angle 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°.
條款44. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 44. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 11.1°±0.2° and at least two peaks at diffraction angles 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°.
條款45. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在11.1° ± 0.2°之繞射角2-θ處具有峰以及在選自12.6° ± 0.2°、17.1° ± 0.2°、6.3° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 45. The amine salt of sulphuric acid of Clause 23 or Clause 24, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 11.1°±0.2° and at least three peaks at diffraction angles 2-θ selected from 12.6°±0.2°, 17.1°±0.2°, 6.3°±0.2° and 18.9°±0.2°.
條款46. 條款23或條款24之緩血酸胺鹽，其特徵在於，使用CuKa輻射在6.3° ± 0.2°、11.1° ± 0.2°、12.6° ± 0.2°、17.1° ± 0.2°及18.9° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 46. The amine salt of sulphuric acid of clause 23 or clause 24, characterised in that it has an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 6.3° ± 0.2°, 11.1° ± 0.2°, 12.6° ± 0.2°, 17.1° ± 0.2° and 18.9° ± 0.2° using CuKa radiation.
條款47. 條款23或條款24之緩血酸胺鹽，其具有實質上如圖6中所示之X射線粉末繞射圖。Clause 47. The sulphonamide salt of Clause 23 or Clause 24, which has an X-ray powder diffraction pattern substantially as shown in Figure 6.
條款48. 一種2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸之特丁胺鹽。Clause 48. The tert-butylamine salt of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid.
條款49. 條款48之特丁胺鹽，其為結晶。Clause 49. The tert-butylamine salt of Clause 48, which is crystalline.
條款50. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在選自以下之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖：6.5° ± 0.2°、10.5° ± 0.2°、11.1° ± 0.2°、15.2° ± 0.2°、15.9° ± 0.2°、17.6° ± 0.2°、18.0° ± 0.2°、19.3° ± 0.2°、21.5° ± 0.2°、22.2° ± 0.2°、22.7° ± 0.2°及26.3° ± 0.2°。Clause 50. The tert-butylamine salt of clause 48 or clause 49, characterized in that it has an X-ray powder diffraction pattern using CuKa radiation having at least one peak at a diffraction angle 2-θ selected from the following: 6.5° ± 0.2°, 10.5° ± 0.2°, 11.1° ± 0.2°, 15.2° ± 0.2°, 15.9° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, 19.3° ± 0.2°, 21.5° ± 0.2°, 22.2° ± 0.2°, 22.7° ± 0.2° and 26.3° ± 0.2°.
條款51. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在11.1 ° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少一個峰的X射線粉末繞射圖。Clause 51. The tert-butylamine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least one peak at a diffraction angle 2-θ selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°.
條款52. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在11.1 ° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少兩個峰的X射線粉末繞射圖。Clause 52. The tert-butylamine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least two peaks at diffraction angles 2-θ selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°.
條款53. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在11.1 ° ± 0.2°之繞射角2-θ處具有峰以及在選自10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有至少三個峰的X射線粉末繞射圖。Clause 53. The tert-butylamine salt of clause 48 or clause 49, characterized by an X-ray powder diffraction pattern having a peak at a diffraction angle 2-θ of 11.1°±0.2° using CuKa radiation and at least three peaks at diffraction angles 2-θ selected from 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°.
條款54. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在11.1 ° ± 0.2°之繞射角2-θ處具有峰以及在10.5° ± 0.2°、15.2° ± 0.2°、18.0° ± 0.2°及19.3° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 54. The tert-butylamine salt of clause 48 or clause 49, characterised by an X-ray powder diffraction pattern using CuKa radiation having a peak at a diffraction angle 2-θ of 11.1°±0.2° and peaks at diffraction angles 2-θ of 10.5°±0.2°, 15.2°±0.2°, 18.0°±0.2° and 19.3°±0.2°.
條款55. 條款48或條款49之特丁胺鹽，其特徵在於，使用CuKa輻射在66.5° ± 0.2°、10.5° ± 0.2°、11.1° ± 0.2°、15.2° ± 0.2°、15.9° ± 0.2°、17.6° ± 0.2°、18.0° ± 0.2°、19.3° ± 0.2°、21.5° ± 0.2°、22.2° ± 0.2°、22.7° ± 0.2°及26.3° ± 0.2°之繞射角2-θ處具有峰的X射線粉末繞射圖。Clause 55. The tert-butylamine salt of clause 48 or clause 49, characterised by an X-ray powder diffraction pattern having peaks at diffraction angles 2-θ of 66.5° ± 0.2°, 10.5° ± 0.2°, 11.1° ± 0.2°, 15.2° ± 0.2°, 15.9° ± 0.2°, 17.6° ± 0.2°, 18.0° ± 0.2°, 19.3° ± 0.2°, 21.5° ± 0.2°, 22.2° ± 0.2°, 22.7° ± 0.2° and 26.3° ± 0.2° using CuKa irradiation.
條款56. 條款48或條款49之特丁胺鹽，其具有實質上如圖7中所示之X射線粉末繞射圖。Clause 56. The terbuthylamine salt of clause 48 or clause 49, which has an X-ray powder diffraction pattern substantially as shown in Figure 7.
條款57. 條款48-56中任一項之特丁胺鹽，其特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、174.8、159.8、151.7、149.5、134.0、132.6、130.7、130.3、129.0、128.1、123.1、122.4、119.4、116.8、115.9、112.3、53.0、47.5、27.4、23.3、21.3及11.3 ppm (分別± 0.2 ppm)。 Clause 57. The tert-butylamine salt of any of clauses 48-56, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the group consisting of 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3 and 11.3 ppm (each ± 0.2 ppm).
條款58. 條款48-56中任一項之特丁胺鹽，其特徵在於，包含至少一個選自以下的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、132.6、27.4、21.3及11.3 ppm (分別± 0.2 ppm)。 Clause 58. The tert-butylamine salt of any of clauses 48-56, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising at least one peak selected from the following: 177.4, 132.6, 27.4, 21.3 and 11.3 ppm (± 0.2 ppm each) referenced to glycine (external reference at 176.5 ppm).
條款59. 條款48-56中任一項之特丁胺鹽，其特徵在於，包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、132.6、27.4、21.3及11.3 ppm (分別± 0.2 ppm)。 Clause 59. The tert-butylamine salt of any of clauses 48-56, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 177.4, 132.6, 27.4, 21.3 and 11.3 ppm (± 0.2 ppm each).
條款60. 條款48-56中任一項之特丁胺鹽，其特徵在於，包含在以下處的以甘胺酸為參考(176.5 ppm處之外部參考)之峰的 13C固態NMR (100.6 MHz)光譜：177.4、174.8、159.8、151.7、149.5、134.0、132.6、130.7、130.3、129.0、128.1、123.1、122.4、119.4、116.8、115.9、112.3、53.0、47.5、27.4、23.3、21.3及11.3 ppm (分別± 0.2 ppm)。 Clause 60. The tert-butylamine salt of any of clauses 48-56, characterized by a 13 C solid state NMR (100.6 MHz) spectrum comprising peaks referenced to glycine (external reference at 176.5 ppm) at: 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3 and 11.3 ppm (± 0.2 ppm each).
條款61. 一種醫藥組合物，其包含條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽或條款48-60中任一項之特丁胺鹽，及醫藥學上可接受之載劑。Clause 61. A pharmaceutical composition comprising the compound of any one of Clauses 1 to 22, the sedative amine salt of any one of Clauses 23 to 47 or the erbumin salt of any one of Clauses 48 to 60, and a pharmaceutically acceptable carrier.
條款62. 一種抑制磷酸肌醇3-激酶(PI3K)之方法，其包含向有需要之患者投與治療有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 62. A method of inhibiting phosphoinositide 3-kinase (PI3K), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款63. 一種治療患有與突變型磷酸肌醇3-激酶(PI3K)相關之疾病之患者的方法，其包含向該患者投與治療有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 63. A method for treating a patient suffering from a disease associated with mutant phosphoinositide 3-kinase (PI3K), comprising administering to the patient a therapeutically effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款64. 條款62或條款63之方法，其中該PI3K為PI3Kα。Clause 64. The method of clause 62 or clause 63, wherein the PI3K is PI3Kα.
條款65. 條款62-64中任一項之方法，其中該PI3K具有H1047R突變。Clause 65. The method of any one of clauses 62-64, wherein the PI3K has a H1047R mutation.
條款66. 條款63-65中任一項之方法，其中該疾病為癌症。Clause 66. The method of any of clauses 63-65, wherein the disease is cancer.
條款67. 條款66之方法，其中該癌症為子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、大腸直腸癌、肺癌、卵巢癌、皮膚癌、頭頸癌、乳癌、腦癌或前列腺癌。Clause 67. The method of Clause 66, wherein the cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
條款68. 條款66之方法，其中該癌症為乳癌。Clause 68. The method of clause 66, wherein the cancer is breast cancer.
條款69. 條款66之方法，其中該癌症為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)晚期或轉移性乳癌。Clause 69. The method of Clause 66, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.
條款70. 條款63-65中任一項之方法，其中該疾病為CLOVES症候群(先天性脂瘤性過度生長、血管畸形、表皮痣、脊柱側凸/骨骼及脊髓症候群)或PIK3CA相關之過度生長症候群(PROS)。Clause 70. The method of any of clauses 63-65, wherein the disease is CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal cord syndrome) or PIK3CA-related hypergrowth syndrome (PROS).
條款71. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 71. A method of treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款72. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 72. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款73. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 73. A method for treating a patient suffering from PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款74. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物。Clause 74. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61.
條款75. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之：CDK4及6抑制劑或其醫藥學上可接受之鹽；SERD或其醫藥學上可接受之鹽；芳香酶抑制劑或其醫藥學上可接受之鹽；紫杉烷或其醫藥學上可接受之鹽；mTOR抑制劑或其醫藥學上可接受之鹽；酪胺酸激酶抑制劑或其醫藥學上可接受之鹽；鉑劑；蒽環黴素或其醫藥學上可接受之鹽；免疫檢查點抑制劑或其醫藥學上可接受之鹽；抗雄激素或其醫藥學上可接受之鹽；抗HER2單株抗體；抗HER2抗體-藥物結合物；KRAS抑制劑或其醫藥學上可接受之鹽；MEK抑制劑或其醫藥學上可接受之鹽；ERK抑制劑或其醫藥學上可接受之鹽；拓樸異構酶抑制劑或其醫藥學上可接受之鹽；SERM或其醫藥學上可接受之鹽；或PARP抑制劑或其醫藥學上可接受之鹽；或其任何組合。Clause 75. A method for treating a patient with a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof. a pharmaceutically acceptable salt thereof; a platinum agent; anthracycline or a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an antiandrogen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or any combination thereof.
條款76. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。Clause 76. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款77. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。Clause 77. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款78. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。Clause 78. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款79. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽。Clause 79. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款80. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERD或其醫藥學上可接受之鹽。Clause 80. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款81. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERD或其醫藥學上可接受之鹽。Clause 81. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款82. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERD或其醫藥學上可接受之鹽。Clause 82. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款83. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERD或其醫藥學上可接受之鹽。Clause 83. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款84. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。Clause 84. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款85. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。Clause 85. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款86. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。Clause 86. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款87. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之SERD或其醫藥學上可接受之鹽。Clause 87. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of a SERD or a pharmaceutically acceptable salt thereof.
條款88. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 88. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款89. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 89. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbium salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款90. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 90. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款91. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 91. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbium salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款92. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之紫杉烷或其醫藥學上可接受之鹽。Clause 92. A method for treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
條款93. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之紫杉烷或其醫藥學上可接受之鹽。Clause 93. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
條款94. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之紫杉烷或其醫藥學上可接受之鹽。Clause 94. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
條款95. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之紫杉烷或其醫藥學上可接受之鹽。Clause 95. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a taxane or a pharmaceutically acceptable salt thereof.
條款96. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之mTOR抑制劑或其醫藥學上可接受之鹽。Clause 96. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款97. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之mTOR抑制劑或其醫藥學上可接受之鹽。Clause 97. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款98. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之酪胺酸激酶抑制劑或其醫藥學上可接受之鹽。Clause 98. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.
條款99. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之酪胺酸激酶抑制劑或其醫藥學上可接受之鹽。Clause 99. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof.
條款100. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之鉑劑。Clause 100. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a platinum agent.
條款101. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之鉑劑。Clause 101. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a platinum agent.
條款102. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。Clause 102. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
條款103. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。Clause 103. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
條款104. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之抗雄激素或其醫藥學上可接受之鹽。Clause 104. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.
條款105. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之抗雄激素或其醫藥學上可接受之鹽。Clause 105. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an antiandrogen or a pharmaceutically acceptable salt thereof.
條款106. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之抗HER2單株抗體或抗HER2抗體-藥物結合物。Clause 106. A method for treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.
條款107. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之抗HER2單株抗體或抗HER2抗體-藥物結合物。Clause 107. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate.
條款108. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之蒽環黴素或其醫藥學上可接受之鹽。Clause 108. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.
條款109. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之蒽環黴素或其醫藥學上可接受之鹽。Clause 109. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an anthracycline or a pharmaceutically acceptable salt thereof.
條款110. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之KRAS抑制劑或其醫藥學上可接受之鹽。Clause 110. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.
條款111. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之KRAS抑制劑或其醫藥學上可接受之鹽。Clause 111. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a KRAS inhibitor or a pharmaceutically acceptable salt thereof.
條款112. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之MEK抑制劑或其醫藥學上可接受之鹽。Clause 112. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.
條款113. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之MEK抑制劑或其醫藥學上可接受之鹽。Clause 113. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a MEK inhibitor or a pharmaceutically acceptable salt thereof.
條款114. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之ERK抑制劑或其醫藥學上可接受之鹽。Clause 114. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.
條款115. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之ERK抑制劑或其醫藥學上可接受之鹽。Clause 115. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an ERK inhibitor or a pharmaceutically acceptable salt thereof.
條款116. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之SERD或其醫藥學上可接受之鹽；及(ii)有效量之mTOR抑制劑或其醫藥學上可接受之鹽。Clause 116. A method for treating a patient having a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款117. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之SERD或其醫藥學上可接受之鹽；及(ii)有效量之mTOR抑制劑或其醫藥學上可接受之鹽。Clause 117. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a SERD or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款118. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。Clause 118. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
條款119. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之CDK4及6抑制劑或其醫藥學上可接受之鹽；及(ii)有效量之免疫檢查點抑制劑或其醫藥學上可接受之鹽。Clause 119. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbium salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and (i) an effective amount of a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; and (ii) an effective amount of an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof.
條款120. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。Clause 120. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
條款121. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。Clause 121. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
條款122. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERM或其醫藥學上可接受之鹽。Clause 122. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a SERM or a pharmaceutically acceptable salt thereof.
條款123. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之SERM或其醫藥學上可接受之鹽。Clause 123. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a SERM or a pharmaceutically acceptable salt thereof.
條款124. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之PARP抑制劑或其醫藥學上可接受之鹽。Clause 124. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.
條款125. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之PARP抑制劑或其醫藥學上可接受之鹽。Clause 125. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of a PARP inhibitor or a pharmaceutically acceptable salt thereof.
條款126. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之鉑劑；及(ii)有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。Clause 126. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
條款127. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及(i)有效量之鉑劑；及(ii)有效量之拓樸異構酶抑制劑或其醫藥學上可接受之鹽。Clause 127. A method for treating a patient with a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbium salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and (i) an effective amount of a platinum agent; and (ii) an effective amount of a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof.
條款128. 一種治療患有PIK3CA突變癌症之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 128. A method for treating a patient suffering from a PIK3CA mutant cancer, comprising administering to the patient an effective amount of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款129. 一種治療患有PIK3CA突變實體腫瘤之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 129. A method for treating a patient having a PIK3CA mutant solid tumor, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款130. 一種治療患有PIK3CA突變乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 130. A method for treating a patient with PIK3CA mutant breast cancer, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款131. 一種治療患有PIK3CA突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，以及有效量之芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 131. A method for treating a patient with advanced or metastatic breast cancer with a PIK3CA mutation, comprising administering to the patient an effective amount of a compound of any one of Clauses 1-22, a styrene salt of any one of Clauses 23-47, an erbumin salt of any one of Clauses 48-60, or a pharmaceutical composition of Clause 61, and an effective amount of an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款132. 條款71、條款75、條款76、條款80、條款84、條款88、條款92、條款96、條款98、條款100、條款102、條款104、條款106、條款108、條款110、條款112、條款114、條款116、條款118、條款120、條款122、條款124、條款126或條款128之方法，其中該PIK3CA突變癌症為PIK3CA H1047R突變型癌症。Clause 132. The method of Clause 71, Clause 75, Clause 76, Clause 80, Clause 84, Clause 88, Clause 92, Clause 96, Clause 98, Clause 100, Clause 102, Clause 104, Clause 106, Clause 108, Clause 110, Clause 112, Clause 114, Clause 116, Clause 118, Clause 120, Clause 122, Clause 124, Clause 126 or Clause 128, wherein the PIK3CA mutant cancer is a PIK3CA H1047R mutant cancer.
條款133. 條款71、條款75、條款76、條款80、條款84、條款88、條款92、條款96、條款98、條款100、條款102、條款104、條款106、條款108、條款110、條款112、條款114、條款116、條款118、條款120、條款122、條款124、條款126、條款128或條款132之方法，其中該PIK3CA突變癌症為子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、大腸直腸癌、肺癌、卵巢癌、皮膚癌、頭頸癌、乳癌、腦癌或前列腺癌。Clause 133. The method of Clause 71, Clause 75, Clause 76, Clause 80, Clause 84, Clause 88, Clause 92, Clause 96, Clause 98, Clause 100, Clause 102, Clause 104, Clause 106, Clause 108, Clause 110, Clause 112, Clause 114, Clause 116, Clause 118, Clause 120, Clause 122, Clause 124, Clause 126, Clause 128 or Clause 132, wherein the PIK3CA mutant cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
條款134. 條款133之方法，其中該PIK3CA突變癌症為子宮內膜癌。Clause 134. The method of clause 133, wherein the PIK3CA mutant cancer is endometrial cancer.
條款135. 條款133之方法，其中該PIK3CA突變癌症為胃癌。Clause 135. The method of clause 133, wherein the PIK3CA mutant cancer is gastric cancer.
條款136. 條款133之方法，其中該PIK3CA突變癌症為白血病。Clause 136. The method of clause 133, wherein the PIK3CA mutant cancer is leukemia.
條款137. 條款133之方法，其中該PIK3CA突變癌症為淋巴瘤。Clause 137. The method of clause 133, wherein the PIK3CA mutant cancer is lymphoma.
條款138. 條款133之方法，其中該PIK3CA突變癌症為肉瘤。Clause 138. The method of clause 133, wherein the PIK3CA mutant cancer is a sarcoma.
條款139. 條款133之方法，其中該PIK3CA突變癌症為大腸直腸癌。Clause 139. The method of clause 133, wherein the PIK3CA mutant cancer is colorectal cancer.
條款140. 條款133之方法，其中該PIK3CA突變癌症為肺癌。Clause 140. The method of clause 133, wherein the PIK3CA mutant cancer is lung cancer.
條款141. 條款133之方法，其中該PIK3CA突變癌症為卵巢癌。Clause 141. The method of clause 133, wherein the PIK3CA mutant cancer is ovarian cancer.
條款142. 條款133之方法，其中該PIK3CA突變癌症為皮膚癌。Clause 142. The method of clause 133, wherein the PIK3CA mutation cancer is skin cancer.
條款143. 條款133之方法，其中該PIK3CA突變癌症為頭頸癌。Clause 143. The method of clause 133, wherein the PIK3CA mutant cancer is head and neck cancer.
條款144. 條款133之方法，其中該PIK3CA突變癌症為乳癌。Clause 144. The method of clause 133, wherein the PIK3CA mutant cancer is breast cancer.
條款145. 條款133之方法，其中該PIK3CA突變癌症為腦癌。Clause 145. The method of clause 133, wherein the PIK3CA mutant cancer is brain cancer.
條款146. 條款133之方法，其中該PIK3CA突變癌症為前列腺癌。Clause 146. The method of clause 133, wherein the PIK3CA mutant cancer is prostate cancer.
條款147. 條款72、條款77、條款81、條款85、條款89、條款93、條款97、條款99、條款101、條款103、條款105、條款107、條款109、條款111、條款113、條款115、條款117、條款119、條款121、條款123、條款125、條款127或條款129之方法，其中該PIK3CA突變實體腫瘤為PIK3CA H1047R突變型實體腫瘤。Clause 147. The method of Clause 72, Clause 77, Clause 81, Clause 85, Clause 89, Clause 93, Clause 97, Clause 99, Clause 101, Clause 103, Clause 105, Clause 107, Clause 109, Clause 111, Clause 113, Clause 115, Clause 117, Clause 119, Clause 121, Clause 123, Clause 125, Clause 127 or Clause 129, wherein the PIK3CA mutant solid tumor is a PIK3CA H1047R mutant solid tumor.
條款148. 條款72、條款77、條款81、條款85、條款89、條款93、條款97、條款99、條款101、條款103、條款105、條款107、條款109、條款111、條款113、條款115、條款117、條款119、條款121、條款123、條款125、條款127、條款129或條款147之方法，其中該PIK3CA突變實體腫瘤係選自婦科癌症、頭頸癌及三陰性乳癌。Clause 148. The method of Clause 72, Clause 77, Clause 81, Clause 85, Clause 89, Clause 93, Clause 97, Clause 99, Clause 101, Clause 103, Clause 105, Clause 107, Clause 109, Clause 111, Clause 113, Clause 115, Clause 117, Clause 119, Clause 121, Clause 123, Clause 125, Clause 127, Clause 129 or Clause 147, wherein the PIK3CA mutant solid tumor is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer.
條款149. 條款148之方法，其中該PIK3CA突變實體腫瘤為婦科癌症。Clause 149. The method of clause 148, wherein the PIK3CA mutant solid tumor is a gynecological cancer.
條款150. 條款148之方法，其中該PIK3CA突變實體腫瘤為頭頸癌。Clause 150. The method of Clause 148, wherein the PIK3CA mutant tumor is head and neck cancer.
條款151. 條款148之方法，其中該PIK3CA突變實體腫瘤為三陰性乳癌。Clause 151. The method of clause 148, wherein the PIK3CA mutant solid tumor is triple-negative breast cancer.
條款152. 根據條款73、條款78、條款82、條款86、條款90、條款94或條款130之方法，其中該PIK3CA突變乳癌為PIK3CA H1047R突變型乳癌。Clause 152. The method according to clause 73, clause 78, clause 82, clause 86, clause 90, clause 94 or clause 130, wherein the PIK3CA mutant breast cancer is PIK3CA H1047R mutant breast cancer.
條款153. 根據條款74、條款79、條款83、條款87、條款91、條款95或條款131之方法，其中該PIK3CA突變晚期或轉移性乳癌為PIK3CA H1047R突變型晚期或轉移性乳癌。Clause 153. The method according to clause 74, clause 79, clause 83, clause 87, clause 91, clause 95 or clause 131, wherein the PIK3CA mutation advanced or metastatic breast cancer is PIK3CA H1047R mutation advanced or metastatic breast cancer.
條款154. 根據條款74、條款79、條款83、條款87、條款91、條款95或條款131之方法，其中該PIK3CA突變晚期或轉移性乳癌為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌，較佳為雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌。Clause 154. A method according to Clause 74, Clause 79, Clause 83, Clause 87, Clause 91, Clause 95 or Clause 131, wherein the PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer, preferably estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer.
條款155. 根據條款74、條款79、條款83、條款87、條款91、條款95或條款131之方法，其中該PIK3CA突變晚期或轉移性乳癌為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌，較佳為雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌。Clause 155. A method according to Clause 74, Clause 79, Clause 83, Clause 87, Clause 91, Clause 95 or Clause 131, wherein the PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer, preferably estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer.
條款156. 根據條款62-155中任一項之方法，其中該患者為停經後女性。Clause 156. A method according to any of clauses 62-155, wherein the patient is a postmenopausal female.
條款157. 根據條款62-156中任一項之方法，其中該患者患有I型糖尿病。Clause 157. A method according to any of clauses 62-156, wherein the patient suffers from type 1 diabetes.
條款158. 根據條款62-156中任一項之方法，其中該患者患有II型糖尿病。Clause 158. A method according to any of clauses 62-156, wherein the patient suffers from type 2 diabetes.
條款159. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至2400 mg之總日劑量投與。Clause 159. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 200 mg to 2400 mg.
條款160. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg至2000 mg之總日劑量投與。Clause 160. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 400 mg to 2000 mg.
條款161. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg至1200 mg之總日劑量投與。Clause 161. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 600 mg to 1200 mg.
條款162. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之總日劑量投與。Clause 162. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 400 mg.
條款163. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之總日劑量投與。Clause 163. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 450 mg.
條款164. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之總日劑量投與。Clause 164. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 500 mg.
條款165. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之總日劑量投與。Clause 165. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 550 mg.
條款166. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之總日劑量投與。Clause 166. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 600 mg.
條款167. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之總日劑量投與。Clause 167. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 650 mg.
條款168. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之總日劑量投與。Clause 168. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 700 mg.
條款169. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之總日劑量投與。Clause 169. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 750 mg.
條款170. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之總日劑量投與。Clause 170. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 800 mg.
條款171. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之總日劑量投與。Clause 171. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 850 mg.
條款172. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之總日劑量投與。Clause 172. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 900 mg.
條款173. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之總日劑量投與。Clause 173. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 950 mg.
條款174. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之總日劑量投與。Clause 174. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1000 mg.
條款175. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之總日劑量投與。Clause 175. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1050 mg.
條款176. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之總日劑量投與。Clause 176. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1100 mg.
條款177. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之總日劑量投與。Clause 177. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1150 mg.
條款178. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之總日劑量投與。Clause 178. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1200 mg.
條款179. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1250 mg之總日劑量投與。Clause 179. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1250 mg.
條款180. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1300 mg之總日劑量投與。Clause 180. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1300 mg.
條款181. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1350 mg之總日劑量投與。Clause 181. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1350 mg.
條款182. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1400 mg之總日劑量投與。Clause 182. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1400 mg.
條款183. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1450 mg之總日劑量投與。Clause 183. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1450 mg.
條款184. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1500 mg之總日劑量投與。Clause 184. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1500 mg.
條款185. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1550 mg之總日劑量投與。Clause 185. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1550 mg.
條款186. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1600 mg之總日劑量投與。Clause 186. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1600 mg.
條款187. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1650 mg之總日劑量投與。Clause 187. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1650 mg.
條款188. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1700 mg之總日劑量投與。Clause 188. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1700 mg.
條款189. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1750 mg之總日劑量投與。Clause 189. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1750 mg.
條款190. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1800 mg之總日劑量投與。Clause 190. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1800 mg.
條款191. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1850 mg之總日劑量投與。Clause 191. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1850 mg.
條款192. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1900 mg之總日劑量投與。Clause 192. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1900 mg.
條款193. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1950 mg之總日劑量投與。Clause 193. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 1950 mg.
條款194. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2000 mg之總日劑量投與。Clause 194. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2000 mg.
條款195. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2050 mg之總日劑量投與。Clause 195. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2050 mg.
條款196. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2100 mg之總日劑量投與。Clause 196. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2100 mg.
條款197. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2150 mg之總日劑量投與。Clause 197. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2150 mg.
條款198. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2200 mg之總日劑量投與。Clause 198. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2200 mg.
條款199. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2250 mg之總日劑量投與。Clause 199. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2250 mg.
條款200. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2300 mg之總日劑量投與。Clause 200. The method of any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2300 mg.
條款201. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2350 mg之總日劑量投與。Clause 201. The method of any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2350 mg.
條款202. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2400 mg之總日劑量投與。Clause 202. The method of any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a total daily dose of 2400 mg.
條款203. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至2400 mg之劑量一天一次投與。Clause 203. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 200 mg to 2400 mg.
條款204. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg至2000 mg之劑量一天一次投與。Clause 204. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 400 mg to 2000 mg.
條款205. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg至1200 mg之劑量一天一次投與。Clause 205. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 600 mg to 1200 mg.
條款206. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg之劑量一天一次投與。Clause 206. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 200 mg.
條款207. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以250 mg之劑量一天一次投與。Clause 207. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 250 mg.
條款208. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg之劑量一天一次投與。Clause 208. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 300 mg.
條款209. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以350 mg之劑量一天一次投與。Clause 209. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 350 mg.
條款210. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之劑量一天一次投與。Clause 210. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 400 mg.
條款211. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之劑量一天一次投與。Clause 211. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 450 mg.
條款212. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之劑量一天一次投與。Clause 212. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 500 mg.
條款213. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之劑量一天一次投與。Clause 213. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 550 mg.
條款214. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之劑量一天一次投與。Clause 214. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 600 mg.
條款215. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之劑量一天一次投與。Clause 215. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 650 mg.
條款216. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之劑量一天一次投與。Clause 216. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 700 mg.
條款217. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之劑量一天一次投與。Clause 217. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 750 mg.
條款218. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之劑量一天一次投與。Clause 218. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 800 mg.
條款219. 根據條款62-158中任一項之方法, 該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之劑量一天一次投與。Clause 219. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 850 mg.
條款220. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之劑量一天一次投與。Clause 220. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 900 mg.
條款221. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之劑量一天一次投與。Clause 221. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 950 mg.
條款222. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之劑量一天一次投與。Clause 222. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1000 mg.
條款223. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之劑量一天一次投與。Clause 223. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1050 mg.
條款224. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之劑量一天一次投與。Clause 224. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1100 mg.
條款225. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之劑量一天一次投與。Clause 225. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1150 mg.
條款226. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之劑量一天一次投與。Clause 226. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1200 mg.
條款227. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1250 mg之劑量一天一次投與。Clause 227. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1250 mg.
條款228. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1300 mg之劑量一天一次投與。Clause 228. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1300 mg.
條款229. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1350 mg之劑量一天一次投與。Clause 229. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1350 mg.
條款230. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1400 mg之劑量一天一次投與。Clause 230. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1400 mg.
條款231. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1450 mg之劑量一天一次投與。Clause 231. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1450 mg.
條款232. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1500 mg之劑量一天一次投與。Clause 232. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1500 mg.
條款233. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1550 mg之劑量一天一次投與。Clause 233. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1550 mg.
條款234. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1600 mg之劑量一天一次投與。Clause 234. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1600 mg.
條款235. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1650 mg之劑量一天一次投與。Clause 235. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1650 mg.
條款236. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1700 mg之劑量一天一次投與。Clause 236. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1700 mg.
條款237. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1750 mg之劑量一天一次投與。Clause 237. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1750 mg.
條款238. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1800 mg之劑量一天一次投與。Clause 238. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1800 mg.
條款239. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1850 mg之劑量一天一次投與。Clause 239. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1850 mg.
條款240. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1900 mg之劑量一天一次投與。Clause 240. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1900 mg.
條款241. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1950 mg之劑量一天一次投與。Clause 241. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 1950 mg.
條款242. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2000 mg之劑量一天一次投與。Clause 242. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2000 mg.
條款243. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2050 mg之劑量一天一次投與。Clause 243. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2050 mg.
條款244. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2100 mg之劑量一天一次投與。Clause 244. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2100 mg.
條款245. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2150 mg之劑量一天一次投與。Clause 245. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2150 mg.
條款246. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2200 mg之劑量一天一次投與。Clause 246. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2200 mg.
條款247. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2250 mg之劑量一天一次投與。Clause 247. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2250 mg.
條款248. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2300 mg之劑量一天一次投與。Clause 248. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2300 mg.
條款249. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2350 mg之劑量一天一次投與。Clause 249. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2350 mg.
條款250. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2400 mg之劑量一天一次投與。Clause 250. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered once a day in a dose of 2400 mg.
條款251. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以100 mg至1200 mg之劑量一天兩次投與。Clause 251. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 100 mg to 1200 mg twice a day.
條款252. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至1000 mg之劑量一天兩次投與。Clause 252. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 200 mg to 1000 mg twice a day.
條款253. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg至600 mg之劑量一天兩次投與。Clause 253. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 300 mg to 600 mg twice a day.
條款254. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以100 mg之劑量一天兩次投與。Clause 254. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 100 mg twice a day.
條款255. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以150 mg之劑量一天兩次投與。Clause 255. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 150 mg twice a day.
條款256. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg之劑量一天兩次投與。Clause 256. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 200 mg twice a day.
條款257. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以250 mg之劑量一天兩次投與。Clause 257. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 250 mg twice a day.
條款258. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg之劑量一天兩次投與。Clause 258. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 300 mg twice a day.
條款259. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以350 mg之劑量一天兩次投與。Clause 259. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 350 mg twice a day.
條款260. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之劑量一天兩次投與。Clause 260. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 400 mg twice a day.
條款261. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之劑量一天兩次投與。Clause 261. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 450 mg twice a day.
條款262. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之劑量一天兩次投與。Clause 262. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 500 mg twice a day.
條款263. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之劑量一天兩次投與。Clause 263. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 550 mg twice a day.
條款264. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之劑量一天兩次投與。Clause 264. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 600 mg twice a day.
條款265. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之劑量一天兩次投與。Clause 265. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 650 mg twice a day.
條款266. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之劑量一天兩次投與。Clause 266. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 700 mg twice a day.
條款267. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之劑量一天兩次投與。Clause 267. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 750 mg twice a day.
條款268. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之劑量一天兩次投與。Clause 268. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 800 mg twice a day.
條款269. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之劑量一天兩次投與。Clause 269. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 850 mg twice a day.
條款270. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之劑量一天兩次投與。Clause 270. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 900 mg twice a day.
條款271. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之劑量一天兩次投與。Clause 271. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 950 mg twice a day.
條款272. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之劑量一天兩次投與。Clause 272. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 1000 mg twice a day.
條款273. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之劑量一天兩次投與。Clause 273. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 1050 mg twice a day.
條款274. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之劑量一天兩次投與。Clause 274. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 1100 mg twice a day.
條款275. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之劑量一天兩次投與。Clause 275. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 1150 mg twice a day.
條款276. 根據條款62-158中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之劑量一天兩次投與。Clause 276. The method according to any one of clauses 62-158, wherein the compound, the sulphonamide salt or the erbumin salt is administered in a dose of 1200 mg twice a day.
條款277. 根據條款62-276中任一項之方法，其中該化合物、該緩血酸胺鹽或該特丁胺鹽經由口服劑型投與。Clause 277. The method according to any one of clauses 62-276, wherein the compound, the sulphonamide salt or the erbumin salt is administered via an oral dosage form.
條款278. 根據條款277之方法，其中該口服劑型為錠劑。Clause 278. A method according to clause 277, wherein the oral dosage form is a tablet.
條款279. 根據條款75-79、84-91、118、119或132-278中任一項之方法，其中該CDK4及6抑制劑或其醫藥學上可接受之鹽為哌柏西利、瑞博西利或阿貝西利或其醫藥學上可接受之鹽。Clause 279. A method according to any one of clauses 75-79, 84-91, 118, 119 or 132-278, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is palbociclib, ribociclib or abemaciclib or a pharmaceutically acceptable salt thereof.
條款280. 根據條款75-79、84-91、118、119或132-278中任一項之方法，其中該CDK4及6抑制劑或其醫藥學上可接受之鹽為阿貝西利。Clause 280. A method according to any one of clauses 75-79, 84-91, 118, 119 or 132-278, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.
條款281. 根據條款280之方法，其中阿貝西利以50-200 mg口服劑量一天兩次投與。Clause 281. The method according to clause 280, wherein abemaciclib is administered orally in a dose of 50-200 mg twice a day.
條款282. 根據條款280之方法，其中阿貝西利以50 mg口服劑量一天兩次投與。Clause 282. The method according to clause 280, wherein abemaciclib is administered in a 50 mg oral dose twice a day.
條款283. 根據條款280之方法，其中阿貝西利以100 mg口服劑量一天兩次投與。Clause 283. The method according to clause 280, wherein abemaciclib is administered in a 100 mg oral dose twice a day.
條款284. 根據條款280之方法，其中阿貝西利以150 mg口服劑量一天兩次投與。Clause 284. The method according to clause 280, wherein abemaciclib is administered in an oral dose of 150 mg twice a day.
條款285. 根據條款280之方法，其中阿貝西利以200 mg口服劑量一天兩次投與。Clause 285. The method according to clause 280, wherein abemaciclib is administered in a dose of 200 mg orally twice a day.
條款286. 根據條款75、80-87、116、117或132-285中任一項之方法，其中該SERD或其醫藥學上可接受之鹽為氟維司群、伊魯司群、吉雷司群、安森司群、瑞妥司群、AZD9833或LSZ102。Clause 286. A method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant, iludostrand, giredostat, ansonostrand, retostat, AZD9833 or LSZ102.
條款287. 根據條款75、80-87、116、117或132-285中任一項之方法，其中該SERD或其醫藥學上可接受之鹽為氟維司群。Clause 287. A method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant.
條款288. 根據條款287之方法，其中氟維司群在第一個28天週期(週期1)之第1天及第15天，及在第二個及任何後續28天週期(週期2及後續週期)之第1天以500 mg肌肉內劑量投與。Clause 288. A method according to clause 287, wherein fulvestrant is administered at a 500 mg intramuscular dose on days 1 and 15 of the first 28-day cycle (Cycle 1), and on day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).
條款289. 根據條款75、80-87、116、117或132-285中任一項之方法，其中該SERD或其醫藥學上可接受之鹽為伊魯司群。Clause 289. A method according to any one of clauses 75, 80-87, 116, 117 or 132-285, wherein the SERD or a pharmaceutically acceptable salt thereof is ilustrant.
條款290. 根據條款289之方法，其中伊魯司群以400 mg口服劑量每天一次投與。Clause 290. The method according to clause 289, wherein ilustrant is administered in an oral dose of 400 mg once daily.
條款291. 根據條款75、88-91或128-285中任一項之方法，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為阿那曲唑、來曲唑或依西美坦。Clause 291. A method according to any one of clauses 75, 88-91 or 128-285, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole, letrozole or exemestane.
條款292. 根據條款291之方法，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為阿那曲唑。Clause 292. A method according to clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole.
條款293. 根據條款292之方法，其中阿那曲唑以1 mg口服劑量每天一次投與。Clause 293. The method according to clause 292, wherein anastrozole is administered in a 1 mg oral dose once daily.
條款294. 根據條款291之方法，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為來曲唑。Clause 294. A method according to clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is letrozole.
條款295. 根據條款294之方法，其中來曲唑以2.5 mg口服劑量每天一次投與，或對於患有肝硬化或嚴重肝損傷之患者，以2.5 mg口服劑量每隔一天一次投與。Clause 295. The method according to clause 294, wherein letrozole is administered at a dose of 2.5 mg orally once daily, or for patients with cirrhosis or severe liver damage, at a dose of 2.5 mg orally once every other day.
條款296. 根據條款291之方法，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為依西美坦。Clause 296. A method according to clause 291, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is exemestane.
條款297. 根據條款296之方法，其中依西美坦以25 mg口服劑量每天一次投與。Clause 297. The method according to clause 296, wherein exemestane is administered in a 25 mg oral dose once daily.
條款298. 根據條款75、92-95或132-278中任一項之方法，其中該紫杉烷或其醫藥學上可接受之鹽為太平洋紫杉醇或多西紫杉醇。Clause 298. The method according to any one of clauses 75, 92-95 or 132-278, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel or docetaxel.
條款299. 根據條款75、92-95或132-278中任一項之方法，其中該紫杉烷或其醫藥學上可接受之鹽為太平洋紫杉醇。Clause 299. A method according to any one of clauses 75, 92-95 or 132-278, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel.
條款300. 根據條款299之方法，其中太平洋紫杉醇在第一個劑量週期之第8天、第15天及第22天，且接著在所有後續劑量週期之第1天、第8天、第15天及第22天以80 mg/m2注射投與。Clause 300. The method of clause 299, wherein paclitaxel is administered by injection at 80 mg/m2 on days 8, 15, and 22 of the first dose cycle, and then on days 1, 8, 15, and 22 of all subsequent dose cycles.
條款301. 根據條款75、96、97、116、117、132-278或286-290中任一項之方法，其中該mTOR抑制劑或其醫藥學上可接受之鹽為西羅莫司、坦羅莫司、依維莫司或RMC-5552。Clause 301. A method according to any one of clauses 75, 96, 97, 116, 117, 132-278 or 286-290, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is sirolimus, temsirolimus, everolimus or RMC-5552.
條款302. 根據條款301之方法，其中該mTOR抑制劑或其醫藥學上可接受之鹽為依維莫司。Clause 302. The method according to clause 301, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is everolimus.
條款303. 根據條款302之方法，其中該依維莫司以10 mg口服劑量每天一次投與。Clause 303. The method according to clause 302, wherein the everolimus is administered in a 10 mg oral dose once daily.
條款304. 根據條款301之方法，其中該mTOR抑制劑或其醫藥學上可接受之鹽為RMC-5552。Clause 304. The method according to clause 301, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is RMC-5552.
條款305. 根據條款75、98、99或132-278中任一項之方法，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為來那替尼或阿法替尼。Clause 305. A method according to any one of clauses 75, 98, 99 or 132-278, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib or afatinib.
條款306. 根據條款305之方法，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為來那替尼。Clause 306. The method according to clause 305, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib.
條款307. 根據條款306之方法，其中該來那替尼以240 mg口服劑量每天一次投與。Clause 307. The method according to clause 306, wherein the neratinib is administered in an oral dose of 240 mg once daily.
條款308. 根據條款305之方法，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為阿法替尼。Clause 308. The method according to clause 305, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is afatinib.
條款309. 根據條款308之方法，其中該阿法替尼以40 mg口服劑量每天一次投與，或在患有嚴重腎損傷之患者中以30 mg口服劑量每天一次投與。Clause 309. The method according to clause 308, wherein the afatinib is administered at a dose of 40 mg orally once daily, or at a dose of 30 mg orally once daily in patients with severe renal impairment.
條款310. 根據條款75、100、101、126、127或132-278中任一項之方法，其中該鉑劑為順鉑、卡鉑或奧沙利鉑。Clause 310. A method according to any one of clauses 75, 100, 101, 126, 127 or 132-278, wherein the platinum agent is cis-platinum, carboplatin or oxaliplatin.
條款311. 根據條款310之方法，其中該鉑劑為順鉑。Clause 311. A method according to clause 310, wherein the platinum agent is cis-platinum.
條款312. 根據條款75、108、109或132-278中任一項之方法，其中該蒽環黴素或其醫藥學上可接受之鹽為多柔比星、道諾黴素、表柔比星或艾達黴素。Clause 312. A method according to any one of clauses 75, 108, 109 or 132-278, wherein the anthracycline or a pharmaceutically acceptable salt thereof is doxorubicin, daunorubicin, epirubicin or idarucizumab.
條款313. 根據條款75、102、103、118、119或132-285中任一項之方法，其中該免疫檢查點抑制劑或其醫藥學上可接受之鹽為CTLA-4抑制劑、PD-1抑制劑或PD-L1抑制劑。Clause 313. A method according to any of clauses 75, 102, 103, 118, 119 or 132-285, wherein the immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.
條款314. 根據條款313之方法，其中該免疫檢查點抑制劑為CTLA-4抑制劑。Clause 314. The method of clause 313, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.
條款315. 根據條款314之方法，其中該CTLA-4抑制劑為伊匹單抗或曲美單抗。Clause 315. The method according to clause 314, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.
條款316. 根據條款313之方法，其中該免疫檢查點抑制劑為PD-1抑制劑。Clause 316. The method according to clause 313, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
條款317. 根據條款316之方法，其中該PD-1抑制劑為帕博利珠單抗、納武利尤單抗、信迪利單抗、西米普利單抗，或替雷利珠單抗。Clause 317. The method according to clause 316, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplizumab, or tislelizumab.
條款318. 根據條款313之方法，其中該免疫檢查點抑制劑為PD-L1抑制劑。Clause 318. The method of clause 313, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.
條款319. 根據條款318之方法，其中該PD-L1抑制劑為阿特珠單抗、阿維魯單抗，或度伐魯單抗。Clause 319. The method according to clause 318, wherein the PD-L1 inhibitor is atezolizumab, avelumab, or durvalumab.
條款320. 根據條款75、104、105或132-278中任一項之方法，其中該抗雄激素或其醫藥學上可接受之鹽為阿比特龍、恩雜魯胺、尼魯米特、氟他胺或達洛魯胺(darolutamide)，較佳為阿比特龍、恩雜魯胺、尼魯米特或氟他胺。Clause 320. A method according to any one of clauses 75, 104, 105 or 132-278, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is abiraterone, enzalutamide, nilutamide, flutamide or darolutamide, preferably abiraterone, enzalutamide, nilutamide or flutamide.
條款321. 根據條款320之方法，其中該抗雄激素或其醫藥學上可接受之鹽為恩雜魯胺。Clause 321. The method according to clause 320, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is enzaluamide.
條款322. 根據條款321之方法，其中該恩雜魯胺以160 mg口服劑量每天一次投與。Clause 322. The method according to clause 321, wherein the enzaluamide is administered in an oral dose of 160 mg once daily.
條款323. 根據條款75、106、107或132-278中任一項之方法，其中該抗HER2單株抗體為曲妥珠單抗、馬戈妥昔單抗或帕妥珠單抗。Clause 323. A method according to any one of clauses 75, 106, 107 or 132-278, wherein the anti-HER2 monoclonal antibody is trastuzumab, magotuximab or pertuzumab.
條款324. 根據條款323之方法，其中該抗HER2單株抗體為曲妥珠單抗。Clause 324. The method according to clause 323, wherein the anti-HER2 monoclonal antibody is trastuzumab.
條款325. 根據條款75、106、107或132-278中任一項之方法，其中該抗HER2抗體-藥物結合物為德曲妥珠單抗或恩美曲妥珠單抗。Clause 325. A method according to any one of clauses 75, 106, 107 or 132-278, wherein the anti-HER2 antibody-drug conjugate is trastuzumab emtansine or trastuzumab emtansine.
條款326. 根據條款325之方法，其中該抗HER2抗體-藥物結合物為德曲妥珠單抗。Clause 326. The method of clause 325, wherein the anti-HER2 antibody-drug conjugate is trastuzumab.
條款327. 根據條款75、110、111或132-278中任一項之方法，其中該KRAS抑制劑或其醫藥學上可接受之鹽為索托拉西布或阿達格拉西布。Clause 327. A method according to any one of clauses 75, 110, 111 or 132-278, wherein the KRAS inhibitor or a pharmaceutically acceptable salt thereof is sotolacizumab or adagracib.
條款328. 根據條款75、112、113或132-278中任一項之方法，其中該MEK抑制劑或其醫藥學上可接受之鹽為曲美替尼。Clause 328. A method according to any one of clauses 75, 112, 113 or 132-278, wherein the MEK inhibitor or a pharmaceutically acceptable salt thereof is trametinib.
條款329. 根據條款75、120、121、126、127、132-278、310或311中任一項之方法，其中該拓樸異構酶抑制劑或其醫藥學上可接受之鹽為依託泊苷。Clause 329. A method according to any one of clauses 75, 120, 121, 126, 127, 132-278, 310 or 311, wherein the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is etoposide.
條款330. 根據條款75、122、123或132-278中任一項之方法，其中該SERM或其醫藥學上可接受之鹽為他莫昔芬或托瑞米芬。Clause 330. A method according to any one of clauses 75, 122, 123 or 132-278, wherein the SERM or a pharmaceutically acceptable salt thereof is tamoxifen or toremifene.
條款331. 根據條款75、124、125或132-278中任一項之方法，其中該PARP抑制劑或其醫藥學上可接受之鹽為奧拉帕尼或他拉唑帕尼。Clause 331. A method according to any one of clauses 75, 124, 125 or 132-278, wherein the PARP inhibitor or a pharmaceutically acceptable salt thereof is olaparib or talazoparib.
條款332. 根據條款62-331中任一項之方法，其中患者先前未接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。Clause 332. A method according to any of clauses 62-331, wherein the patient has not previously been treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款333. 根據條款62-331中任一項之方法，其中該患者先前接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。Clause 333. A method according to any of clauses 62-331, wherein the patient has previously been treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款334. 根據條款333之方法，其中該PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽為阿培利司或伊納沃利西布(inavolisib)。Clause 334. The method according to clause 333, wherein the PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellisib or inavolisib.
條款335. 根據條款334之方法，其中該PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽為阿培利司。Clause 335. The method according to clause 334, wherein the PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellis.
條款336. 根據條款62-335中任一項之方法，其中患者先前未接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。Clause 336. A method according to any of clauses 62-335, wherein the patient has not previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款337. 根據條款62-335中任一項之方法，其中該患者先前接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。Clause 337. A method according to any of clauses 62-335, wherein the patient has previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款338. 根據條款62-335中任一項之方法，其中該患者先前接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療，以及內分泌療法。Clause 338. A method according to any of clauses 62-335, wherein the patient has previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and endocrine therapy.
條款339. 根據條款62-338中任一項之方法，其中患者先前未接受過SERD或其醫藥學上可接受之鹽治療。Clause 339. A method according to any of clauses 62-338, wherein the patient has not been previously treated with a SERD or a pharmaceutically acceptable salt thereof.
條款340. 根據條款62-338中任一項之方法，其中該患者先前接受過SERD或其醫藥學上可接受之鹽治療。Clause 340. A method according to any of clauses 62-338, wherein the patient has previously been treated with a SERD or a pharmaceutically acceptable salt thereof.
條款341. 根據條款62-340中任一項之方法，其中患者先前未接受過芳香酶抑制劑或其醫藥學上可接受之鹽治療。Clause 341. A method according to any of clauses 62-340, wherein the patient has not been previously treated with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款342. 根據條款62-340中任一項之方法，其中該患者先前接受過芳香酶抑制劑或其醫藥學上可接受之鹽治療。Clause 342. A method according to any of clauses 62-340, wherein the patient has previously been treated with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款343. 根據條款62-342中任一項之方法，其中患者先前未接受過紫杉烷或其醫藥學上可接受之鹽治療。Clause 343. The method of any of clauses 62-342, wherein the patient has not previously received treatment with a taxane or a pharmaceutically acceptable salt thereof.
條款344. 根據條款62-342中任一項之方法，其中該患者先前接受過紫杉烷或其醫藥學上可接受之鹽治療。Clause 344. The method according to any one of clauses 62-342, wherein the patient has previously been treated with a taxane or a pharmaceutically acceptable salt thereof.
條款345. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於療法中。Clause 345. A compound according to any one of clauses 1 to 22, a sedative amine salt according to any one of clauses 23 to 47, an erbumin salt according to any one of clauses 48 to 60 or a pharmaceutical composition according to clause 61 for use in therapy.
條款346. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於治療與突變型磷酸肌醇3-激酶(PI3K)相關之疾病。Clause 346. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61 for use in treating a disease associated with mutant phosphoinositide 3-kinase (PI3K).
條款347. 根據條款346之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PI3K為PI3Kα。Clause 347. A compound, a sulphonamide salt, an erbumin salt or a pharmaceutical composition for use according to clause 346, wherein the PI3K is PI3Kα.
條款348. 根據條款346或347之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PI3K具有H1047R突變。Clause 348. A compound, a sulphonamide salt, an erbumin salt or a pharmaceutical composition for use according to clause 346 or 347, wherein the PI3K has a H1047R mutation.
條款349. 根據條款346-348中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該疾病為癌症。Clause 349. A compound, a sedative salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 346 to 348, wherein the disease is cancer.
條款350. 根據條款349之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該癌症為子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、大腸直腸癌、肺癌、卵巢癌、皮膚癌、頭頸癌、乳癌、腦癌或前列腺癌。Clause 350. A compound, a sulphonamide salt, an erbumin salt or a pharmaceutical composition for use according to clause 349, wherein the cancer is endometrial cancer, gastric cancer, leukaemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
條款351. 根據條款349之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該癌症為乳癌。Clause 351. A compound, a sedative salt, an erbumin salt or a pharmaceutical composition for use according to clause 349, wherein the cancer is breast cancer.
條款352. 根據條款349之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該癌症為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)晚期或轉移性乳癌。Clause 352. A compound, a sulphonamide salt, an erbumin salt or a pharmaceutical composition for use according to clause 349, wherein the cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer.
條款353. 根據條款346-348中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該疾病為CLOVES症候群(先天性脂瘤性過度生長、血管畸形、表皮痣、脊柱側凸/骨骼及脊髓症候群)或PIK3CA相關之過度生長症候群(PROS)。Clause 353. A compound, a styrene salt, an terbumin salt or a pharmaceutical composition for use according to any one of clauses 346 to 348, wherein the disease is CLOVES syndrome (congenital lipomatous hypergrowth, vascular malformations, epidermal nevus, scoliosis/skeletal and spinal cord syndrome) or PIK3CA-related hypergrowth syndrome (PROS).
條款354. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於治療PIK3CA突變癌症。Clause 354. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61 for use in treating a PIK3CA mutant cancer.
條款355. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於治療PIK3CA突變實體腫瘤。Clause 355. A compound according to any one of clauses 1 to 22, a sedative amine salt according to any one of clauses 23 to 47, an erbumin salt according to any one of clauses 48 to 60 or a pharmaceutical composition according to clause 61 for use in the treatment of a PIK3CA mutant solid tumor.
條款356. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於治療PIK3CA突變乳癌。Clause 356. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61 for use in the treatment of PIK3CA mutant breast cancer.
條款357. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其用於治療PIK3CA突變晚期或轉移性乳癌。Clause 357. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61 for use in the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款358. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：CDK4及6抑制劑或其醫藥學上可接受之鹽；SERD或其醫藥學上可接受之鹽；芳香酶抑制劑或其醫藥學上可接受之鹽；紫杉烷或其醫藥學上可接受之鹽；mTOR抑制劑或其醫藥學上可接受之鹽；酪胺酸激酶抑制劑或其醫藥學上可接受之鹽；鉑劑；蒽環黴素或其醫藥學上可接受之鹽；免疫檢查點抑制劑或其醫藥學上可接受之鹽；抗雄激素或其醫藥學上可接受之鹽；抗HER2單株抗體；抗HER2抗體-藥物結合物；KRAS抑制劑或其醫藥學上可接受之鹽；MEK抑制劑或其醫藥學上可接受之鹽；ERK抑制劑或其醫藥學上可接受之鹽；拓樸異構酶抑制劑或其醫藥學上可接受之鹽；SERM或其醫藥學上可接受之鹽；或PARP抑制劑或其醫藥學上可接受之鹽；或其組合；用於治療PIK3CA突變癌症。Clause 358. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, for use in combination with the following simultaneously, separately or sequentially: a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof; a SERD or a pharmaceutically acceptable salt thereof; an aromatase inhibitor or a pharmaceutically acceptable salt thereof; a taxane or a pharmaceutically acceptable salt thereof; an mTOR inhibitor or a pharmaceutically acceptable salt thereof; a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof; a platinum agent; an anthracycline or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable salt thereof; an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof; an antiandrogen or a pharmaceutically acceptable salt thereof; an anti-HER2 monoclonal antibody; an anti-HER2 antibody-drug conjugate; a KRAS inhibitor or a pharmaceutically acceptable salt thereof; a MEK inhibitor or a pharmaceutically acceptable salt thereof; an ERK inhibitor or a pharmaceutically acceptable salt thereof; a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof; a SERM or a pharmaceutically acceptable salt thereof; or a PARP inhibitor or a pharmaceutically acceptable salt thereof; or a combination thereof; for treating a PIK3CA mutant cancer.
條款359. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 359. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款360. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 360. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款361. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。Clause 361. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant breast cancer.
條款362. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 362. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of advanced or metastatic breast cancer with PIK3CA mutation.
條款363. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 363. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERD or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款364. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 364. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERD or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款365. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。Clause 365. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERD or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant breast cancer.
條款366. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERD或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 366. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERD or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款367. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。Clause 367. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant cancer.
條款368. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。Clause 368. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款369. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變乳癌。Clause 369. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant breast cancer.
條款370. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 370. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof, for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款371. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。Clause 371. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbamide salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant cancer.
條款372. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。Clause 372. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbamide salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款373. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變乳癌。Clause 373. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbamide salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant breast cancer.
條款374. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 374. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbamide salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款375. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 375. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a taxane or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款376. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 376. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a taxane or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款377. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。Clause 377. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a taxane or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant breast cancer.
條款378. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 378. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a taxane or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款379. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 379. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination, either simultaneously, separately or sequentially, with an mTOR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款380. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與mTOR抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 380. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an mTOR inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款381. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 381. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款382. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與酪胺酸激酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 382. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款383. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與鉑劑同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 383. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a platinum agent, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款384. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與鉑劑同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 384. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a platinum agent, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款385. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 385. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款386. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與免疫檢查點抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 386. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款387. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與抗雄激素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 387. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an antiandrogen or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款388. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與抗雄激素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 388. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an antiandrogen or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款389. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 389. A compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate for the treatment of PIK3CA mutant cancer.
條款390. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與抗HER2單株抗體或抗HER2抗體-藥物結合物同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 390. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an anti-HER2 monoclonal antibody or an anti-HER2 antibody-drug conjugate for the treatment of a PIK3CA mutant solid tumor.
條款391. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 391. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, a terbufamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an anthracycline or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款392. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與蒽環黴素或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 392. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, a terbufamide salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61, used in combination with an anthracycline or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款393. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 393. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination, either simultaneously, separately or sequentially, with a KRAS inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款394. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與KRAS抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 394. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a KRAS inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款395. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 395. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a MEK inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款396. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與MEK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 396. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a MEK inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款397. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 397. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an ERK inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款398. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與ERK抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 398. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an ERK inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款399. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。Clause 399. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant cancer.
條款400. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) SERD或其醫藥學上可接受之鹽，及(ii) mTOR抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。Clause 400. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a SERD or a pharmaceutically acceptable salt thereof, and (ii) an mTOR inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款401. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。Clause 401. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, for use simultaneously, separately or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant cancer.
條款402. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)免疫檢查點抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。Clause 402. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款403. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 403. A compound of any one of clauses 1 to 22, a sulphonamide salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of PIK3CA mutant cancer.
條款404. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與拓樸異構酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 404. A compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款405. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERM或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 405. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERM or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款406. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與SERM或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 406. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a SERM or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款407. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 407. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款408. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與PARP抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 408. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with a PARP inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of a PIK3CA mutant solid tumor.
條款409. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變癌症。Clause 409. A compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbium salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with: (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of PIK3CA mutant cancer.
條款410. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與以下同時、分開或依序組合使用：(i)鉑劑，及(ii)拓樸異構酶抑制劑或其醫藥學上可接受之鹽，用於治療PIK3CA突變實體腫瘤。Clause 410. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, for use in combination, either simultaneously, separately or sequentially, with: (i) a platinum agent, and (ii) a topoisomerase inhibitor or a pharmaceutically acceptable salt thereof, for the treatment of a PIK3CA mutant solid tumor.
條款411. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變癌症。Clause 411. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant cancer.
條款412. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變實體腫瘤。Clause 412. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination simultaneously, separately or sequentially with an aromatase inhibitor or a pharmaceutically acceptable salt thereof for the treatment of a PIK3CA mutant solid tumor.
條款413. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變乳癌。Clause 413. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of PIK3CA mutant breast cancer.
條款414. 條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物，其與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合使用，用於治療PIK3CA突變晚期或轉移性乳癌。Clause 414. A compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbumin salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61, used in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof, either simultaneously, separately or sequentially, for the treatment of advanced or metastatic breast cancer with PIK3CA mutation.
條款415. 根據條款354、條款358、條款359、條款363、條款367、條款371、條款375、條款379、條款381、條款383、條款385、條款387、條款389、條款391、條款393、條款395、條款397、條款399、條款401、條款403、條款405、條款407、條款409或條款411之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為PIK3CA H1047R突變型癌症。Clause 415. A compound, styrene salt, terbuthion salt or pharmaceutical composition for use according to clause 354, clause 358, clause 359, clause 363, clause 367, clause 371, clause 375, clause 379, clause 381, clause 383, clause 385, clause 387, clause 389, clause 391, clause 393, clause 395, clause 397, clause 399, clause 401, clause 403, clause 405, clause 407, clause 409 or clause 411, wherein the PIK3CA mutant cancer is a PIK3CA H1047R mutant cancer.
條款416. 根據條款354、條款358、條款359、條款363、條款367、條款371、條款375、條款379、條款381、條款383、條款385、條款387、條款389、條款391、條款393、條款395、條款397、條款399、條款401、條款403、條款405、條款407、條款409、條款411或條款415之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為子宮內膜癌、胃癌、白血病、淋巴瘤、肉瘤、大腸直腸癌、肺癌、卵巢癌、皮膚癌、頭頸癌、乳癌、腦癌或前列腺癌。Article 416. Pursuant to Article 354, Article 358, Article 359, Article 363, Article 367, Article 371, Article 375, Article 379, Article 381, Article 383, Article 385, Article 387, Article 389, Article 391, Article 393, Article 395, Article 397, Article 399, Article 401, Article 403 , Clause 405, Clause 407, Clause 409, Clause 411 or Clause 415, a compound, a styrene salt, an terbuthylamine salt or a pharmaceutical composition for use, wherein the PIK3CA mutation cancer is endometrial cancer, gastric cancer, leukemia, lymphoma, sarcoma, colorectal cancer, lung cancer, ovarian cancer, skin cancer, head and neck cancer, breast cancer, brain cancer or prostate cancer.
條款417. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為子宮內膜癌。Clause 417. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is endometrial cancer.
條款418. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為胃癌。Clause 418. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is gastric cancer.
條款419. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為白血病。Clause 419. A compound, a styrene salt, an terbufamide salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is leukemia.
條款420. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為淋巴瘤。Clause 420. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is lymphoma.
條款421. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為肉瘤。Clause 421. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is a sarcoma.
條款422. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為大腸直腸癌。Clause 422. A compound, a styrene salt, an terbufamide salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is colorectal cancer.
條款423. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為肺癌。Clause 423. A compound, a styrene salt, an terbufamide salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is lung cancer.
條款424. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為卵巢癌。Clause 424. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is ovarian cancer.
條款425. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為皮膚癌。Clause 425. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is skin cancer.
條款426. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為頭頸癌。Clause 426. A compound, a styrene salt, an terbufamide salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is head and neck cancer.
條款427. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為乳癌。Clause 427. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutant cancer is breast cancer.
條款428. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為腦癌。Clause 428. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is brain cancer.
條款429. 根據條款416之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變癌症為前列腺癌。Clause 429. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 416, wherein the PIK3CA mutation cancer is prostate cancer.
條款430. 根據條款355、條款360、條款364、條款368、條款372、條款376、條款380、條款382、條款384、條款386、條款388、條款390、條款392、條款394、條款396、條款398、條款400、條款402、條款404、條款406、條款408、條款410或條款412之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變實體腫瘤為PIK3CA H1047R突變型實體腫瘤。Clause 430. A compound, styrene salt, terbufamide salt or pharmaceutical composition for use according to Clause 355, Clause 360, Clause 364, Clause 368, Clause 372, Clause 376, Clause 380, Clause 382, Clause 384, Clause 386, Clause 388, Clause 390, Clause 392, Clause 394, Clause 396, Clause 398, Clause 400, Clause 402, Clause 404, Clause 406, Clause 408, Clause 410 or Clause 412, wherein the PIK3CA mutant entity tumor is a PIK3CA H1047R mutant entity tumor.
條款431. 根據條款355、條款360、條款364、條款368、條款372、條款376、條款380、條款382、條款384、條款386、條款388、條款390、條款392、條款394、條款396、條款398、條款400、條款402、條款404、條款406、條款408、條款410、條款412或條款430之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變實體腫瘤係選自婦科癌症、頭頸癌及三陰性乳癌。Clause 431. A compound, styrene salt, terbufamide salt or pharmaceutical composition for use according to clause 355, clause 360, clause 364, clause 368, clause 372, clause 376, clause 380, clause 382, clause 384, clause 386, clause 388, clause 390, clause 392, clause 394, clause 396, clause 398, clause 400, clause 402, clause 404, clause 406, clause 408, clause 410, clause 412 or clause 430, wherein the PIK3CA mutant entity tumor is selected from gynecological cancer, head and neck cancer and triple-negative breast cancer.
條款432. 根據條款431之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變實體腫瘤為婦科癌症。Clause 432. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 431, wherein the PIK3CA mutant tumour is a gynaecological cancer.
條款433. 根據條款431之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變實體腫瘤為頭頸癌。Clause 433. A compound, a styrene salt, an terbufamide salt or a pharmaceutical composition for use according to clause 431, wherein the PIK3CA mutant tumour is head and neck cancer.
條款434. 根據條款431之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變實體腫瘤為三陰性乳癌。Clause 434. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to clause 431, wherein the PIK3CA mutant tumour is triple-negative breast cancer.
條款435. 根據條款356、條款361、條款365、條款369、條款373、條款377或條款413之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變乳癌為PIK3CA H1047R突變型乳癌。Clause 435. A compound, sulphonamide salt, terbuthamide salt or pharmaceutical composition for use according to clause 356, clause 361, clause 365, clause 369, clause 373, clause 377 or clause 413, wherein the PIK3CA mutant breast cancer is PIK3CA H1047R mutant breast cancer.
條款436. 根據條款357、條款362、條款366、條款370、條款374、條款378或條款414之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變晚期或轉移性乳癌為PIK3CA H1047R突變型晚期或轉移性乳癌。Clause 436. A compound, styrene salt, terbuthion salt or pharmaceutical composition for use according to clause 357, clause 362, clause 366, clause 370, clause 374, clause 378 or clause 414, wherein the PIK3CA mutation advanced or metastatic breast cancer is PIK3CA H1047R mutation advanced or metastatic breast cancer.
條款437. 根據條款357、條款362、條款366、條款370、條款374、條款378或條款414之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變晚期或轉移性乳癌為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌，較佳為雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA突變晚期或轉移性乳癌。Clause 437. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to Clause 357, Clause 362, Clause 366, Clause 370, Clause 374, Clause 378 or Clause 414, wherein the PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer, preferably estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA mutation advanced or metastatic breast cancer.
條款438. 根據條款357、條款362、條款366、條款370、條款374、條款378或條款414之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PIK3CA突變晚期或轉移性乳癌為激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌，較佳為雌激素受體陽性(ER+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變型晚期或轉移性乳癌。Clause 438. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 357, clause 362, clause 366, clause 370, clause 374, clause 378 or clause 414, wherein the PIK3CA mutation advanced or metastatic breast cancer is hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer, preferably estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutant advanced or metastatic breast cancer.
條款439. 根據條款345-438中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者為停經後女性。Clause 439. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-438, wherein the patient is a postmenopausal female.
條款440. 根據條款345-439中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者患有I型糖尿病。Clause 440. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient suffers from type 1 diabetes.
條款441. 根據條款345-439中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者患有II型糖尿病。Clause 441. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-439, wherein the patient suffers from type II diabetes.
條款442. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至2400 mg之總日劑量投與。Clause 442. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 200 mg to 2400 mg.
條款443. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg至2000 mg之總日劑量投與。Clause 443. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 400 mg to 2000 mg.
條款444. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg至1200 mg之總日劑量投與。Clause 444. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 600 mg to 1200 mg.
條款445. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之總日劑量投與。Clause 445. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 400 mg.
條款446. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之總日劑量投與。Clause 446. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 450 mg.
條款447. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之總日劑量投與。Clause 447. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 500 mg.
條款448. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之總日劑量投與。Clause 448. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 550 mg.
條款449. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之總日劑量投與。Clause 449. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 600 mg.
條款450. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之總日劑量投與。Clause 450. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 650 mg.
條款451. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之總日劑量投與。Clause 451. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 700 mg.
條款452. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之總日劑量投與。Clause 452. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 750 mg.
條款453. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之總日劑量投與。Clause 453. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 800 mg.
條款454. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之總日劑量投與。Clause 454. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 850 mg.
條款455. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之總日劑量投與。Clause 455. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 900 mg.
條款456. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之總日劑量投與。Clause 456. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 950 mg.
條款457. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之總日劑量投與。Clause 457. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1000 mg.
條款458. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之總日劑量投與。Clause 458. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1050 mg.
條款459. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之總日劑量投與。Clause 459. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1100 mg.
條款460. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之總日劑量投與。Clause 460. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1150 mg.
條款461. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之總日劑量投與。Clause 461. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1200 mg.
條款462. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1250 mg之總日劑量投與。Clause 462. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1250 mg.
條款463. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1300 mg之總日劑量投與。Clause 463. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1300 mg.
條款464. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1350 mg之總日劑量投與。Clause 464. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1350 mg.
條款465. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1400 mg之總日劑量投與。Clause 465. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1400 mg.
條款466. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1450 mg之總日劑量投與。Clause 466. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1450 mg.
條款467. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1500 mg之總日劑量投與。Clause 467. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1500 mg.
條款468. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1550 mg之總日劑量投與。Clause 468. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1550 mg.
條款469. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1600 mg之總日劑量投與。Clause 469. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1600 mg.
條款470. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1650 mg之總日劑量投與。Clause 470. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1650 mg.
條款471. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1700 mg之總日劑量投與。Clause 471. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1700 mg.
條款472. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1750 mg之總日劑量投與。Clause 472. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1750 mg.
條款473. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1800 mg之總日劑量投與。Clause 473. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1800 mg.
條款474. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1850 mg之總日劑量投與。Clause 474. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1850 mg.
條款475. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1900 mg之總日劑量投與。Clause 475. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1900 mg.
條款476. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1950 mg之總日劑量投與。Clause 476. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 1950 mg.
條款477. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2000 mg之總日劑量投與。Clause 477. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2000 mg.
條款478. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2050 mg之總日劑量投與。Clause 478. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2050 mg.
條款479. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2100 mg之總日劑量投與。Clause 479. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2100 mg.
條款480. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2150 mg之總日劑量投與。Clause 480. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2150 mg.
條款481. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2200 mg之總日劑量投與。Clause 481. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2200 mg.
條款482. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2250 mg之總日劑量投與。Clause 482. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2250 mg.
條款483. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2300 mg之總日劑量投與。Clause 483. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2300 mg.
條款484. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2350 mg之總日劑量投與。Clause 484. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2350 mg.
條款485. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2400 mg之總日劑量投與。Clause 485. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a total daily dose of 2400 mg.
條款486. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至2400 mg之劑量一天一次投與。Clause 486. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 200 mg to 2400 mg.
條款487. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg至2000 mg之劑量一天一次投與。Clause 487. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 400 mg to 2000 mg.
條款488. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg至1200 mg之劑量一天一次投與。Clause 488. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 600 mg to 1200 mg.
條款489. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg之劑量一天一次投與。Clause 489. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 200 mg.
條款490. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以250 mg之劑量一天一次投與。Clause 490. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 250 mg.
條款491. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg之劑量一天一次投與。Clause 491. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 300 mg.
條款492. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以350 mg之劑量一天一次投與。Clause 492. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 350 mg.
條款493. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之劑量一天一次投與。Clause 493. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 400 mg.
條款494. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之劑量一天一次投與。Clause 494. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 450 mg.
條款495. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之劑量一天一次投與。Clause 495. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 500 mg.
條款496. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之劑量一天一次投與。Clause 496. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 550 mg.
條款497. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之劑量一天一次投與。Clause 497. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 600 mg.
條款498. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之劑量一天一次投與。Clause 498. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 650 mg.
條款499. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之劑量一天一次投與。Clause 499. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 700 mg.
條款500. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之劑量一天一次投與。Clause 500. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 750 mg.
條款501. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之劑量一天一次投與。Clause 501. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 800 mg.
條款502. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物, 該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之劑量一天一次投與。Clause 502. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 850 mg.
條款503. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之劑量一天一次投與。Clause 503. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 900 mg.
條款504. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之劑量一天一次投與。Clause 504. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 950 mg.
條款505. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之劑量一天一次投與。Clause 505. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1000 mg.
條款506. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之劑量一天一次投與。Clause 506. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1050 mg.
條款507. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之劑量一天一次投與。Clause 507. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1100 mg.
條款508. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之劑量一天一次投與。Clause 508. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1150 mg.
條款509. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之劑量一天一次投與。Clause 509. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1200 mg.
條款510. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1250 mg之劑量一天一次投與。Clause 510. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1250 mg.
條款511. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1300 mg之劑量一天一次投與。Clause 511. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1300 mg.
條款512. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1350 mg之劑量一天一次投與。Clause 512. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1350 mg.
條款513. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1400 mg之劑量一天一次投與。Clause 513. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1400 mg.
條款514. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1450 mg之劑量一天一次投與。Clause 514. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1450 mg.
條款515. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1500 mg之劑量一天一次投與。Clause 515. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1500 mg.
條款516. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1550 mg之劑量一天一次投與。Clause 516. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1550 mg.
條款517. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1600 mg之劑量一天一次投與。Clause 517. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1600 mg.
條款518. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1650 mg之劑量一天一次投與。Clause 518. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1650 mg.
條款519. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1700 mg之劑量一天一次投與。Clause 519. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1700 mg.
條款520. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1750 mg之劑量一天一次投與。Clause 520. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1750 mg.
條款521. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1800 mg之劑量一天一次投與。Clause 521. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1800 mg.
條款522. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1850 mg之劑量一天一次投與。Clause 522. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1850 mg.
條款523. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1900 mg之劑量一天一次投與。Clause 523. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1900 mg.
條款524. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1950 mg之劑量一天一次投與。Clause 524. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 1950 mg.
條款525. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2000 mg之劑量一天一次投與。Clause 525. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2000 mg.
條款526. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2050 mg之劑量一天一次投與。Clause 526. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2050 mg.
條款527. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2100 mg之劑量一天一次投與。Clause 527. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2100 mg.
條款528. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2150 mg之劑量一天一次投與。Clause 528. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2150 mg.
條款529. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2200 mg之劑量一天一次投與。Clause 529. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2200 mg.
條款530. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2250 mg之劑量一天一次投與。Clause 530. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2250 mg.
條款531. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2300 mg之劑量一天一次投與。Clause 531. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2300 mg.
條款532. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2350 mg之劑量一天一次投與。Clause 532. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2350 mg.
條款533. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以2400 mg之劑量一天一次投與。Clause 533. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered once a day in a dose of 2400 mg.
條款534. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以100 mg至1200 mg之劑量一天兩次投與。Clause 534. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 100 mg to 1200 mg twice a day.
條款535. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg至1000 mg之劑量一天兩次投與。Clause 535. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 200 mg to 1000 mg twice a day.
條款536. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg至600 mg之劑量一天兩次投與。Clause 536. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 300 mg to 600 mg twice a day.
條款537. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以100 mg之劑量一天兩次投與。Clause 537. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 100 mg twice a day.
條款538. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以150 mg之劑量一天兩次投與。Clause 538. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 150 mg twice a day.
條款539. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以200 mg之劑量一天兩次投與。Clause 539. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 200 mg twice a day.
條款540. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以250 mg之劑量一天兩次投與。Clause 540. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 250 mg twice a day.
條款541. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以300 mg之劑量一天兩次投與。Clause 541. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 300 mg twice a day.
條款542. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以350 mg之劑量一天兩次投與。Clause 542. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 350 mg twice a day.
條款543. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以400 mg之劑量一天兩次投與。Clause 543. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 400 mg twice a day.
條款544. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以450 mg之劑量一天兩次投與。Clause 544. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 450 mg twice a day.
條款545. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以500 mg之劑量一天兩次投與。Clause 545. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 500 mg twice a day.
條款546. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以550 mg之劑量一天兩次投與。Clause 546. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 550 mg twice a day.
條款547. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以600 mg之劑量一天兩次投與。Clause 547. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 600 mg twice a day.
條款548. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以650 mg之劑量一天兩次投與。Clause 548. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 650 mg twice a day.
條款549. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以700 mg之劑量一天兩次投與。Clause 549. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 700 mg twice a day.
條款550. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以750 mg之劑量一天兩次投與。Clause 550. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 750 mg twice a day.
條款551. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以800 mg之劑量一天兩次投與。Clause 551. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 800 mg twice a day.
條款552. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以850 mg之劑量一天兩次投與。Clause 552. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 850 mg twice a day.
條款553. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以900 mg之劑量一天兩次投與。Clause 553. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 900 mg twice a day.
條款554. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以950 mg之劑量一天兩次投與。Clause 554. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 950 mg twice a day.
條款555. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1000 mg之劑量一天兩次投與。Clause 555. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 1000 mg twice a day.
條款556. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1050 mg之劑量一天兩次投與。Clause 556. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 1050 mg twice a day.
條款557. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1100 mg之劑量一天兩次投與。Clause 557. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 1100 mg twice a day.
條款558. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1150 mg之劑量一天兩次投與。Clause 558. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 1150 mg twice a day.
條款559. 根據條款345-441中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽以1200 mg之劑量一天兩次投與。Clause 559. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-441, wherein the compound, the styrene salt or the erbumin salt is administered in a dose of 1200 mg twice a day.
條款560. 根據條款345-559中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該化合物、該緩血酸胺鹽或該特丁胺鹽經由口服劑型投與。Clause 560. A compound, a styrene salt, an erbumin salt or a pharmaceutical composition for use according to any one of clauses 345-559, wherein the compound, the styrene salt or the erbumin salt is administered via an oral dosage form.
條款561. 根據條款560之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該口服劑型為錠劑。Clause 561. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 560, wherein the oral dosage form is a tablet.
條款562. 根據條款358-362、367-374、401、402或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該CDK4及6抑制劑或其醫藥學上可接受之鹽為哌柏西利、瑞博西利或阿貝西利或其醫藥學上可接受之鹽。Clause 562. A compound, sulphonamide salt, terbucillamide salt or pharmaceutical composition for use according to any one of clauses 358-362, 367-374, 401, 402 or 415-561, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is palbociclib, ribociclib or abemaciclib or a pharmaceutically acceptable salt thereof.
條款563. 根據條款358-362、367-374、401、402或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該CDK4及6抑制劑或其醫藥學上可接受之鹽為阿貝西利。Clause 563. A compound, sedative amine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358-362, 367-374, 401, 402 or 415-561, wherein the CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof is abemaciclib.
條款564. 根據條款563之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿貝西利以50-200 mg口服劑量一天兩次投與。Clause 564. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered orally in a dose of 50-200 mg twice a day.
條款565. 根據條款563之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿貝西利以50 mg口服劑量一天兩次投與。Clause 565. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered orally in a dose of 50 mg twice a day.
條款566. 根據條款563之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿貝西利以100 mg口服劑量一天兩次投與。Clause 566. A compound, a sulphonamide salt, an erbumin salt or a pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered orally in a dose of 100 mg twice a day.
條款567. 根據條款563之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿貝西利以150 mg口服劑量一天兩次投與。Clause 567. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered in an oral dose of 150 mg twice a day.
條款568. 根據條款563之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿貝西利以200 mg口服劑量一天兩次投與。Clause 568. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 563, wherein abemaciclib is administered orally in a dose of 200 mg twice a day.
條款569. 根據條款358、363-370、399、400或415-568中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該SERD或其醫藥學上可接受之鹽為氟維司群、伊魯司群、吉雷司群、安森司群、瑞妥司群、AZD9833或LSZ102。Clause 569. A compound, sedative salt, terbuprofen salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant, ilulostrand, giredostat, ansonostrand, retostat, AZD9833 or LSZ102.
條款570. 根據條款358、363-370、399、400或415-568中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該SERD或其醫藥學上可接受之鹽為氟維司群。Clause 570. A compound, sedative salt, terbuprofen salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or a pharmaceutically acceptable salt thereof is fulvestrant.
條款571. 根據條款570之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中氟維司群在第一個28天週期(週期1)之第1天及第15天，及在第二個及任何後續28天週期(週期2及後續週期)之第1天以500 mg肌肉內劑量投與。Clause 571. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 570, wherein fulvestrant is administered in a 500 mg intramuscular dose on days 1 and 15 of the first 28-day cycle (Cycle 1) and on day 1 of the second and any subsequent 28-day cycles (Cycle 2 and subsequent cycles).
條款572. 根據條款358、363-370、399、400或415-568中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該SERD或其醫藥學上可接受之鹽為伊魯司群。Clause 572. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 363-370, 399, 400 or 415-568, wherein the SERD or a pharmaceutically acceptable salt thereof is ilustrant.
條款573. 根據條款572之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中伊魯司群以400 mg口服劑量每天一次投與。Clause 573. A compound, a sedative salt, an erbumin salt or a pharmaceutical composition for use according to clause 572, wherein ilustrant is administered orally in a dose of 400 mg once daily.
條款574. 根據條款358、371-374或411-568中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為阿那曲唑、來曲唑或依西美坦。Clause 574. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to any one of clauses 358, 371-374 or 411-568, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole, letrozole or exemestane.
條款575. 根據條款574之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為阿那曲唑。Clause 575. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is anastrozole.
條款576. 根據條款575之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中阿那曲唑以1 mg口服劑量每天一次投與。Clause 576. A compound, a sulphonamide salt, an terbumin salt or a pharmaceutical composition for use according to clause 575, wherein anastrozole is administered in a 1 mg oral dose once daily.
條款577. 根據條款574之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為來曲唑。Clause 577. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is letrozole.
條款578. 根據條款577之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中來曲唑以2.5 mg口服劑量每天一次投與，或對於患有肝硬化或嚴重肝損傷之患者，以2.5 mg口服劑量每隔一天一次投與。Clause 578. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to clause 577, wherein letrozole is administered orally in a dose of 2.5 mg once a day or, for patients with cirrhosis or severe liver damage, in a dose of 2.5 mg once every other day.
條款579. 根據條款574之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該芳香酶抑制劑或其醫藥學上可接受之鹽為依西美坦。Clause 579. A compound, sulphonamide salt, erbumin salt or pharmaceutical composition for use according to clause 574, wherein the aromatase inhibitor or a pharmaceutically acceptable salt thereof is exemestane.
條款580. 根據條款579之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中依西美坦以25 mg口服劑量每天一次投與。Clause 580. A compound, a sedative amine salt, an erbumin salt or a pharmaceutical composition for use according to clause 579, wherein exemestane is administered in an oral dose of 25 mg once a day.
條款581. 根據條款358、375-378或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該紫杉烷或其醫藥學上可接受之鹽為太平洋紫杉醇或多西紫杉醇。Clause 581. A compound, sedative salt, terbuprenorphine salt or pharmaceutical composition for use according to any one of clauses 358, 375-378 or 415-561, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel or docetaxel.
條款582. 根據條款358、375-378或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該紫杉烷或其醫藥學上可接受之鹽為太平洋紫杉醇。Clause 582. A compound, sedative salt, terbuprofen salt or pharmaceutical composition for use according to any one of clauses 358, 375-378 or 415-561, wherein the taxane or a pharmaceutically acceptable salt thereof is paclitaxel.
條款583. 根據條款582之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中太平洋紫杉醇在第一個劑量週期之第8天、第15天及第22天，且接著在所有後續劑量週期之第1天、第8天、第15天及第22天以80 mg/m2注射投與。Clause 583. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 582, wherein paclitaxel is administered by injection at 80 mg/m2 on days 8, 15 and 22 of the first dosing cycle and then on days 1, 8, 15 and 22 of all subsequent dosing cycles.
條款584. 根據條款358、379、380、399、400、415-561或569-573中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該mTOR抑制劑或其醫藥學上可接受之鹽為西羅莫司、坦羅莫司、依維莫司或RMC-5552。Clause 584. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 379, 380, 399, 400, 415-561 or 569-573, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is sirolimus, temsirolimus, everolimus or RMC-5552.
條款585. 根據條款584之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該mTOR抑制劑或其醫藥學上可接受之鹽為依維莫司。Clause 585. A compound, sedative amine salt, terbumin salt or pharmaceutical composition for use according to clause 584, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is everolimus.
條款586. 根據條款585之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該依維莫司以10 mg口服劑量每天一次投與。Clause 586. A compound, a sedative amine salt, an erbumin salt or a pharmaceutical composition for use according to clause 585, wherein the everolimus is administered in a 10 mg oral dose once daily.
條款587. 根據條款584之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該mTOR抑制劑或其醫藥學上可接受之鹽為RMC-5552。Clause 587. A compound, sedative amine salt, terbumin salt or pharmaceutical composition for use according to clause 584, wherein the mTOR inhibitor or a pharmaceutically acceptable salt thereof is RMC-5552.
條款588. 根據條款358、381、382或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為來那替尼或阿法替尼。Clause 588. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to any one of clauses 358, 381, 382 or 415-561, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib or afatinib.
條款589. 根據條款588之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為來那替尼。Clause 589. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to clause 588, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is neratinib.
條款590. 根據條款589之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該來那替尼以240 mg口服劑量每天一次投與。Clause 590. A compound, a serotonin salt, a terbumin salt or a pharmaceutical composition for use according to clause 589, wherein the neratinib is administered orally in a dose of 240 mg once daily.
條款591. 根據條款588之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該酪胺酸激酶抑制劑或其醫藥學上可接受之鹽為阿法替尼。Clause 591. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to clause 588, wherein the tyrosine kinase inhibitor or a pharmaceutically acceptable salt thereof is afatinib.
條款592. 根據條款591之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該阿法替尼以40 mg口服劑量每天一次投與，或在患有嚴重腎損傷之患者中，以30 mg口服劑量每天一次投與。Clause 592. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to clause 591, wherein the afatinib is administered at a dose of 40 mg orally once daily, or in patients with severe renal impairment, at a dose of 30 mg orally once daily.
條款593. 根據條款358、383、384、409、410或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該鉑劑為順鉑、卡鉑或奧沙利鉑。Clause 593. A compound, sulphonamide salt, terbuthamide salt or pharmaceutical composition for use according to any one of clauses 358, 383, 384, 409, 410 or 415-561, wherein the platinum agent is cisplatin, carboplatin or oxaliplatin.
條款594. 根據條款593之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該鉑劑為順鉑。Clause 594. A compound, sulphonamide salt, terbuthamide salt or pharmaceutical composition for use according to clause 593, wherein the platinum agent is cis-platinum.
條款595. 根據條款358、391、392或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該蒽環黴素或其醫藥學上可接受之鹽為多柔比星、道諾黴素、表柔比星或艾達黴素。Clause 595. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 391, 392 or 415-561, wherein the anthracycline or a pharmaceutically acceptable salt thereof is doxorubicin, daunorubicin, epirubicin or idarucizumab.
條款596. 根據條款358、385、386、401、402或415-568中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該免疫檢查點抑制劑或其醫藥學上可接受之鹽為CTLA-4抑制劑、PD-1抑制劑或PD-L1抑制劑。Clause 596. A compound, sedative amine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 385, 386, 401, 402 or 415-568, wherein the immune checkpoint inhibitor or a pharmaceutically acceptable salt thereof is a CTLA-4 inhibitor, a PD-1 inhibitor or a PD-L1 inhibitor.
條款597. 根據條款596之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該免疫檢查點抑制劑為CTLA-4抑制劑。Clause 597. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to clause 596, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.
條款598. 根據條款597之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該CTLA-4抑制劑為伊匹單抗或曲美單抗。Clause 598. A compound, a sedative amine salt, a terbumin salt or a pharmaceutical composition for use according to clause 597, wherein the CTLA-4 inhibitor is ipilimumab or tremelimumab.
條款599. 根據條款596之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該免疫檢查點抑制劑為PD-1抑制劑。Clause 599. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 596, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
條款600. 根據條款599之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PD-1抑制劑為帕博利珠單抗、納武利尤單抗、信迪利單抗、西米普利單抗或替雷利珠單抗。Clause 600. A compound, a serotonin salt, a terbumin salt or a pharmaceutical composition for use according to clause 599, wherein the PD-1 inhibitor is pembrolizumab, nivolumab, sintilimab, cemiplizumab or tislelizumab.
條款601. 根據條款596之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該免疫檢查點抑制劑為PD-L1抑制劑。Clause 601. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 596, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.
條款602. 根據條款601之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PD-L1抑制劑為阿特珠單抗、阿維魯單抗或度伐魯單抗。Clause 602. A compound, a sedative amine salt, a terbumin salt or a pharmaceutical composition for use according to clause 601, wherein the PD-L1 inhibitor is atezolizumab, avelumab or durvalumab.
條款603. 根據條款358、387、388或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗雄激素或其醫藥學上可接受之鹽為阿比特龍、恩雜魯胺、尼魯米特、氟他胺或達洛魯胺，較佳為阿比特龍、恩雜魯胺、尼魯米特或氟他胺。Clause 603. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 387, 388 or 415-561, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is abiraterone, enzalumide, nilutamide, flutamide or darolamide, preferably abiraterone, enzalumide, nilutamide or flutamide.
條款604. 根據條款603之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗雄激素或其醫藥學上可接受之鹽為恩雜魯胺。Clause 604. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 603, wherein the antiandrogen or a pharmaceutically acceptable salt thereof is enzalutamide.
條款605. 根據條款604之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該恩雜魯胺以160 mg口服劑量每天一次投與。Clause 605. A compound, a sulphonamide salt, an terbumin salt or a pharmaceutical composition for use according to clause 604, wherein the enzaluamide is administered in an oral dose of 160 mg once daily.
條款606. 根據條款358、389、390或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗HER2單株抗體為曲妥珠單抗、馬戈妥昔單抗或帕妥珠單抗。Clause 606. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 389, 390 or 415-561, wherein the anti-HER2 monoclonal antibody is trastuzumab, magotuximab or pertuzumab.
條款607. 根據條款606之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗HER2單株抗體為曲妥珠單抗。Clause 607. A compound, a sedative amine salt, a terbumin salt or a pharmaceutical composition for use according to clause 606, wherein the anti-HER2 monoclonal antibody is trastuzumab.
條款608. 根據條款358、389、390或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗HER2抗體-藥物結合物為德曲妥珠單抗或恩美曲妥珠單抗。Clause 608. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 389, 390 or 415-561, wherein the anti-HER2 antibody-drug conjugate is trastuzumab emtansine or trastuzumab emtansine.
條款609. 根據條款608之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該抗HER2抗體-藥物結合物為德曲妥珠單抗。Clause 609. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 608, wherein the anti-HER2 antibody-drug conjugate is trastuzumab.
條款610. 根據條款358、393、394或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該KRAS抑制劑或其醫藥學上可接受之鹽為索托拉西布或阿達格拉西布。Clause 610. A compound, sedative amine salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 393, 394 or 415-561, wherein the KRAS inhibitor or a pharmaceutically acceptable salt thereof is sotolacizumab or adagracib.
條款611. 根據條款358、395、396或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該MEK抑制劑或其醫藥學上可接受之鹽為曲美替尼。Clause 611. A compound, sulphonamide salt, terbuminamide salt or pharmaceutical composition for use according to any one of clauses 358, 395, 396 or 415-561, wherein the MEK inhibitor or a pharmaceutically acceptable salt thereof is trametinib.
條款612. 根據條款358、403、404、409、410、414-561、593或594中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該拓樸異構酶抑制劑或其醫藥學上可接受之鹽為依託泊苷。Clause 612. A compound, sulphonamide salt, terbufamide salt or pharmaceutical composition for use according to any one of clauses 358, 403, 404, 409, 410, 414-561, 593 or 594, wherein the topoisomerase inhibitor or a pharmaceutically acceptable salt thereof is etoposide.
條款613. 根據條款358、405、406或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該SERM或其醫藥學上可接受之鹽為他莫昔芬或托瑞米芬。Clause 613. A compound, sedative amine salt, terbufamine salt or pharmaceutical composition for use according to any one of clauses 358, 405, 406 or 415-561, wherein the SERM or a pharmaceutically acceptable salt thereof is tamoxifen or toremifene.
條款614. 根據條款358、407、408或415-561中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PARP抑制劑或其醫藥學上可接受之鹽為奧拉帕尼或他拉唑帕尼。Clause 614. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 358, 407, 408 or 415-561, wherein the PARP inhibitor or a pharmaceutically acceptable salt thereof is olaparib or talazoparib.
條款615. 根據條款345-614中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中患者先前未接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。Clause 615. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-614, wherein the patient has not previously been treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款616. 根據條款345-614中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽治療。Clause 616. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-614, wherein the patient has previously been treated with a PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof.
條款617. 根據條款616之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽為阿培利司或伊納沃利西布。Clause 617. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to clause 616, wherein the PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellisib or inavolisibub.
條款618. 根據條款617之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該PI3K/AKT/mTOR抑制劑或其醫藥學上可接受之鹽為阿培利司。Clause 618. A compound, sulphonamide salt, terbuprenorphine salt or pharmaceutical composition for use according to clause 617, wherein the PI3K/AKT/mTOR inhibitor or a pharmaceutically acceptable salt thereof is apellis.
條款619. 根據條款345-618中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中患者先前未接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。Clause 619. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-618, wherein the patient has not previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款620. 根據條款345-618中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療。Clause 620. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-618, wherein the patient has previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款621. 根據條款345-618中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過CDK4及6抑制劑或其醫藥學上可接受之鹽治療，以及內分泌療法。Clause 621. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-618, wherein the patient has previously been treated with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and endocrine therapy.
條款622. 根據條款345-621中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中患者先前未接受過SERD或其醫藥學上可接受之鹽治療。Clause 622. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any of clauses 345-621, wherein the patient has not previously been treated with a SERD or a pharmaceutically acceptable salt thereof.
條款623. 根據條款345-621中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過SERD或其醫藥學上可接受之鹽治療。Clause 623. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any of clauses 345-621, wherein the patient has previously been treated with a SERD or a pharmaceutically acceptable salt thereof.
條款624. 根據條款345-623中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中患者先前未接受過芳香酶抑制劑或其醫藥學上可接受之鹽治療。Clause 624. A compound, sedative salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-623, wherein the patient has not previously been treated with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款625. 根據條款345-623中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過芳香酶抑制劑或其醫藥學上可接受之鹽治療。Clause 625. A compound, sulphonamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-623, wherein the patient has previously been treated with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款626. 根據條款345-625中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中患者先前未接受過紫杉烷或其醫藥學上可接受之鹽治療。Clause 626. A compound, selexicam salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-625, wherein the patient has not previously received treatment with a taxane or a pharmaceutically acceptable salt thereof.
條款627. 根據條款345-625中任一項之供使用之化合物、緩血酸胺鹽、特丁胺鹽或醫藥組合物，其中該患者先前接受過紫杉烷或其醫藥學上可接受之鹽治療。Clause 627. A compound, selexiamide salt, terbumin salt or pharmaceutical composition for use according to any one of clauses 345-625, wherein the patient has previously been treated with a taxane or a pharmaceutically acceptable salt thereof.
條款628. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑。Clause 628. Use of a compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer.
條款629. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑。Clause 629. Use of a compound of any one of clauses 1 to 22, a styrene salt of any one of clauses 23 to 47, an erbium salt of any one of clauses 48 to 60 or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant tumor.
條款630. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑。Clause 630. Use of a compound of any one of clauses 1-22, a sedative amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for the treatment of PIK3CA mutant breast cancer.
條款631. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑。Clause 631. Use of a compound of any one of clauses 1 to 22, a sedative amine salt of any one of clauses 23 to 47, an erbamide salt of any one of clauses 48 to 60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation.
條款632. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 632. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款633. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 633. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款634. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 634. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for the treatment of PIK3CA mutant breast cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款635. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與CDK4及6抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 635. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof.
條款636. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 636. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.
條款637. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 637. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.
條款638. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 638. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.
條款639. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與SERD或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 639. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a SERD or a pharmaceutically acceptable salt thereof.
條款640. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。Clause 640. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
條款641. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。Clause 641. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
條款642. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。Clause 642. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
條款643. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii) SERD或其醫藥學上可接受之鹽。Clause 643. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) a SERD or a pharmaceutically acceptable salt thereof.
條款644. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 644. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款645. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 645. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款646. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 646. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款647. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與以下同時、分開或依序組合投與：(i) CDK4及6抑制劑或其醫藥學上可接受之鹽，及(ii)芳香酶抑制劑或其醫藥學上可接受之鹽。Clause 647. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is administered simultaneously, separately, or sequentially in combination with: (i) a CDK4 and 6 inhibitor or a pharmaceutically acceptable salt thereof, and (ii) an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款648. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 648. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant cancer, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately, or sequentially.
條款649. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 649. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a taxane or a pharmaceutically acceptable salt thereof.
條款650. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 650. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutant breast cancer, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered in combination with a taxane or a pharmaceutically acceptable salt thereof simultaneously, separately, or sequentially.
條款651. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與紫杉烷或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 651. Use of a compound of any one of clauses 1-22, a selenoic acid amine salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for the treatment of advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the selenoic acid amine salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with a taxane or a pharmaceutically acceptable salt thereof.
條款652. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變癌症用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 652. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating PIK3CA mutation cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款653. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變實體腫瘤用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 653. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating a PIK3CA mutant solid tumor, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款654. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 654. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for the treatment of PIK3CA mutant breast cancer, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款655. 一種條款1-22中任一項之化合物、條款23-47中任一項之緩血酸胺鹽、條款48-60中任一項之特丁胺鹽或條款61之醫藥組合物的用途，其用於製造供治療PIK3CA突變晚期或轉移性乳癌用的藥劑，其中該化合物、該緩血酸胺鹽、該特丁胺鹽或該醫藥組合物將與芳香酶抑制劑或其醫藥學上可接受之鹽同時、分開或依序組合投與。Clause 655. Use of a compound of any one of clauses 1-22, a styrene salt of any one of clauses 23-47, an erbumin salt of any one of clauses 48-60, or a pharmaceutical composition of clause 61 for the manufacture of a medicament for treating advanced or metastatic breast cancer with a PIK3CA mutation, wherein the compound, the styrene salt, the erbumin salt, or the pharmaceutical composition is to be administered simultaneously, separately, or sequentially in combination with an aromatase inhibitor or a pharmaceutically acceptable salt thereof.
條款656. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 656. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
條款657. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與200 mg至800 mg、較佳300 mg至600 mg總日劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 657. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg, of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of fulvestrant.
條款658. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天一次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 658. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient once a day a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
條款659. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天一次向該患者投與600 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 659. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient once a day a 600 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
條款660. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天兩次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 660. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant twice a day.
條款661. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 661. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of Fulvestrant.
條款662. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與200 mg至800 mg、較佳300 mg至600 mg總日劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 662. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg, of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of fulvestrant.
條款663. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天一次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 663. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient once a day a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of fulvestrant.
條款664. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天一次向該患者投與600 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 664. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient once a day a 600 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of fulvestrant.
條款665. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天兩次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之氟維司群。Clause 665. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of fulvestrant twice a day.
條款666. 條款656-665中任一項之方法，其中氟維司群在第1天、第15天及第29天以及此後每個月一次以500 mg肌肉內劑量投與。Clause 666. The method of any of clauses 656-665, wherein fulvestrant is administered in a 500 mg intramuscular dose on day 1, day 15, and day 29 and once monthly thereafter.
條款667. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 667. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款668. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含向該患者投與200 mg至800 mg、較佳300 mg至600 mg總日劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 668. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg, of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款669. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天一次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 669. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient once a day a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款670. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天一次向該患者投與600 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 670. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient once a day a 600 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款671. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之患者的方法，其包含一天兩次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 671. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, comprising administering to the patient a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant twice a day.
條款672. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與有效量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 672. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient an effective amount of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款673. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含向該患者投與200 mg至800 mg、較佳300 mg至600 mg總日劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 673. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg, of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款674. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天一次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 674. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient once a day a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款675. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天一次向該患者投與600 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 675. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient once a day a 600 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant.
條款676. 一種治療患有激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌之先前用內分泌療法治療之患者的方法，其包含一天兩次向該患者投與300 mg劑量之化合物A或其醫藥學上可接受之鹽，以及有效量之伊魯司群。Clause 676. A method for treating a patient with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer who has been previously treated with endocrine therapy, comprising administering to the patient a 300 mg dose of Compound A or a pharmaceutically acceptable salt thereof, and an effective amount of ilustrant twice a day.
條款677. 條款667-676中任一項之方法，其中伊魯司群以400 mg之劑量一天一次投與。Clause 677. The method of any of clauses 667-676, wherein ilustrant is administered once a day in a dose of 400 mg.
條款678. 條款656-677中任一項之方法，其中該患者已在進行單獨或與CDK4/6抑制劑組合之內分泌療法時或之後進展或復發。Clause 678. The method of any of clauses 656-677, wherein the patient has progressed or relapsed during or after endocrine therapy, alone or in combination with a CDK4/6 inhibitor.
條款679. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。Clause 679. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant, either simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
條款680. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中化合物A或其醫藥學上可接受之鹽以200 mg至800 mg，較佳300 mg至600 mg之總日劑量投與患者。Clause 680. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg.
條款681. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Article 681. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款682. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中600 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Article 682. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款683. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天兩次投與患者。Article 683. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient twice a day.
條款684. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。Clause 684. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant, either simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy.
條款685. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中化合物A或其醫藥學上可接受之鹽以200 mg至800 mg，較佳300 mg至600 mg之總日劑量投與患者。Clause 685. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg.
條款686. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Clause 686. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款687. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中600 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Clause 687. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款688. 化合物A或其醫藥學上可接受之鹽，其與氟維司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天兩次投與患者。Clause 688. Compound A or a pharmaceutically acceptable salt thereof, used in combination with fulvestrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient twice a day.
條款689. 供條款679-688中任一項使用之化合物或其醫藥學上可接受之鹽，其中氟維司群在第1天、第15天及第29天以及此後每個月一次以500 mg肌肉內劑量投與該患者。Clause 689. A compound or a pharmaceutically acceptable salt thereof for use in any one of clauses 679-688, wherein fulvestrant is administered to the patient in a 500 mg intramuscular dose on day 1, day 15 and day 29 and once monthly thereafter.
條款690. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。Clause 690. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer.
條款691. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中化合物A或其醫藥學上可接受之鹽以200 mg至800 mg，較佳300 mg至600 mg之總日劑量投與患者。Article 691. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg.
條款692. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Article 692. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款693. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中600 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Clause 693. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款694. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天兩次投與患者。Clause 694. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient twice a day.
條款695. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌。Clause 695. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant, either simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy.
條款696. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中化合物A或其醫藥學上可接受之鹽以200 mg至800 mg，較佳300 mg至600 mg之總日劑量投與患者。Clause 696. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein Compound A or a pharmaceutically acceptable salt thereof is administered to the patient in a total daily dose of 200 mg to 800 mg, preferably 300 mg to 600 mg.
條款697. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Article 697. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款698. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中600 mg之化合物A或其醫藥學上可接受之鹽一天一次投與患者。Clause 698. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially, for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 600 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient once a day.
條款699. 化合物A或其醫藥學上可接受之鹽，其與伊魯司群同時、分開或依序組合使用，用於治療先前用內分泌療法治療之激素受體陽性(HR+)、人類表皮生長因子受體2陰性(HER2-)、PIK3CA H1047R突變晚期或轉移性乳癌，其中300 mg之化合物A或其醫藥學上可接受之鹽一天兩次投與患者。Clause 699. Compound A or a pharmaceutically acceptable salt thereof, used in combination with ilustrant simultaneously, separately or sequentially for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA H1047R mutation advanced or metastatic breast cancer previously treated with endocrine therapy, wherein 300 mg of Compound A or a pharmaceutically acceptable salt thereof is administered to the patient twice a day.
條款700. 供條款690-699中任一項使用之化合物或其醫藥學上可接受之鹽，其中伊魯司群以400 mg之劑量一天一次投與。Clause 700. A compound or a pharmaceutically acceptable salt thereof for use in any one of clauses 690-699, wherein ilustrant is administered once a day in a dose of 400 mg.
條款701. 供條款679-700中任一項使用之化合物或其醫藥學上可接受之鹽，其中該患者已在進行單獨或與CDK4/6抑制劑組合之內分泌療法時或之後進展或復發。 實例 Clause 701. A compound or a pharmaceutically acceptable salt thereof for use in any of clauses 679-700, wherein the patient has progressed or relapsed during or following endocrine therapy, alone or in combination with a CDK4/6 inhibitor.
除非另外說明，否則如所陳述在400 MHz或300 MHz下且在300.3 K下記錄核磁共振(NMR)光譜；以百萬分率(ppm)為單位報導化學位移(δ)。使用Bruker或Varian儀器進行8、16或32次掃描以記錄光譜。 Unless otherwise stated, nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz and at 300.3 K as stated; chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using 8, 16, or 32 scans using Bruker or Varian instruments.
使用諸如Luna-C18 2.0×30 mm或Xbridge Shield RPC18 2.1×50 mm之C-18管柱，使用Agilent 1200或Shimadzu LC-20 AD&MS 2020儀器記錄LC-MS層析圖及光譜。注射體積為0.7-8.0 μl，且流速典型地為0.8或1.2 ml/min。偵測方法為二極體陣列(DAD)及蒸發光散射(ELSD)以及正離子電噴霧電離。MS範圍為100-1000 Da。溶劑為水與乙腈之梯度，其均含有改質劑(通常為0.01-0.04%)，諸如三氟乙酸或碳酸銨。 LC-MS chromatograms and spectra were recorded using Agilent 1200 or Shimadzu LC-20 AD&MS 2020 instruments using C-18 columns such as Luna-C18 2.0×30 mm or Xbridge Shield RPC18 2.1×50 mm. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml/min. The detection methods were diode array (DAD) and evaporative light scattering (ELSD) and positive ion electrospray ionization. The MS range was 100-1000 Da. The solvent was a gradient of water and acetonitrile, both containing a modifier (usually 0.01-0.04%), such as trifluoroacetic acid or ammonium carbonate.
在配備有CuKα (1.5418Å)源及Linxeye偵測器，在40 kV及40 mA下操作之Bruker D8 Endeavor X射線粉末繞射儀上獲得結晶固體之XRPD圖。在4與42 2θ°之間掃描樣品，其中步長為0.009 2θ°且掃描速率為0.5秒/步，且使用0.3°主要狹縫開口及3.9° PSD開口；或在4與30 2θ°之間掃描樣品，其中步長為0.009 2θ°且掃描速率為0.25秒/步，且使用0.3°主要狹縫開口及3.9° PSD開口。將乾粉裝填於石英樣品固持器上且使用玻璃載片獲得平滑表面。在環境溫度及相對濕度下收集晶形繞射圖。在基於在8.853及26.774 2θ°處具有峰之內部NIST 675標準品進行整個圖移動之後，在MDI-Jade中確定晶體峰位置。結晶學技術中已熟知，對於任何既定晶形，由於由諸如晶體結構及習性之因素所產生之較佳取向，繞射峰之相對強度可能變化。在存在較佳取向之影響的情況下，峰強度改變，但多晶型物之特徵峰位置不變。參見例如The United States Pharmacopeia #23, National Formulary #18, 第1843-1844頁, 1995。此外，結晶學技術中亦熟知，對於任何既定晶形，角峰位置可略微變化。舉例而言，峰位置可能由於分析樣品時之溫度變化、樣品移位或存在或不存在內標而偏移。在本發明之情況下，假定± 0.2 2θ°之峰位置變化以考慮此等潛在變化而不妨礙明確鑑別指定晶形。可基於區分峰之任何獨特組合進行晶形之確認。 XRPD patterns of crystalline solids were obtained on a Bruker D8 Endeavor X-ray powder diffraction spectrometer equipped with a CuKα (1.5418Å) source and a Linxeye detector, operated at 40 kV and 40 mA. Samples were scanned between 4 and 42 2θ° with a step size of 0.009 2θ° and a scan rate of 0.5 sec/step, using a 0.3° major slit opening and a 3.9° PSD opening; or between 4 and 30 2θ° with a step size of 0.009 2θ° and a scan rate of 0.25 sec/step, using a 0.3° major slit opening and a 3.9° PSD opening. The dry powder was packed on a quartz sample holder and a glass slide was used to obtain a smooth surface. Crystalline diffraction patterns were collected at ambient temperature and relative humidity. Crystalline peak positions were determined in MDI-Jade after an entire map shift based on an internal NIST 675 standard with peaks at 8.853 and 26.774 2θ°. It is well known in the art of crystallography that for any given crystalline form, the relative intensity of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal structure and behavior. In the presence of the effect of preferred orientation, the peak intensity changes, but the characteristic peak position of the polymorph remains unchanged. See, for example, The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is well known in the art of crystallography that for any given crystalline form, the angular peak positions may vary slightly. For example, the peak positions may shift due to temperature changes when analyzing the sample, sample displacement, or the presence or absence of an internal standard. In the case of the present invention, a peak position variation of ± 0.2 2θ° is assumed to account for these potential variations without hindering the unambiguous identification of a given crystalline form. Confirmation of a crystalline form may be based on any unique combination of distinguishing peaks.
單晶X射線繞射。在配備有銅陽極微聚焦密封X射線管(Cu Kα λ = 1.54184 Å)及Dectris Pilatus3 R 200K混合像素陣列偵測器之Rigaku SuperNova繞射儀上進行初步檢驗及資料收集。使用CRYSALISPRO (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction，2015))實現細胞優化及資料簡化。在室溫下收集資料，直至151.16°或151.992°之最大繞射角(2θ)。使用SHELXT藉由直接方法解析結構(Sheldrick, G.M. Acta Cryst.2015, A71, 3-8)。使用SHELXL-2014精修結構(Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122)。存在於氮上之氫原子經獨立精修。所有其他氫原子包括在精修中，但限於騎在其鍵結之原子上。以全矩陣最小平方精修結構。在MERCURY晶體建模軟體中使用單晶結構之單位晶胞參數及原子座標產生模擬XRPD圖。 Single crystal X-ray diffraction. Preliminary inspection and data collection were performed on a Rigaku SuperNova diffraction instrument equipped with a copper anode microfocus sealed X-ray tube (Cu Kα λ = 1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector. Cell optimization and data reduction were performed using CRYSALISPRO (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). Data were collected at room temperature to a maximum diffraction angle (2θ) of 151.16° or 151.992°. The structure was solved by direct methods using SHELXT (Sheldrick, GM Acta Cryst. 2015, A71, 3-8). The structure was refined using SHELXL-2014 (Sheldrick, GM Acta Cryst. 2008, A64, 112-122). Hydrogen atoms present on nitrogen were refined independently. All other hydrogen atoms were included in the refinement, but were limited to atoms riding on their bonds. The structure was refined using full matrix least squares. The simulated XRPD pattern was generated in MERCURY crystal modeling software using the unit cell parameters and atomic coordinates of the single crystal structure.
使用由TA Thermal Advantage軟體v5.2.6操作之TA Q2000 DSC進行差示掃描熱量測定(DSC)分析，且藉由Universal Analysis 2000 v4.5a分析資料。使樣品在卷邊鋁盤中在25℃下平衡，接著刺穿，接著以10℃/min加熱至300℃且以50 mL/min之氮氣吹掃。溫度及熱流針對銦熔融校準。 Differential scanning calorimetry (DSC) analysis was performed using a TA Q2000 DSC operated by TA Thermal Advantage software v5.2.6, and data were analyzed by Universal Analysis 2000 v4.5a. Samples were equilibrated at 25°C in a crimped aluminum pan, then pierced, then heated to 300°C at 10°C/min and purged with nitrogen at 50 mL/min. Temperature and heat flow were calibrated to indium melt.
使用TA Instruments Q5000 TGA (藉由TA Thermal Advantage軟體v5.2.6操作)收集熱解重量分析，且藉由Universal Analysis 2000 v4.5a分析資料。以10℃/min之速率將樣品(3-10 mg)自環境溫度(大約25℃)加熱至200℃。N 2為載氣(10 mL/min)及吹掃(50 mL/min)氣體。藉由使用鎳及阿留麥爾鎳合金標準品之居里溫度(Curie temperature)測定來校準溫度。用製造商供應之標準品進行重量校準。 Thermogravimetric analyses were collected using a TA Instruments Q5000 TGA (operated by TA Thermal Advantage software v5.2.6) and data were analyzed by Universal Analysis 2000 v4.5a. Samples (3-10 mg) were heated from ambient temperature (approximately 25°C) to 200°C at a rate of 10°C/min. N2 was the carrier (10 mL/min) and sweep (50 mL/min) gas. Temperature was calibrated by Curie temperature determination using nickel and Aluma nickel alloy standards. Weight calibration was performed using manufacturer supplied standards.
固態NMR (ssNMR)在Agilent DD2-400 NMR光譜儀上獲得且用VnmrJ v3.2A處理。資料以176.5 ppm處之甘胺酸為外部參考。
ssNMR參數
縮寫： ACN 乙腈 AcOH 乙酸 ADP 二磷酸腺苷 ATP 三磷酸腺苷 CDCl 3氯仿- dDCM 二氯甲烷 DMF N,N-二甲基甲醯胺 DMSO 二甲亞碸 DMSO- d 6 六氘化二甲亞碸 DSC 差示掃描熱量測定 eq 當量 EtOAc 乙酸乙酯 EtOH 乙醇 h 小時 1H NMR 質子核磁共振光譜學 IPA 異丙醇 Kg 公斤 L 公升 LC-MS 液相層析-質譜分析 MeOH 甲醇 MPa 兆帕斯卡 2-MeTHF 2-甲基四氫呋喃 min 分鐘 MS ES 質譜分析電噴霧 ppm 百萬分率 rt 室溫 SFC 超臨界流體層析 THF 四氫呋喃 TGA 熱解重量分析 XRD X射線繞射 XRPD X射線粉末繞射 實例 1 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸 ( 「 化合物 A 」 )中間物1：丙酸(2-溴-4-甲基-苯基)酯 Abbreviations: ACN acetonitrile AcOH acetic acid ADP adenosine diphosphate ATP adenosine triphosphate CDCl 3 chloroform- d DCM dichloromethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO- d 6 hexadeuterated dimethyl sulfoxide DSC differential scanning calorimetry eq equivalent EtOAc ethyl acetate EtOH ethanol h hour 1 H NMR proton nuclear magnetic resonance spectroscopy IPA isopropyl alcohol Kg kilogram L litre LC-MS liquid chromatography-mass spectrometry MeOH methanol MPa megapascal 2-MeTHF 2-methyltetrahydrofuran min minute MS ES mass spectrometry electrospray ppm parts per million rt room temperature SFC supercritical fluid chromatography THF tetrahydrofuran TGA thermogravimetric analysis XRD X-ray diffraction XRPD X-ray powder diffraction Example 1 2-[[(1R)-1-(3,6 -dimethyl -4- oxo -2- phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid ( " Compound A " ) Intermediate 1: Propionic acid (2-bromo-4-methyl-phenyl) ester
在0℃用丙醯氯(5.44 g，58.8 mmol)處理2-溴-4-甲基-苯酚(10.0 g，53.5 mmol)及吡啶(6.34 g，80.2 mmol)於DCM (100 mL)中之混合物且在25℃攪拌16小時。用水(100 mL)稀釋混合物，用HCl (2 M)將pH調節至5，且用DCM (2×100 mL)萃取。將合併之有機萃取物用鹽水(2×150 mL)洗滌，經無水Na 2SO 4乾燥，過濾且濃縮，得到呈油狀之產物(13 g，粗產物)。 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H)。 中間物2：1-(3-溴-2-羥基-5-甲基-苯基)丙-1-酮 A mixture of 2-bromo-4-methyl-phenol (10.0 g, 53.5 mmol) and pyridine (6.34 g, 80.2 mmol) in DCM (100 mL) was treated with propionyl chloride (5.44 g, 58.8 mmol) at 0 °C and stirred at 25 °C for 16 h. The mixture was diluted with water (100 mL), the pH was adjusted to 5 with HCl (2 M), and extracted with DCM (2 x 100 mL). The combined organic extracts were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4 , filtered and concentrated to give the product as an oil (13 g, crude). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.6 Hz, 3H), 2.30 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 7.11-7.18 (m, 1H), 7.19-7.26 (m, 1H), 7.50-7.55 (m, 1H). Intermediate 2: 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one
途徑1：在140℃下將丙酸(2-溴-4-甲基-苯基)酯(12.5 g，51.4 mmol)與AlCl 3(24.0 g，180 mmol)之混合物攪拌1小時。當冷卻至室溫時，滴加水(80 mL)淬滅混合物且攪拌30分鐘。用EtOAc (3×100 mL)萃取混合物。將合併之有機萃取物用鹽水(2×200 mL)洗滌，經無水Na 2SO 4乾燥，且過濾。濃縮濾液且用石油醚(20 mL)濕磨，得到呈固體狀之產物(9.82 g，79%)。 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H)。 Route 1: A mixture of (2-bromo-4-methyl-phenyl) propanoate (12.5 g, 51.4 mmol) and AlCl 3 (24.0 g, 180 mmol) was stirred at 140 °C for 1 hour. When cooled to room temperature, the mixture was quenched by adding water (80 mL) dropwise and stirred for 30 minutes. The mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (2×200 mL), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated and triturated with petroleum ether (20 mL) to give the product as a solid (9.82 g, 79%). 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 7.66-7.73 (m, 1H), 7.77-7.83 (m, 1H), 12.66 (s, 1H).
途徑2：將丙酸(2-溴-4-甲基-苯基)酯(120 g，496 mmol)轉移至反應器，冷卻至-20℃，且用三氟甲磺酸(216 mL)處理。在添加完成之後，在60℃下攪拌反應1小時。使反應物冷卻至室溫且倒入冰水(600 mL)中。藉由過濾移除呈黃色固體狀之產物(114 g，95%)。MS ES- m/z241, 243 [M-H] -。 1H NMR (400 MHz, CDCl 3) δ ppm 1.26 (t, 3H), 2.33 (s, 3H), 3.06 (q, 2H), 7.55 (m, 2H), 12.87 (s, 1H)。 中間物3：(E)-1-(3-溴-2-羥基-5-甲基-苯基)-2-甲基-3-苯基-丙-2-烯-1-酮 Route 2: Transfer (2-bromo-4-methyl-phenyl) propanoate (120 g, 496 mmol) to the reactor, cool to -20 °C, and treat with trifluoromethanesulfonic acid (216 mL). After the addition is complete, stir the reaction at 60 °C for 1 hour. Allow the reaction to cool to room temperature and pour into ice water (600 mL). Remove the product as a yellow solid (114 g, 95%) by filtration. MS ES- m/z 241, 243 [MH] - . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 1.26 (t, 3H), 2.33 (s, 3H), 3.06 (q, 2H), 7.55 (m, 2H), 12.87 (s, 1H). Intermediate 3: (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one
在70℃下攪拌1-(3-溴-2-羥基-5-甲基-苯基)丙-1-酮(200 g，822.72 mmol)、苯甲醛(96.04 g，904.99 mmol)、AcOH (105.23 g，1.75 mol)及哌啶(172.33 g，2.02 mol)於EtOH (1600 mL)中之混合物16小時。將所得深色溶液倒入水(3 L)中，過濾，且將固體溶解於6 L DCM中。有機溶液經無水Na 2SO 4乾燥，過濾且濃縮，得到呈深色膠狀之產物。MS ES+ m/z331, 333 [M+H] +。 中間物4：8-溴-3,6-二甲基-2-苯基-色烯-4-酮 A mixture of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (200 g, 822.72 mmol), benzaldehyde (96.04 g, 904.99 mmol), AcOH (105.23 g, 1.75 mol) and piperidine (172.33 g, 2.02 mol) in EtOH (1600 mL) was stirred at 70 °C for 16 h. The resulting dark solution was poured into water (3 L), filtered, and the solid was dissolved in 6 L DCM. The organic solution was dried over anhydrous Na2SO4 , filtered and concentrated to give the product as a dark gum. MS ES+ m/z 331, 333 [M+H] + . Intermediate 4: 8-Bromo-3,6-dimethyl-2-phenyl-chromen-4-one
途徑1：在140℃下攪拌(E)-1-(3-溴-2-羥基-5-甲基-苯基)-2-甲基-3-苯基-丙-2-烯-1-酮(284 g，857.48 mmol)與碘(21.76 g，85.75 mmol，17.27 mL，0.1 eq)於DMSO (1200 mL)中之混合物2小時，得到深褐色溶液。冷卻至室溫，將反應物倒入3 L水中，過濾，將固體產物溶解於DCM (4 L)中，經無水Na 2SO 4乾燥，過濾，且濃縮，得到殘餘物。用石油醚/EtOAc (1:1，1 L)濕磨殘餘物，得到呈淡黃色固體狀之產物(195 g，69%)。MS ES+ m/z329, 331 [M+H] +。 Route 1: A mixture of (E)-1-(3-bromo-2-hydroxy-5-methyl-phenyl)-2-methyl-3-phenyl-prop-2-en-1-one (284 g, 857.48 mmol) and iodine (21.76 g, 85.75 mmol, 17.27 mL, 0.1 eq) in DMSO (1200 mL) was stirred at 140 °C for 2 hours to give a dark brown solution. Cool to room temperature, pour the reaction into 3 L of water, filter, dissolve the solid product in DCM (4 L), dry over anhydrous Na2SO4 , filter, and concentrate to give a residue. The residue was triturated with petroleum ether/EtOAc (1:1, 1 L) to give the product as a light yellow solid (195 g, 69%). MS ES+ m/z 329, 331 [M+H] + .
途徑2：使1-(3-溴-2-羥基-5-甲基-苯基)丙-1-酮(50.0 g，205.7 mmol)於THF (100 mL)中之溶液冷卻至-80℃且用雙(三甲基矽基)胺基鋰(1 M於THF中，617 mmol)處理。在-80℃下攪拌1小時後，使混合物升溫至0℃且攪拌1小時。將混合物冷卻至-80℃且滴加苯甲醯氯(37.6 g，267.4 mmol)處理。在添加完成之後，在25℃下攪拌反應16小時。使反應冷卻至-20℃且用50%乙酸水溶液將pH調節至4。真空移除THF且藉由過濾移除沉澱物。將固體溶解於乙酸與HCl水溶液(250 mL/10 mL)中且在100℃下攪拌所得溶液1小時。將混合物冷卻至20℃且用水(100 mL)稀釋。藉由過濾移除固體且用水(50 mL)洗滌且在室溫下用200 mL EtOAc濕磨30分鐘。藉由過濾收集呈灰白色固體狀之產物(170.7 g，83%)。MS ES+ m/z329, 331 [M+H] +。 1H NMR (400 MHz, CDCl 3) δ ppm 2.24 (s, 3H), 2.48 (s, 3H), 7.55-7.57 (m, 3H), 7.75-7.78 (m, 3H), 8.00 (s, 1H)。 中間物5：8-乙醯基-3,6-二甲基-2-苯基-色烯-4-酮 [0136] Route 2: A solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)propan-1-one (50.0 g, 205.7 mmol) in THF (100 mL) was cooled to -80 °C and treated with lithium bis(trimethylsilyl)amide (1 M in THF, 617 mmol). After stirring at -80 °C for 1 hour, the mixture was warmed to 0 °C and stirred for 1 hour. The mixture was cooled to -80 °C and treated with benzoyl chloride (37.6 g, 267.4 mmol) dropwise. After the addition was complete, the reaction was stirred at 25 °C for 16 hours. The reaction was cooled to -20 °C and the pH was adjusted to 4 with 50% aqueous acetic acid. The THF was removed in vacuo and the precipitate was removed by filtration. The solid was dissolved in acetic acid and aqueous HCl (250 mL/10 mL) and the resulting solution was stirred at 100 °C for 1 hour. The mixture was cooled to 20 °C and diluted with water (100 mL). The solid was removed by filtration and washed with water (50 mL) and triturated with 200 mL EtOAc at room temperature for 30 minutes. The product was collected by filtration as an off-white solid (170.7 g, 83%). MS ES+ m/z 329, 331 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 2.24 (s, 3H), 2.48 (s, 3H), 7.55-7.57 (m, 3H), 7.75-7.78 (m, 3H), 8.00 (s, 1H). Intermediate 5: 8-Acetyl-3,6-dimethyl-2-phenyl-chromen-4-one
途徑1：在N 2下在95℃下攪拌8-溴-3,6-二甲基-2-苯基-色烯-4-酮(195 g，592.37 mmol)、二氯化雙(三苯膦)鈀(II) (20.79 g，29.62 mmol)及三丁基(1-乙氧基乙烯基)錫烷(256.72 g，710.84 mmol，239.92 mL)於二㗁烷(1600 mL)中之混合物16小時，得到黑褐色溶液。冷卻至室溫後，用1M HCl水溶液(100 mL)處理反應物且在20℃下攪拌30分鐘。將混合物用KF飽和水溶液(2000 mL)淬滅，攪拌30分鐘，且過濾。用含10% MeOH之DCM (5×5000 mL)洗滌濾餅。合併之萃取物經無水Na 2SO 4乾燥，過濾且濃縮，得到殘餘物。用石油醚/EtOAc (5/1，1000 mL)濕磨殘餘物，得到粗產物，用DCM/MeOH (10/1，500 mL)濕磨粗產物，得到呈淡黃色固體狀之產物(180 g，96%，92%純度)。MS ES+ m/z293 [M+H] +。 Route 1 : A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (195 g, 592.37 mmol), bis(triphenylphosphine)palladium(II) dichloride (20.79 g, 29.62 mmol) and tributyl(1-ethoxyvinyl)tinane (256.72 g, 710.84 mmol, 239.92 mL) in dioxane (1600 mL) was stirred at 95 °C under N2 for 16 hours to give a dark brown solution. After cooling to room temperature, the reaction was treated with 1M aqueous HCl (100 mL) and stirred at 20 °C for 30 minutes. The mixture was quenched with saturated aqueous KF (2000 mL), stirred for 30 minutes, and filtered. The filter cake was washed with 10% MeOH in DCM (5 x 5000 mL). The combined extracts were dried over anhydrous Na2SO4 , filtered and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (5/1, 1000 mL) to give a crude product, which was triturated with DCM/MeOH (10/1, 500 mL) to give the product as a light yellow solid (180 g, 96%, 92% purity). MS ES+ m/z 293 [M+H] + .
途徑2：在氮氣氛圍下在100℃下攪拌8-溴-3,6-二甲基-2-苯基-色烯-4-酮(50.0 g，151.9 mmol)、乙酸鈀(0.34 g，1.52 mmol)、1,3-雙(二苯膦基)丙烷(1.25 g，3.04 mmol)、三乙胺(46.17 g，455.7 mmol)、正丁基乙烯醚(76 g，759.5 mmol)及乙二醇(400 mL)之混合物7小時。使反應物冷卻至30℃且用3 g活性碳處理且攪拌。懸浮液經矽藻土過濾且用HCl將濾液之pH調至3-4且在60℃下攪拌12小時。使反應冷卻至40℃且藉由過濾移除固體。將固體在250 mL THF中漿化且在60℃下攪拌5小時。使反應物冷卻至30℃且藉由過濾移除產物(40 g，90%)且在50℃下乾燥，得到灰白色固體。MS ES+ m/z293 [M+H] +。1H NMR (400 mHz, CDCl 3) δ ppm 2.21 (s, 3H), 2.52 (s, 3H), 2.73 (s, 3H), 7.55-7.58 (m, 3H), 7.67-7.70 (m, 2H), 7.97 (s, 1H), 8.26-8.27 (m, 1H)。 中間物6：(NE,R)-N-[1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)亞乙基]-2-甲基-丙烷-2-亞磺醯胺 Route 2: A mixture of 8-bromo-3,6-dimethyl-2-phenyl-chromen-4-one (50.0 g, 151.9 mmol), sodium acetate (0.34 g, 1.52 mmol), 1,3-bis(diphenylphosphino)propane (1.25 g, 3.04 mmol), triethylamine (46.17 g, 455.7 mmol), n-butyl vinyl ether (76 g, 759.5 mmol) and ethylene glycol (400 mL) was stirred at 100 °C under nitrogen atmosphere for 7 hours. The reaction was cooled to 30 °C and treated with 3 g of activated carbon and stirred. The suspension was filtered through celite and the pH of the filtrate was adjusted to 3-4 with HCl and stirred at 60 °C for 12 hours. The reaction was cooled to 40 °C and the solids were removed by filtration. The solids were slurried in 250 mL THF and stirred at 60 °C for 5 hours. The reaction was cooled to 30 °C and the product (40 g, 90%) was removed by filtration and dried at 50 °C to give an off-white solid. MS ES+ m/z 293 [M+H] + . 1H NMR (400 mHz, CDCl 3 ) δ ppm 2.21 (s, 3H), 2.52 (s, 3H), 2.73 (s, 3H), 7.55-7.58 (m, 3H), 7.67-7.70 (m, 2H), 7.97 (s, 1H), 8.26-8.27 (m, 1H). Intermediate 6: (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide
向8-乙醯基-3,6-二甲基-2-苯基-色烯-4-酮(180 g，615.75 mmol)與(R)-2-甲基丙烷-2-亞磺醯胺(149.26 g，1.23 mol)於THF (1500 mL)中之混合物中添加四異丙氧基鈦(700.01 g，2.46 mol，726.90 mL)。在80℃下攪拌混合物56小時，得到黑褐色溶液。冷卻至室溫後，用鹽水(2000 mL)淬滅反應且攪拌30分鐘及過濾。用EtOAc (4000 mL)洗滌濾餅。在分離有機層之後，用EtOAc (1000 mL)萃取水層。合併之有機萃取物經無水Na 2SO 4乾燥，過濾且濃縮，得到殘餘物。用石油醚/EtOAc (1/1，600 mL)濕磨殘餘物，得到呈白色固體狀之產物(186 g，76%)。MS ES+ m/z396 [M+H] +. 中間物7：(R)-N-[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]-2-甲基-丙烷-2-亞磺醯胺 To a mixture of 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (180 g, 615.75 mmol) and (R)-2-methylpropane-2-sulfenamide (149.26 g, 1.23 mol) in THF (1500 mL) was added titanium tetraisopropoxide (700.01 g, 2.46 mol, 726.90 mL). The mixture was stirred at 80 °C for 56 hours to obtain a dark brown solution. After cooling to room temperature, the reaction was quenched with brine (2000 mL) and stirred for 30 minutes and filtered. The filter cake was washed with EtOAc (4000 mL). After separation of the organic layer, the aqueous layer was extracted with EtOAc (1000 mL). The combined organic extracts were dried over anhydrous Na2SO4 , filtered and concentrated to give a residue. The residue was triturated with petroleum ether/EtOAc (1/1, 600 mL) to give the product as a white solid (186 g, 76%). MS ES+ m/z 396 [M+H] + . Intermediate 7: (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide
在15℃下向(NE,R)-N-[1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)亞乙基]-2-甲基-丙烷-2-亞磺醯胺(186 g，470.27 mmol)與CeCl 3 .7H 2O (87.61 g，235.14 mmol，22.35 mL)於MeOH (1600 mL)中之混合物中添加NaBH 4(26.69 g，705.41 mmol)。在15℃下攪拌混合物1小時，得到深色懸浮液。在15℃下用NH 4Cl飽和水溶液(1500 mL)淬滅反應。用DCM (2×1500 mL)萃取，用鹽水(1500 mL)洗滌合併之有機相，有機相經無水Na 2SO 4乾燥，過濾且濃縮，得到呈黃色固體狀之產物(180 g，96%)。MS ES+ m/z398 [M+H] +。 中間物8：8-[(1R)-1-胺基乙基]-3,6-二甲基-2-苯基-色烯-4-酮 To a mixture of (NE,R)-N-[1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethylidene]-2-methyl-propane-2-sulfenamide (186 g, 470.27 mmol) and CeCl 3 . 7H 2 O (87.61 g, 235.14 mmol, 22.35 mL) in MeOH (1600 mL) at 15° C. was added NaBH 4 (26.69 g, 705.41 mmol). The mixture was stirred at 15° C. for 1 hour to give a dark suspension. The reaction was quenched with saturated aqueous NH 4 Cl solution (1500 mL) at 15° C. Extract with DCM (2×1500 mL), wash the combined organic phases with brine (1500 mL), dry over anhydrous Na 2 SO 4 , filter and concentrate to give the product as a yellow solid (180 g, 96%). MS ES+ m/z 398 [M+H] + . Intermediate 8: 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
用HCl/MeOH (4 M，300 mL)處理(R)-N-[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]-2-甲基-丙烷-2-亞磺醯胺(180 g，452.80 mmol)於MeOH (1500 mL)中之混合物且在15℃下攪拌混合物1小時，得到白色懸浮液。濃縮反應物，將殘餘物倒入水(1000 mL)及DCM (2000 mL)中，用含NH 3之H 2O (25%)將pH調至12，且用DCM (2×1000 mL)萃取。將合併之有機相用鹽水(1000 mL)洗滌，經無水Na 2SO 4乾燥，過濾且濃縮，得到殘餘物。用DCM (200 mL)濕磨殘餘物，得到呈白色固體狀之產物(122 g，89%)。MS ES+ m/z294 [M+H] +. 中間物9：8-[(1S)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮 A mixture of (R)-N-[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]-2-methyl-propane-2-sulfenamide (180 g, 452.80 mmol) in MeOH (1500 mL) was treated with HCl/MeOH (4 M, 300 mL) and the mixture was stirred at 15 °C for 1 hour to give a white suspension. The reaction was concentrated, the residue was poured into water (1000 mL) and DCM (2000 mL), the pH was adjusted to 12 with NH3 in H2O (25%), and extracted with DCM (2 x 1000 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na2SO4 , filtered and concentrated to give a residue. The residue was triturated with DCM (200 mL) to give the product as a white solid (122 g, 89%). MS ES+ m/z 294 [M+H] + . Intermediate 9: 8-[(1S)-1-Hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
向配備有塔頂攪拌及溫度探針之燒瓶中裝入8-乙醯基-3,6-二甲基-2-苯基-色烯-4-酮(11.0 g，37.25 mmol)及氯仿(200 mL)。用甲酸(5.14 g，111.76 mmol)處理攪拌漿液且在冰浴中冷卻至約10℃。用1,8-二氮雜雙環[5.4.0]十一-7-烯(17.01 g，111.76 mmol)緩慢處理冷溶液，保持溫度低於25℃。自冷卻浴移除反應物且用RuCl(對異丙基甲苯)[(S,S)-Ts-DPEN] (CAS 192139-90-5，0.66 g，1.12 mmol)處理。在45℃下攪拌反應16小時。將反應物轉移至分液漏斗，且用2M HCl水溶液(2×50 mL)洗滌。在45-50℃下有機層真空濃縮至50-100 mL。用ACN (150 mL)稀釋且在45-50℃下真空濃縮至50 mL。再次進行溶劑交換直至溶劑量為50 mL。使物質在1-2小時內冷卻至室溫且使漿液老化4小時。藉由過濾收集產物(10.10 g，92%)，用ACN (25 mL)洗滌，用庚烷(50 mL)洗滌，且在45℃下真空乾燥。 中間物10：甲烷磺酸[(1S)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]酯 To a flask equipped with overhead stirring and a temperature probe was charged 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (11.0 g, 37.25 mmol) and chloroform (200 mL). The stirred slurry was treated with formic acid (5.14 g, 111.76 mmol) and cooled to about 10 °C in an ice bath. The cold solution was treated slowly with 1,8-diazabicyclo[5.4.0]undec-7-ene (17.01 g, 111.76 mmol), keeping the temperature below 25 °C. Remove the reaction from the cooling bath and treat with RuCl(p-isopropyltoluene)[(S,S)-Ts-DPEN] (CAS 192139-90-5, 0.66 g, 1.12 mmol). Stir the reaction at 45 °C for 16 hours. Transfer the reaction to a separatory funnel and wash with 2M aqueous HCl (2 x 50 mL). Concentrate the organic layer under vacuum to 50-100 mL at 45-50 °C. Dilute with ACN (150 mL) and concentrate under vacuum to 50 mL at 45-50 °C. Perform solvent exchange again until the solvent volume is 50 mL. Allow the material to cool to room temperature in 1-2 hours and age the slurry for 4 hours. The product (10.10 g, 92%) was collected by filtration, washed with ACN (25 mL), washed with heptane (50 mL), and dried under vacuum at 45 °C. Intermediate 10: Methanesulfonic acid [(1S)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl] ester
向燒瓶中裝入8-[(1S)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮(2.0 g，6.79 mmol)、甲磺酸酐(1.42 g，8.15 mmol)及DCM (20 mL)。溶液在冰浴中冷卻至＜10℃。經5分鐘用三乙胺(1.38 g，13.59 mmol)緩慢處理反應物。自冰浴移出且在室溫下攪拌1小時。按原樣使用此反應混合物。 中間物11：8-[(1R)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮 A flask was charged with 8-[(1S)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (2.0 g, 6.79 mmol), methanesulfonic anhydride (1.42 g, 8.15 mmol) and DCM (20 mL). The solution was cooled to <10 °C in an ice bath. The reaction was treated slowly with triethylamine (1.38 g, 13.59 mmol) over 5 min. Remove from the ice bath and stir at room temperature for 1 h. The reaction mixture was used as is. Intermediate 11: 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
向配備有塔頂攪拌、冷凝器及溫度探針之燒瓶中裝入8-乙醯基-3,6-二甲基-2-苯基-色烯-4-酮(10 g，34.2 mmol)及RuCl(對異丙基甲苯)[(R,R)-TsDPEN] (CAS 192139-92-7，0.65 g，1.03 mmol) 添加50 mL甲醇且開始攪拌。使反應物冷卻至10℃且用1,8-二氮雜雙環[5.4.0]十一-7-烯(15.62 g，102.62 mmol)緩慢處理，保持溫度低於25℃。添加完成後，使反應物冷卻回至10℃，且用甲酸(4.72 g，102.62 mmol)逐份處理反應物，維持溫度低於15℃。在添加後，在55℃下攪拌反應物約3小時。將反應物冷卻至20℃且經1小時用4 M HCl水溶液(50 mL)處理，且在室溫下攪拌所得漿液隔夜。藉由過濾分離產物(9.35 g，95%)，用水洗滌且在45℃下真空乾燥。 中間物11之替代性合成：8-[(1R)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮 To a flask equipped with overhead stirring, condenser and temperature probe was charged 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (10 g, 34.2 mmol) and RuCl(p-isopropyltoluene)[(R,R)-TsDPEN] (CAS 192139-92-7, 0.65 g, 1.03 mmol) Add 50 mL of methanol and start stirring. The reaction was cooled to 10 °C and treated slowly with 1,8-diazabicyclo[5.4.0]undec-7-ene (15.62 g, 102.62 mmol) keeping the temperature below 25 °C. After the addition was complete, the reaction was cooled back to 10 °C and treated with formic acid (4.72 g, 102.62 mmol) portionwise, maintaining the temperature below 15 °C. After the addition, the reaction was stirred at 55 °C for about 3 hours. The reaction was cooled to 20 °C and treated with 4 M aqueous HCl (50 mL) over 1 hour, and the resulting slurry was stirred at room temperature overnight. The product (9.35 g, 95%) was isolated by filtration, washed with water and dried in vacuo at 45 °C. Alternative Synthesis of Intermediate 11: 8-[(1R)-1-Hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
向反應器中裝入THF (3 L/kg，360 L)、8-乙醯基-3,6-二甲基-2-苯基-色烯-4-酮(120 kg，410 mol)及甲醇鈉(2.2 kg，41 mol，0.10 eq)。抽空反應器且用氮氣再填充三次。向反應器中裝入(S)-RUCY-XylBINAP [CAS號1312713-89-5] (364 g，0.31 mol，0.00075 eq)且用THF (2 L/kg，240 L)洗滌反應器。抽空且用氮氣再填充三次。將反應器加壓至1 MPa氫氣且在40℃下攪拌反應物18小時。冷卻至25℃後，抽取樣品用於分析。若反應不完全，則用1 MPa氫氣再填充反應器且在40℃下再攪拌6小時。Charge THF (3 L/kg, 360 L), 8-acetyl-3,6-dimethyl-2-phenyl-chromen-4-one (120 kg, 410 mol) and sodium methoxide (2.2 kg, 41 mol, 0.10 eq) to the reactor. Evacuate the reactor and refill with nitrogen three times. Charge (S)-RUCY-XylBINAP [CAS No. 1312713-89-5] (364 g, 0.31 mol, 0.00075 eq) to the reactor and wash the reactor with THF (2 L/kg, 240 L). Evacuate and refill with nitrogen three times. Pressurize the reactor to 1 MPa hydrogen and stir the reactants at 40°C for 18 hours. After cooling to 25°C, withdraw samples for analysis. If the reaction was not complete, the reactor was refilled with 1 MPa hydrogen and stirred at 40 °C for another 6 hours.
反應完成後，向反應器中裝入2-MeTHF (5 L/kg，600 L)及純化水(5 L/kg，600 L)且在25℃下攪拌30分鐘。過濾反應物且用2-MeTHF (1 L/kg，120 L)洗滌固體。靜置30分鐘。移除水層且將有機層之溶劑更換成ACN (4 L/kg，480 L)。經10小時冷卻至5℃，且在5℃下攪拌混合物6小時。過濾混合物，用ACN (1.52 L/kg，182 L)及正庚烷(5.0 L/kg，600 L)洗滌固體，且在45℃下真空乾燥12小時，得到標題化合物(102.7 kg，85%)。 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, 3H, J = 6.5 Hz), 2.03 (s, 3H), 2.41 (s, 3H), 5.24 (dq, 1H, J = 4.2, 6.5 Hz), 5.38 (d, 1H, J = 4.2 Hz), 7.58 (m, 3H), 7.73 (m, 4H)。 中間物12：8-[(1S)-1-氯乙基]-3,6-二甲基-2-苯基-色烯-4-酮 After the reaction was completed, 2-MeTHF (5 L/kg, 600 L) and purified water (5 L/kg, 600 L) were charged into the reactor and stirred at 25°C for 30 minutes. The reactant was filtered and the solid was washed with 2-MeTHF (1 L/kg, 120 L). Let stand for 30 minutes. The aqueous layer was removed and the solvent of the organic layer was replaced with ACN (4 L/kg, 480 L). Cooled to 5°C over 10 hours, and the mixture was stirred at 5°C for 6 hours. The mixture was filtered, the solid was washed with ACN (1.52 L/kg, 182 L) and n-heptane (5.0 L/kg, 600 L), and vacuum dried at 45°C for 12 hours to obtain the title compound (102.7 kg, 85%). 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, 3H, J = 6.5 Hz), 2.03 (s, 3H), 2.41 (s, 3H), 5.24 (dq, 1H, J = 4.2, 6.5 Hz), 5.38 (d, 1H, J = 4.2 Hz), 7.58 (m, 3H), 7.73 (m, 4H). Intermediate 12: 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
向配備有塔頂攪拌之燒瓶中裝入8-[(1R)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮(20.0 g，68.0 mmol)及環戊基甲基醚(200 ml)。添加2,4,6-三氯[1,3,5]三𠯤(12.5 g，23.8 mmol)，接著添加DMF (7.9 mL，102 mmol)且在室溫下攪拌隔夜。用2 M NaOH水溶液(100 mL)緩慢處理反應物且攪拌10分鐘。將反應物轉移至分液漏斗中且移除有機層。用水(100 mL)及NaHCO 3飽和水溶液(100 mL)稀釋有機層。在移除水層之後，用5% LiCl水溶液洗滌有機層。將有機層轉移至燒瓶中，且藉由向燒瓶中裝入200 mL IPA且濃縮至100 mL三次來用IPA交換溶劑。接著使漿液升溫至45℃且在該溫度下攪拌2小時且使其冷卻至室溫。經4小時經由注射泵用80 mL水處理物質且使反應物老化隔夜。藉由過濾收集產物(18.4 g，87%)，用40 mL之1:1 IPA/水洗滌且在45℃下乾燥。 中間物12之替代性合成：8-[(1S)-1-氯乙基]-3,6-二甲基-2-苯基-色烯-4-酮 To a flask equipped with overhead stirring was charged 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (20.0 g, 68.0 mmol) and cyclopentyl methyl ether (200 ml). 2,4,6-trichloro[1,3,5]trioxane (12.5 g, 23.8 mmol) was added followed by DMF (7.9 mL, 102 mmol) and stirred at room temperature overnight. The reaction was slowly treated with 2 M aqueous NaOH (100 mL) and stirred for 10 minutes. The reaction was transferred to a separatory funnel and the organic layer was removed. The organic layer was diluted with water (100 mL) and saturated aqueous NaHCO 3 (100 mL). After removing the aqueous layer, the organic layer was washed with 5% aqueous LiCl solution. The organic layer was transferred to a flask and the solvent was exchanged with IPA by charging 200 mL of IPA into the flask and concentrating to 100 mL three times. The slurry was then warmed to 45 °C and stirred at that temperature for 2 hours and allowed to cool to room temperature. The material was treated with 80 mL of water via a syringe pump over 4 hours and the reaction was aged overnight. The product (18.4 g, 87%) was collected by filtration, washed with 40 mL of 1:1 IPA/water and dried at 45 °C. Alternative Synthesis of Intermediate 12: 8-[(1S)-1-Chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one
向反應器中裝入2-MeTHF (5 L/kg，480 L)及8-[(1R)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮(96 kg，326.5 mol)且冷卻至10℃。向反應器中裝入1-甲醯基吡咯啶(32.4 kg，326.5 mol，1 eq)，且接著經2小時添加苯甲醯氯(91.8 kg，653 mol，2 eq)。使反應物升溫至25℃且攪拌18小時。反應完成後，用2-MeTHF (5 L/kg，480 L)稀釋反應物且冷卻至15℃。緩慢添加3M NaOH水溶液(5 L/kg，480 L)，使混合物升溫至25℃，且攪拌混合物45分鐘。在靜置30分鐘之後，移除水層。向反應器中裝入水(5 L/kg，480 L)且攪拌15分鐘。在靜置30分鐘之後，移除水層且過濾所得有機層。使濾液靜置30分鐘且再次移除水層。將所得有機溶液之溶劑更換成異丙醇(5 L/kg，480 L)且不經進一步純化即用於下一步驟中。 中間物13：2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸；(1S)-1-苯基乙胺 The reactor was charged with 2-MeTHF (5 L/kg, 480 L) and 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (96 kg, 326.5 mol) and cooled to 10°C. The reactor was charged with 1-formylpyrrolidine (32.4 kg, 326.5 mol, 1 eq) and then benzoyl chloride (91.8 kg, 653 mol, 2 eq) was added over 2 hours. The reactants were allowed to warm to 25°C and stirred for 18 hours. After the reaction was complete, the reactants were diluted with 2-MeTHF (5 L/kg, 480 L) and cooled to 15°C. 3M NaOH aqueous solution (5 L/kg, 480 L) was slowly added, the mixture was warmed to 25°C, and the mixture was stirred for 45 minutes. After standing for 30 minutes, the aqueous layer was removed. Water (5 L/kg, 480 L) was charged to the reactor and stirred for 15 minutes. After standing for 30 minutes, the aqueous layer was removed and the resulting organic layer was filtered. The filtrate was allowed to stand for 30 minutes and the aqueous layer was removed again. The solvent of the resulting organic solution was replaced with isopropanol (5 L/kg, 480 L) and used in the next step without further purification. Intermediate 13: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid; (1S)-1-phenylethylamine
滴加鄰胺基苯甲酸(2.79 g，20.38 mmol)及三乙胺(1.38 g，13.59 mmol)處理甲烷磺酸[(1S)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]酯之DCM溶液(20 mL)。將反應物在室溫下攪拌隔夜。用1M HCl水溶液(3×10 mL)及鹽水洗滌反應物。收集有機層，經MgSO 4乾燥，且濃縮至10 mL。裝入20 mL 2-甲基四氫呋喃且濃縮至10 mL。再次用2-甲基四氫呋喃進行溶劑交換，濃縮至70至80 mL且加熱至45-50℃。經3小時添加(S)-α-甲基苯甲胺(0.91 g，7.48 mmol)。冷卻至室溫且老化隔夜。藉由過濾收集標題化合物(2.13 g，59%)，用2-甲基四氫呋喃(2×10 mL)洗滌，且在45℃下真空乾燥。 化合物A：2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸 Treat a solution of methanesulfonic acid [(1S)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl] ester in DCM (20 mL) with oxadiazine (2.79 g, 20.38 mmol) and triethylamine (1.38 g, 13.59 mmol) dropwise. Stir the reaction at room temperature overnight. Wash the reaction with 1M aqueous HCl (3×10 mL) and brine. Collect the organic layer, dry over MgSO 4 , and concentrate to 10 mL. Charge 20 mL of 2-methyltetrahydrofuran and concentrate to 10 mL. Solvent exchange again with 2-methyltetrahydrofuran, concentrate to 70 to 80 mL and heat to 45-50°C. (S)-α-Methylbenzylamine (0.91 g, 7.48 mmol) was added over 3 hours. Cool to room temperature and age overnight. The title compound (2.13 g, 59%) was collected by filtration, washed with 2-methyltetrahydrofuran (2×10 mL), and dried under vacuum at 45° C. Compound A: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid
途徑1：將8-[(1R)-1-胺基乙基]-3,6-二甲基-2-苯基-色烯-4-酮(30 g，102.3 mmol)、2-碘苯甲酸(25.36 g，102.26 mmol)、銅(13.00 g，204.5 mmol)及碳酸鉀(21.20 g，153.4 mmol)之混合物懸浮於DMF (300 mL)中且在100℃下攪拌3小時。將反應物與相同量之另一反應物合併，用2 M HCl水溶液將pH值調至pH 3，用1000 mL DCM及500 mL水稀釋，過濾且分離各層。就有機層用3×1000 mL鹽水洗滌，收集，經Na 2SO 4乾燥且濃縮。藉由矽膠層析用5%乙酸乙酯/石油醚至50% EtOAc/石油醚溶離來純化殘餘物。用300 mL EtOAc濕磨所得固體且藉由過濾收集。將所得固體懸浮於500 mL沸騰乙腈中且藉由過濾收集，得到呈白色固體狀之產物(33 g；39%)。MS ES+ m/z414 [M+H] +。 Route 1: A mixture of 8-[(1R)-1-aminoethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (30 g, 102.3 mmol), 2-iodobenzoic acid (25.36 g, 102.26 mmol), copper (13.00 g, 204.5 mmol) and potassium carbonate (21.20 g, 153.4 mmol) was suspended in DMF (300 mL) and stirred at 100 °C for 3 hours. The reaction was combined with the same amount of another reaction, the pH was adjusted to pH 3 with 2 M aqueous HCl, diluted with 1000 mL DCM and 500 mL water, filtered and the layers were separated. The organic layer was washed with 3×1000 mL of brine, collected, dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel chromatography eluting with 5% ethyl acetate/petroleum ether to 50% EtOAc/petroleum ether. The resulting solid was triturated with 300 mL of EtOAc and collected by filtration. The resulting solid was suspended in 500 mL of boiling acetonitrile and collected by filtration to give the product as a white solid (33 g; 39%). MS ES+ m/z 414 [M+H] + .
途徑2：將2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸；(1S)-1-苯基乙胺(15 g)與DCM (150 mL)混合。添加1M HCl水溶液(75 mL)且攪拌混合物5分鐘。添加1M HCl水溶液(75 mL)且再次攪拌混合物5分鐘。將反應物濃縮至約45 mL。添加DCM (30 mL)及ACN (150 mL)且將混合物濃縮至約75 mL。添加ACN (150 mL)且將混合物濃縮至約120 mL。在短時間內加熱至80℃。冷卻至65℃且攪拌2小時。經4小時冷卻至25℃且再攪拌4小時。藉由過濾收集產物(7.50 g，65%)且用5 mL ACN洗滌，用75 mL庚烷洗滌，且在真空烘箱中在45℃下乾燥。MS ES+ m/z414 [M+H] +。 Route 2: Mix 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid; (1S)-1-phenylethylamine (15 g) with DCM (150 mL). Add 1M aqueous HCl (75 mL) and stir the mixture for 5 minutes. Add 1M aqueous HCl (75 mL) and stir the mixture again for 5 minutes. Concentrate the reaction to about 45 mL. Add DCM (30 mL) and ACN (150 mL) and concentrate the mixture to about 75 mL. Add ACN (150 mL) and concentrate the mixture to about 120 mL. Heat to 80°C in a short time. Cool to 65°C and stir for 2 hours. Cool to 25 °C over 4 h and stir for another 4 h. Collect the product (7.50 g, 65%) by filtration and wash with 5 mL ACN, wash with 75 mL heptane, and dry in a vacuum oven at 45 °C. MS ES+ m/z 414 [M+H] + .
途徑3：向燒瓶中裝入8-[(1S)-1-氯乙基]-3,6-二甲基-2-苯基-色烯-4-酮(5.0 g，16.0 mmol)及IPA (50 mL)。接著用鄰胺基苯甲酸(6.58 g，48.0 mmol)處理反應物且滴加三乙胺(6.7 mL，48.0 mmol)處理。在60℃下攪拌反應隔夜。將反應物冷卻至室溫且添加50 mL 2-甲基四氫呋喃，且將反應物濃縮至約50 mL。用25 mL 2-甲基四氫呋喃再交換此溶劑3次。添加25 mL 2M HCl水溶液且攪拌。轉移至分液漏斗中且移除水層。將剩餘有機層用2 M HCl水溶液(2×25 mL)洗滌，且接著用50 mL ACN稀釋且三次濃縮至約50 mL，留下黏稠漿液。使漿液歷時1小時升溫至80℃，且接著在65℃下持續2小時。反應物經約5小時冷卻至室溫且攪拌隔夜。藉由過濾收集產物(5.19 g，79%)且用5 mL ACN洗滌，用25 mL庚烷洗滌，且在真空烘箱中在45℃下乾燥。 Route 3: Charge a flask with 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one (5.0 g, 16.0 mmol) and IPA (50 mL). Then treat the reaction with amine benzoic acid (6.58 g, 48.0 mmol) and triethylamine (6.7 mL, 48.0 mmol) dropwise. Stir the reaction at 60 °C overnight. Cool the reaction to room temperature and add 50 mL of 2-methyltetrahydrofuran, and concentrate the reaction to about 50 mL. Exchange this solvent three more times with 25 mL of 2-methyltetrahydrofuran. Add 25 mL of 2M aqueous HCl and stir. Transfer to a separatory funnel and remove the aqueous layer. The remaining organic layer was washed with 2 M aqueous HCl (2×25 mL), and then diluted with 50 mL ACN and concentrated three times to about 50 mL, leaving a viscous slurry. The slurry was warmed to 80°C over 1 hour, and then continued at 65°C for 2 hours. The reaction was cooled to room temperature over about 5 hours and stirred overnight. The product (5.19 g, 79%) was collected by filtration and washed with 5 mL ACN, washed with 25 mL heptane, and dried in a vacuum oven at 45°C.
途徑4：根據中間物12之替代性合成製備的8-[(1S)-1-氯乙基]-3,6-二甲基-2-苯基-色烯-4-酮於異丙醇中之溶液裝入反應器且添加鄰胺基苯甲酸(111.9 kg，816.3 mol，2.5 eq)及碳酸氫鈉(41.1 kg，489.4 mol，1.5 eq)。添加異丙醇(2 L/kg，192 L)且在65℃下攪拌反應24小時。完成後，將反應溶劑更換成2-MeTHF (15 L/kg，1400 L)。在20℃下，添加4 M HCl水溶液(5 L/kg，480 L)且攪拌30分鐘。在靜置30分鐘之後，移除水層。將2-MeTHF (2 L/kg，192 L)及2M HCl水溶液(3 L/kg，288 L)添加至有機層且在20℃下攪拌30分鐘。在靜置30分鐘之後，移除水層。添加2-MeTHF (3 L/Kg，288 L)及水(5 L/kg，480 L)且攪拌30分鐘。在靜置30分鐘之後，移除水層。所得溶液未經純化即用於下一步驟中。[注意：量係相對於8-[(1R)-1-羥基乙基]-3,6-二甲基-2-苯基-色烯-4-酮而言。] 中間物13之替代性合成：2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸；(1S)-1-苯基乙胺 Route 4: A solution of 8-[(1S)-1-chloroethyl]-3,6-dimethyl-2-phenyl-chromen-4-one prepared according to the alternative synthesis of intermediate 12 in isopropanol was charged into a reactor and 1-aminobenzoic acid (111.9 kg, 816.3 mol, 2.5 eq) and sodium bicarbonate (41.1 kg, 489.4 mol, 1.5 eq) were added. Isopropanol (2 L/kg, 192 L) was added and the reaction was stirred at 65 °C for 24 hours. Upon completion, the reaction solvent was replaced with 2-MeTHF (15 L/kg, 1400 L). At 20 °C, 4 M aqueous HCl solution (5 L/kg, 480 L) was added and stirred for 30 minutes. After standing for 30 minutes, the aqueous layer was removed. 2-MeTHF (2 L/kg, 192 L) and 2M HCl aqueous solution (3 L/kg, 288 L) were added to the organic layer and stirred at 20°C for 30 minutes. After standing for 30 minutes, the aqueous layer was removed. 2-MeTHF (3 L/Kg, 288 L) and water (5 L/kg, 480 L) were added and stirred for 30 minutes. After standing for 30 minutes, the aqueous layer was removed. The resulting solution was used in the next step without purification. [Note: The amount is relative to 8-[(1R)-1-hydroxyethyl]-3,6-dimethyl-2-phenyl-chromen-4-one. ] Alternative synthesis of intermediate 13: 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid; (1S)-1-phenylethylamine
根據以上途徑4步驟，將2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸於2-MeTHF中之溶液裝入反應器中且濃縮至10 L/kg (960 L)。將混合物加熱至50℃且經1小時添加(S)-甲基苯甲胺(6.72 kg，55.5 mol，0.17 eq)。在50℃下攪拌所得漿液45分鐘，且經2小時再添加(S)-甲基苯甲胺(303.6 mol，0.93當量) 在65℃下攪拌漿液2小時之後經12小時冷卻至20℃。在20℃下攪拌4小時之後，過濾漿液且用1:1 2-MeTHF/正庚烷(3 L/kg，288 L)及正庚烷(3 L/kg，288 L)洗滌濕濾餅，且接著在45℃下真空乾燥16小時，得到標題化合物，3個步驟產率為77%。 實例 2 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸形式 A ( 「化合物 A 形式 A 」 ) According to step 4 of route 4 above, a solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid in 2-MeTHF was charged to a reactor and concentrated to 10 L/kg (960 L). The mixture was heated to 50°C and (S)-methylbenzylamine (6.72 kg, 55.5 mol, 0.17 eq) was added over 1 hour. The resulting slurry was stirred at 50°C for 45 minutes and (S)-methylbenzylamine (303.6 mol, 0.93 eq) was added over 2 hours. The slurry was stirred at 65°C for 2 hours and then cooled to 20°C over 12 hours. After stirring at 20°C for 4 hours, the slurry was filtered and the filter cake was washed with 1:1 2-MeTHF/n-heptane (3 L/kg, 288 L) and n-heptane (3 L/kg, 288 L), and then dried under vacuum at 45°C for 16 hours to give the title compound in 77% yield over 3 steps. Example 2 2-[[(1R)-1-(3,6 -dimethyl -4- oxo -2 - phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid Form A ( "Compound A Form A " )
根據實例1之程序獲得化合物A形式A。 Compound A Form A was obtained according to the procedure of Example 1.
圖1中所示之化合物A形式A之XRPD圖已成功地索引化，確認該實驗圖案表示單一結晶相，且單位晶胞體積與無水晶形一致 XRPD The XRPD pattern of Compound A Form A shown in Figure 1 has been successfully indexed, confirming that the experimental pattern represents a single crystalline phase and the unit cell volume is consistent with the anhydrous crystalline form XRPD
所製備的形式A之樣品的特徵在於，使用CuKα輻射具有如下表1中所描述之繞射峰(2-θ值)，且尤其在12.1°處具有峰以及在選自由14.1°、16.8°、18.9°及20.7°組成之群的2-θ處具有一或多個峰的XRD圖；繞射角之公差為0.2°。
表1. XRPD峰
根據自25℃加熱至200℃時未偵測到質量損失，確認形式A係無水的。在185℃處之尖銳吸熱峰係由形式A熔融所致。在192℃處觀測到放熱轉變，接著在211℃處觀測到吸熱事件，分別與形式C結晶及熔融一致。 實例 3 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸形式 B ( 「化合物 A 形式 B 」 ) Form A was confirmed to be anhydrous based on the fact that no mass loss was detected upon heating from 25°C to 200°C. The sharp endotherm at 185°C was due to the melting of Form A. An exothermic transition was observed at 192°C, followed by an endothermic event at 211°C, consistent with crystallization and melting of Form C, respectively. Example 3 2-[[(1R)-1-(3,6 -dimethyl - 4-oxo -2 - phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid Form B ( "Compound A Form B " )
藉由在環境溫度下緩慢蒸發2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸於THF中之飽和溶液來製備THF溶劑合物。圖2中所示的THF溶劑合物濾液之XRPD圖已成功地索引化，確認物質為單一結晶相，稱為形式B。單位晶胞體積與單THF溶劑合物一致。 XRPD The THF solvent complex was prepared by slow evaporation of a saturated solution of 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid in THF at ambient temperature. The XRPD pattern of the THF solvent complex filtrate shown in Figure 2 was successfully indexed to confirm that the material was a single crystalline phase, referred to as Form B. The unit cell volume was consistent with a mono-THF solvent complex. XRPD
所製備的形式B之樣品的特徵在於，使用CuKα輻射具有如下表2中所描述之繞射峰(2-θ值)，且尤其在9.7°處具有峰以及在選自由14.9°、11.9°、17.4°及7.0°組成之群的2-θ處具有一或多個峰的XRD圖；繞射角之公差為0.2°。
表2. XRPD峰
在以10℃ /min之速率加熱時，低溫吸熱事件係由去溶劑化所致，接著有可能化合物A形式C在213℃下熔融。在TGA上，加熱時所觀測到之質量損失與0.8莫耳當量之THF一致。 實例 4 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸形式 C ( 「化合物 A 形式 C 」 ) Upon heating at a rate of 10°C/min, a low temperature endothermic event was due to desolvation, followed by melting of Compound A Form C at 213°C. The mass loss observed upon heating was consistent with 0.8 molar equivalents of THF on the TGA. Example 4 2-[[(1R)-1-(3,6 -dimethyl -4- oxo -2 - phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid Form C ( "Compound A Form C " )
藉由在194℃下使化合物A形式A退火30分鐘產生形式C。根據XRPD索引(圖3)，確認形式C之相位純度，且單位晶胞體積與無水物質一致。 XRPD Form C was produced by annealing Compound A Form A at 194°C for 30 minutes. Based on the XRPD index (Figure 3), the phase purity of Form C was confirmed and the unit cell volume was consistent with the anhydrous material. XRPD
所製備的形式C之樣品的特徵在於，使用CuKα輻射具有如下表3中所描述之繞射峰(2-θ值)，且尤其在13.4°處具有峰以及在選自由8.5°、15.7°、10.6°及7.4°組成之群的2-θ處具有一或多個峰的XRD圖；繞射角之公差為0.2°。
表3. XRPD峰
經分離之化合物A形式C之DSC展示由於熔融而在209℃下發生之吸熱事件。 實例 5 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸緩血酸胺鹽形式 A ( 「化合物 A 緩血酸胺鹽形式 A 」 ) DSC of the isolated Compound A Form C showed an endothermic event at 209°C due to melting. Example 5 2-[[(1R)-1-(3,6 -dimethyl -4- oxo -2- phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid succinate amine salt Form A ( "Compound A succinate amine salt Form A " )
藉由將2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸(2.4 g，5.80 mmol)及參(羥基甲基)胺基甲烷(714.5 mg，5.90 mmol)溶解於4:1 THF:MeOH (15.9 mL)中，同時在60℃下以850 rpm攪拌來製備化合物A緩血酸胺鹽形式A。在攪拌的同時，在60℃下經12小時添加庚烷(15.8 mL)。使漿液經4小時冷卻至10℃，接著在10℃下攪拌隔夜。在真空下在惠特曼紙(Whatman paper)上分離固體產物，得到標題化合物(1.72 g，88%產率)。 對掌性增強 Compound A buffer amine salt Form A was prepared by dissolving 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (2.4 g, 5.80 mmol) and tris(hydroxymethyl)aminomethane (714.5 mg, 5.90 mmol) in 4:1 THF:MeOH (15.9 mL) while stirring at 60 °C at 850 rpm. While stirring, heptane (15.8 mL) was added at 60 °C for 12 hours. The slurry was cooled to 10 °C over 4 hours and then stirred at 10 °C overnight. The solid product was separated on Whatman paper under vacuum to give the title compound (1.72 g, 88% yield). Improved palm-to-palm performance
化合物A緩血酸胺鹽形式A之產生及分離使得(R)-鏡像異構物相對於游離酸(R)-鏡像異構物含量之對掌性增強。游離酸起始物質之HPLC顯示96.6%之(R)-鏡像異構物及3.4%之(S)-鏡像異構物。結晶緩血酸胺鹽之HPLC顯示＞99.9%之(R)-鏡像異構物。 XRPD The generation and isolation of Compound A sulphonic acid amine salt Form A results in an increased chirality of the (R)-mirror image isomer relative to the free acid (R)-mirror image isomer content. HPLC of the free acid starting material showed 96.6% (R)-mirror image isomer and 3.4% (S)-mirror image isomer. HPLC of the crystalline sulphonic acid amine salt showed >99.9% (R)-mirror image isomer. XRPD
所製備的結晶緩血酸胺鹽之樣品的特徵在於，使用CuKα輻射具有如下表4中所描述之繞射峰(2-θ值)，且尤其在6.4°處具有峰以及在選自由8.4°、10.9°、16.9°及22.1°組成之群的2-θ處具有一或多個峰的XRD圖(圖4)；繞射角之公差為0.2°。
表4. XRPD峰
根據加熱至200℃時偵測到可忽略的質量損失，確認化合物A緩血酸胺鹽形式A係無水的。DSC分析顯示由於形式A轉化成形式D而在68℃ (起點)處發生之小型吸熱事件。藉由連續加熱，在203℃ (起點)處觀測到吸熱事件，其與形式D之熔融一致。 單晶結構分析 Based on the negligible mass loss detected upon heating to 200°C, Compound A sulphate amine salt Form A was confirmed to be anhydrous. DSC analysis showed a small endothermic event at 68°C (onset) due to the conversion of Form A to Form D. With continued heating, an endothermic event was observed at 203°C (onset), which is consistent with the melting of Form D. Single Crystal Structure Analysis
選擇適合之單晶且藉由單晶X射線繞射測定法分析。測定化合物A緩血酸胺鹽形式A之單晶結構以確認分子結構及絕對組態。經測定，結構為由一個化合物A陰離子及一個緩血酸胺陽離子在不對稱單元中構成的無水晶形。根據晶體結構測定絕對結構且發現分子以R組態鍵結。 固態NMR Select a suitable single crystal and analyze it by single crystal X-ray diffraction measurement. Determine the single crystal structure of compound A sulphuric acid amine salt form A to confirm the molecular structure and absolute configuration. It was determined that the structure is an amorphous crystalline form composed of one compound A anion and one sulphuric acid amine cation in an asymmetric unit. The absolute structure was determined based on the crystal structure and it was found that the molecule is bonded in R configuration. Solid-state NMR
藉由固態NMR來表徵所製備的化合物A緩血酸胺鹽形式A之樣品。 13C固態NMR (100.6 MHz) δ 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, 11.6 ppm。 替代實例 5 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸緩血酸胺鹽形式 A ( 「化合物 A 緩血酸胺鹽形式 A 」 ) A sample of the prepared Compound A sulphatide salt Form A was characterized by solid state NMR. 13 C solid state NMR (100.6 MHz) δ 179.0, 158.7, 151.7, 149.7, 136.3, 134.7, 132.9, 129.3, 127.4, 125.2, 121.7, 117.0, 115.5, 115.2, 110.4, 64.1, 63.2, 45.3, 22.6, 20.3, 11.6 ppm. Alternative Example 5 2-[[(1R)-1-(3,6 -dimethyl -4- oxo -2- phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid succinate amine salt form A ( "Compound A succinate amine salt form A " )
在25℃下，向反應器中裝入2-MeTHF (10 L/kg)、2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸；(1S)-1-苯基乙胺及2N HCl水溶液(4 L/kg)。攪拌所得雙相混合物30分鐘，使其靜置30分鐘，且接著移除水層。將2N HCl水溶液(4 L/kg)添加至有機層中，攪拌30分鐘，且接著使其靜置30分鐘。移除水層且將水(4 L/kg)添加至有機層中。在攪拌30分鐘之後，使混合物靜置30分鐘且移除水層。將所得有機層之溶劑更換成THF (1.93 L/kg)。添加MeOH (1.93 L/kg)，接著添加胺基參(羥基甲基)甲烷(0.95當量)。將溶液加熱至40℃，精緻過濾(0.22 μm過濾器)，且老化30分鐘，添加正庚烷(1.29 L/kg)且將結晶體種晶(2.5 wt%)且老化30分鐘。在40℃下，經8小時添加正庚烷(3.24 L/kg)。經4小時再添加正庚烷(3.24 L/kg)。所得漿液經5小時冷卻至10℃且在10℃下攪拌4小時。過濾漿液且相繼用1:2 (1:1 THF/MeOH):正庚烷(3.8 L/kg)及正庚烷(3.8 L/kg)洗滌濕濾餅。在50℃下真空乾燥濕濾餅，得到標題化合物，87%產率。在Hosokawa Alpine 160 UPZ針磨機中針磨固體，獲得粒徑小於20微米之材料。關於4批2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸緩血酸胺鹽形式A之粒徑分析記錄，參見表8。
表8. D90量測
藉由將參(羥基甲基)胺基甲烷(＞1 eq)溶解於水(0.5-1.7 mL)及丙酮(0.1-0.2 mL)或約3:1之水:丙酮(0.6 mL)中，接著添加化合物A形式A (30-100 mg)來製備晶種材料。若所得漿液難以攪動，則添加額外丙酮。在室溫下攪拌樣品數小時或隔夜。將懸浮液在室溫下離心5分鐘且在室溫下乾燥隔夜，得到與呈單水合物形式之化合物A緩血酸胺鹽形式C一致的固體。 Seed material was prepared by dissolving tris(hydroxymethyl)aminomethane (>1 eq) in water (0.5-1.7 mL) and acetone (0.1-0.2 mL) or about 3:1 water:acetone (0.6 mL), followed by the addition of Compound A Form A (30-100 mg). If the resulting slurry was difficult to stir, additional acetone was added. The sample was stirred at room temperature for several hours or overnight. The suspension was centrifuged at room temperature for 5 minutes and dried at room temperature overnight to give a solid consistent with Compound A sulphate amine salt Form C in monohydrate form.
藉由將約3:1之丙酮:水(16.5 mL)與化合物A緩血酸胺鹽形式A (4.93 g，經研磨)組合來製備化合物A緩血酸胺鹽形式C。在室溫下攪拌(750 rpm)混合物5分鐘。將晶種材料(單水合物化合物A緩血酸胺鹽形式C，45 mg)添加至懸浮液中，在室溫下攪拌(750 rpm)混合物隔夜且在相同先前條件下攪拌樣品隔夜。將懸浮液在室溫下離心5分鐘，得到與呈單水合物形式之化合物A緩血酸胺鹽形式C一致的固體。 XRPD Compound A sulphate amine salt Form C was prepared by combining approximately 3:1 acetone:water (16.5 mL) with Compound A sulphate amine salt Form A (4.93 g, ground). The mixture was stirred (750 rpm) at room temperature for 5 minutes. Seed material (monohydrate Compound A sulphate amine salt Form C, 45 mg) was added to the suspension, the mixture was stirred (750 rpm) at room temperature overnight and the sample was stirred overnight under the same previous conditions. The suspension was centrifuged at room temperature for 5 minutes to give a solid consistent with Compound A sulphate amine salt Form C in monohydrate form. XRPD
所製備的化合物A緩血酸胺鹽形式C之樣品的特徵在於，使用CuKα輻射具有如下表5中所描述之繞射峰(2-θ值)，且尤其在15.9°處具有峰以及在選自由10.6°、17.4°、13.2°及14.5°組成之群的2-θ處具有一或多個峰的XRD圖(圖5)；繞射角之公差為0.2°。
表5. XRPD峰
在熱分析時，形式C去溶劑化係由3.1%之重量損失指示，此與單水合物形式之理論值3.4%一致。 實例 7 2-[[(1R)-1-(3,6- 二甲基 -4- 側氧基 -2- 苯基 - 色烯 -8- 基 ) 乙基 ] 胺基 ] 苯甲酸緩血酸胺鹽形式 D ( 「化合物 A 緩血酸胺鹽形式 D 」 ) Desolvation of Form C was indicated by a 3.1% weight loss during thermal analysis, which is consistent with the theoretical value of 3.4% for the monohydrate form. Example 7 2-[[(1R)-1-(3,6 -dimethyl - 4 -oxo -2- phenyl - chromen -8- yl ) ethyl ] amino ] benzoic acid succinate amine salt Form D ( "Compound A succinate amine salt Form D " )
藉由將化合物A緩血酸胺鹽形式A分配至平板XRPD樣品固持器上且加熱至150℃來製備化合物A緩血酸胺鹽形式D。在加熱期間發生形式A至形式D之轉化。 XRPD Compound A succinate amine salt Form D was prepared by dispensing Compound A succinate amine salt Form A onto a flat plate XRPD sample holder and heating to 150°C. Conversion from Form A to Form D occurred during heating. XRPD
僅原位觀測到形式D(VT-XRPD)。經由XRPD發現，嘗試經由高溫退火產生形式D引起形式A產生，表明向形式A之轉化在室溫下在數分鐘內發生。 Only Form D was observed in situ (VT-XRPD). Attempts to produce Form D via high temperature annealing resulted in the production of Form A as revealed by XRPD, indicating that conversion to Form A occurs within minutes at room temperature.
在VT-XRPD上在150℃下收集之形式D之XRPD圖(圖6)已成功地索引化，確認實驗圖案表示單一結晶相之實驗圖案。化合物A緩血酸胺鹽形式D的特徵在於，使用CuKα輻射具有如下表6中所描述之繞射峰(2-θ值)，且尤其在11.1°處具有峰以及在選自由12.6°、17.1°、6.3°及18.9°組成之群的2-θ處具有一或多個峰的XRD圖；繞射角之公差為0.2°。
表6. XRPD峰
使2-[[(1R)-1-(3,6-二甲基-4-側氧基-2-苯基-色烯-8-基)乙基]胺基]苯甲酸(0.752 g，1.82 mmol)懸浮於丙酮(30 mL)中，同時在55℃下以500 rpm攪拌。添加三級丁胺(0.220 mL，2.09 mmol)。添加丙酮(5 mL)以稀釋所得漿液。在55℃下以450 rpm攪拌漿液45分鐘，冷卻至室溫，且在真空下在惠特曼紙上分離，得到標題化合物(0.849 g，96%產率)。 XRPD Suspend 2-[[(1R)-1-(3,6-dimethyl-4-oxo-2-phenyl-chromen-8-yl)ethyl]amino]benzoic acid (0.752 g, 1.82 mmol) in acetone (30 mL) while stirring at 500 rpm at 55 °C. Add tributylamine (0.220 mL, 2.09 mmol). Add acetone (5 mL) to dilute the resulting slurry. Stir the slurry at 450 rpm at 55 °C for 45 minutes, cool to room temperature, and separate on Whitman paper under vacuum to give the title compound (0.849 g, 96% yield). XRPD
所製備的結晶特丁胺鹽之樣品的特徵在於，使用CuKα輻射具有如下表7中所描述之繞射峰(2-θ值)，且尤其在11.1處具有峰以及在選自由10.5、15.2、18.0及19.3組成之群的2-θ處具有一或多個峰的XRD圖(圖7)；繞射角之公差為0.2°。
表7. XRPD峰
藉由固態NMR來表徵所製備的化合物A特丁胺鹽形式A之樣品。 13C固態NMR (100.6 MHz) δ 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, 11.3 ppm。 實例 9 基於活體外細胞之 PI3K- α 激酶 (PIK3CA) 活性之分析 A sample of the prepared Compound A tert-butylamine salt Form A was characterized by solid state NMR. 13 C solid state NMR (100.6 MHz) δ 177.4, 174.8, 159.8, 151.7, 149.5, 134.0, 132.6, 130.7, 130.3, 129.0, 128.1, 123.1, 122.4, 119.4, 116.8, 115.9, 112.3, 53.0, 47.5, 27.4, 23.3, 21.3, 11.3 ppm. Example 9 Analysis of PI3K -α kinase (PIK3CA) activity in vitro cells
為量測化合物A對活體外癌細胞中PI3Kα H1047R信號傳導之抑制作用，向未添加血清之MDA-MB-453細胞給與濃度增加之抑制劑。處理3小時之後，細胞溶解且使用SureFire® Ultra®分析儀(PerkinElmer，目錄號ALSUR-PAKT-B50K)監測磷酸化-AKT Ser473。 To measure the inhibitory effect of Compound A on PI3Kα H1047R signaling in cancer cells in vitro, increasing concentrations of the inhibitor were administered to MDA-MB-453 cells without the addition of serum. After 3 hours of treatment, cells were lysed and phosphorylated-AKT Ser473 was monitored using a SureFire® Ultra® Analyzer (PerkinElmer, Catalog No. ALSUR-PAKT-B50K).
MDA-MB-453 (ATCC-HTB-131)細胞株係獲自美國典型培養物保藏中心(American Type Culture Collection) (Manassas，VA)。將細胞保持在杜氏改良型伊格爾培養基(Dulbecco's Modified Eagle Media，DMEM；Gibco 11965-092)中，該培養基補充有10%熱不活化胎牛血清(FBS HI, Gibco 10082-147)、1X非必需胺基酸(NEAA, Gibco 11140-050)及1 mM丙酮酸鈉(Gibco 11360-070)。培養物維持於含濕氣培育箱中37℃下5% CO 2/95%空氣下。 MDA-MB-453 (ATCC-HTB-131) cell line was obtained from the American Type Culture Collection (Manassas, VA). Cells were maintained in Dulbecco's Modified Eagle Media (DMEM; Gibco 11965-092) supplemented with 10% heat-inactivated fetal bovine serum (FBS HI, Gibco 10082-147), 1X non-essential amino acids (NEAA, Gibco 11140-050), and 1 mM sodium pyruvate (Gibco 11360-070). Cultures were maintained in a humidified incubator at 37°C in 5% CO 2 /95% air.
為在0% FBS中測試化合物，將MDA-MB-453細胞於20 µl具有1X NEAA、1 mM丙酮酸鈉及1 µg/mL人類胰島素(Sigma I9278)之最小必需培養基(MEM)分析培養基中以1.5×10 4個細胞/孔之密度接種於白色384孔盤中。將在DMSO中溶解成10 mM儲備溶液之化合物在DMSO中以1:3連續稀釋，以產生10點稀釋系列，且使用聲學液體處置器系統(Echo 550系列液體處置器，Labcyte)塗鋪。隨後在具有1X NEAA及1 mM丙酮酸鈉之MEM中製備5X中間化合物稀釋盤(1.5% DMSO中150 µM起始化合物濃度)。將5 µl之中間連續稀釋物化合物添加至細胞盤中直至於0.3% DMSO中之最終濃度範圍為30 mM至0.0015 mM。單獨的0.3% DMSO用於建立最大(MAX)信號，且使用最終濃度為1 µM之GDC-0032作為最小(MIN)信號的參考化合物。在處理3小時之後，移出培養基，且使細胞在室溫下藉由震盪10分鐘在10 µL之1X SureFire溶解緩衝液中溶解。藉由在合併之反應緩衝液1及反應緩衝液2中將活化緩衝液稀釋25倍來製備受體混合物(反應緩衝液1 + 反應緩衝液2 + 活化緩衝液 + SureFire Ultra受體珠粒)。將受體珠粒在合併之反應緩衝液中稀釋50倍。將5 µL之受體混合物添加至各孔中，將盤密封且用箔片覆蓋且在室溫下培育1小時。藉由在稀釋緩衝液中將供體珠粒稀釋50倍來製備供體混合物(稀釋緩衝液+ SureFire Ultra供體珠粒)。將5 µL之供體混合物添加至各孔中，且將盤密封且用箔片覆蓋且在室溫下於暗處培育1小時。使用標準AlphaLisa設定，在來自Biotek之Neo2盤式讀取器儀器上讀取各盤。 To test compounds in 0% FBS, MDA-MB-453 cells were plated at 1.5×10 4 cells/well in 20 µl of Minimum Essential Medium (MEM) assay medium with 1X NEAA, 1 mM sodium pyruvate, and 1 µg/mL human insulin (Sigma I9278) in white 384-well plates. Compounds dissolved in DMSO as a 10 mM stock solution were serially diluted 1:3 in DMSO to generate a 10-point dilution series and plated using an acoustic liquid handler system (Echo 550 Series Liquid Handler, Labcyte). 5X intermediate compound dilution plates (150 µM starting compound concentration in 1.5% DMSO) were then prepared in MEM with 1X NEAA and 1 mM sodium pyruvate. 5 µl of intermediate serial dilution compounds were added to the cell plates to a final concentration range of 30 mM to 0.0015 mM in 0.3% DMSO. 0.3% DMSO alone was used to establish the maximum (MAX) signal, and GDC-0032 at a final concentration of 1 µM was used as a reference compound for the minimum (MIN) signal. After 3 hours of treatment, the medium was removed and the cells were lysed in 10 µL of 1X SureFire Lysis Buffer by shaking for 10 minutes at room temperature. Prepare the receptor mix by diluting the activation buffer 25-fold in the combined reaction buffer 1 and reaction buffer 2 (Reaction Buffer 1 + Reaction Buffer 2 + Activation Buffer + SureFire Ultra Receptor Beads). Dilute the receptor beads 50-fold in the combined reaction buffer. Add 5 µL of the receptor mix to each well, seal and cover the plate with foil and incubate at room temperature for 1 hour. Prepare the donor mix by diluting the donor beads 50-fold in the dilution buffer (Dilution Buffer + SureFire Ultra Donor Beads). 5 μL of donor mix was added to each well and the plate was sealed and covered with foil and incubated in the dark at room temperature for 1 hour. Each plate was read on a Neo2 plate reader instrument from Biotek using standard AlphaLisa settings.
一式兩份地測試化合物且使用各化合物濃度下之平均抑制%來產生單一劑量反應曲線。使用Genedata-Screener工具處理資料。相對IC 50值係使用發光單位，藉由計算相對於盤內(in-plate)「MIN」(GDC-0032參考對照)及「MAX」(DMSO)對照的抑制百分比來測定。使用4參數非線性邏輯斯蒂方程式(logistic equation) (四參數邏輯斯蒂濃度-反應曲線)分析資料： Y = 底部 + [(頂部 - 底部)/1+(X / IC50)斜率] 其中Y =抑制%，X =抑制劑之濃度，底部 =曲線-擬合達到之y最小值，頂部 =曲線-擬合達到之y最大值，且斜率 = IC 50處之曲線斜度。 抑制% = [(X處之信號-中值Min)/ (中值Max-中值Min)]×100 IC 50：使既定反應(配位體結合、酶反應)降低50%之化合物的濃度。相對IC 50：提供化合物之最大反應之一半的濃度。 Compounds were tested in duplicate and the average % inhibition at each compound concentration was used to generate a single dose response curve. Data were processed using the Genedata-Screener tool. Relative IC50 values were determined using luminescence units by calculating the percent inhibition relative to in-plate "MIN" (GDC-0032 reference control) and "MAX" (DMSO) controls. Data were analyzed using a 4-parameter nonlinear logistic equation (4-parameter logistic concentration-response curve): Y = bottom + [(top - bottom)/1 + (X / IC50) slope] where Y = % inhibition, X = concentration of inhibitor, bottom = minimum y value reached by curve-fit, top = maximum y value reached by curve-fit, and slope = slope of curve at IC50 . % inhibition = [(signal at X - medianMin)/ (medianMax - medianMin)] × 100 IC50 : The concentration of a compound that reduces a given reaction (ligand binding, enzyme reaction) by 50%. Relative IC50 : The concentration that gives half the maximal response of a compound.
經測定，化合物A之IC 50值為6.83奈莫耳濃度。 單一藥劑研究 實例 10 在植入小鼠中之 SUM185PE 、 PI3Ka H1047R +/+ 三陰性乳癌 (TNBC) 異種移植模型中的活體內腫瘤生長抑制研究 The IC50 value of compound A was determined to be 6.83 nanomolar concentration. Single agent study example 10 In vivo tumor growth inhibition study in a SUM185PE , PI3Ka H1047R +/+ triple negative breast cancer (TNBC) xenograft model implanted in mice
以下異種移植腫瘤抑制分析之目的係量測回應於作為單一藥劑投與之化合物A的腫瘤體積減小。 The purpose of the following xenograft tumor inhibition assay is to measure the reduction in tumor size in response to Compound A administered as a single agent.
SUM185PE人類乳癌細胞株係獲自Asterand Bioscience (BioIVT, PaloAlto, CA)。SUM185PE細胞維持在補充有5%胎牛血清、10 mM HEPES、1 μg/ml氫化可體松、5 μg/ml人類胰島素(Thermo Fisher Scientific, Waltham MA)之HAM's F-12中37℃下含5% CO
2之空氣氛圍中。收穫在指數生長期中生長之細胞，且計數以用於腫瘤接種。各小鼠(雌性NOD SCID Gamma)在右側腹皮下接種5×10
6/200 μl在與等體積基質膠混合之漢克氏平衡鹽溶液(Hank's Balanced Salt Solution，HBSS)中的存活率超過95%之單細胞懸浮液。當平均腫瘤體積達到約260 mm
3時開始分組及處理。基於腫瘤體積，將小鼠分配至各別組以使得各處理組之平均起始腫瘤尺寸及體重相同。研究組及每組動物數目展示於表8中。
表8.研究組之概述
在適當媒劑(去離子H 2O + 1莫耳當量1N NaOH)中製備化合物A且藉由經口管飼投與14天，BID (一天兩次)。 Compound A was prepared in appropriate vehicle (deionized H2O + 1 molar equivalent of 1 N NaOH) and administered by oral gavage for 14 days, BID (twice a day).
藉由在處理期間一週兩次進行腫瘤體積量測來測定腫瘤反應，且每當量測腫瘤體積時，將體重評估用作毒性之一般量度。 Tumor response was determined by measuring tumor volume twice a week during treatment, and body weight assessment was used as a general measure of toxicity whenever tumor volume was measured.
發現化合物A具有如表9中所提供之ΔT/C%值。此等結果指示，化合物A展現小鼠中之口服生體可用率及SUM185PE (TNBC)人類乳癌異種移植模型中之抗腫瘤活性及腫瘤消退。
表9. SUM185PE異種移植模型中化合物A對腫瘤生長及體重之作用的概述
對腫瘤體積之分析係基於Log10及SpatialPower共變異數結構，且p值係基於指定組與對照組之間的比較。對處理第14天資料進行統計分析。 The analysis of tumor volume was based on Log10 and SpatialPower covariate structure, and the p-value was based on the comparison between the designated group and the control group. Statistical analysis was performed on the data of treatment day 14.
相較於媒劑對照，p≤0.05被視為統計顯著差異。 Compared with the vehicle control, p≤0.05 was considered statistically significant.
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C% (dT/C%)。式為100×(T-BL)/(C-BL)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。基線(BL)為所有組在基線(隨機化)日之腫瘤體積之總平均值。在終點體積低於基線時計算消退百分比(消退%)。式為100×(T-BL)/BL。 實例 11 在植入小鼠中之 ER+ 、 HER2- 、 PI3Ka H1047R+/- 乳癌 PDX 腫瘤模型中的活體內腫瘤生長抑制研究 ΔT/C% (dT/C%) was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula is 100×(T-BL)/(C-BL), where T and C are the average endpoint tumor volumes in the treatment group or control group, respectively. Baseline (BL) is the total mean of the tumor volumes of all groups on the baseline (randomization) day. The percentage of regression (regression %) was calculated when the endpoint volume was below baseline. The formula is 100×(T-BL)/BL. Example 11 In vivo tumor growth inhibition study in the ER+ , HER2- , PI3Ka H1047R+/- breast cancer PDX tumor model implanted in mice
以下異種移植腫瘤抑制分析之目的係量測PIK3CA H1047R+/-乳癌患者來源之異種移植物(PDX)模型中回應於化合物A投與的腫瘤體積減小。 The purpose of the following xenograft tumor inhibition assay is to measure the reduction in tumor size in response to Compound A administration in a PIK3CA H1047R+/- breast cancer patient-derived xenograft (PDX) model.
向無胸腺裸小鼠之左側腹皮下植入來自模型CTG-3401之腫瘤片段。在腫瘤達到約200-350 mm³之後，以表10中定義之劑量用測試化合物經口處理小鼠(n=6/組)。在適當媒劑(去離子H 2O + 1莫耳當量1N NaOH)中製備化合物A且藉由經口管飼投與60天，BID。 Tumor fragments from model CTG-3401 were implanted subcutaneously into the left flank of athymic nude mice. After tumors reached approximately 200-350 mm³, mice (n=6/group) were orally treated with test compounds at the doses defined in Table 10. Compound A was prepared in appropriate vehicle (deionized H 2 O + 1 molar equivalent of 1N NaOH) and administered by oral gavage for 60 days, BID.
藉由在處理期間一週兩次進行腫瘤體積量測來測定腫瘤反應，且每當量測腫瘤體積時，將體重評估用作毒性之一般量度。 Tumor response was determined by measuring tumor volume twice a week during treatment, and body weight assessment was used as a general measure of toxicity whenever tumor volume was measured.
發現化合物A具有如表10中所提供之ΔT/C%值。此等結果指示，化合物A展現小鼠中之口服生體可用率及ER+、HER2-人類乳癌PDX模型中之抗腫瘤活性及腫瘤消退。
表10.化合物A對PI3Kα H1047R PDX模型中之腫瘤生長之作用
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C% (dT/C%)。式為100×(T-BL)/(C-BL)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。基線(BL)為所有組在基線(隨機化)日之腫瘤體積之總平均值。在終點體積低於基線時計算消退百分比(消退%)。式為100×(T-BL)/BL。 實例 12 T47D 、 T47D ESR1 突變型、 T47D 阿貝西利抗性及 T47D 阿貝西利加氟維司群抗性細胞株中之單一藥劑活性的活體外細胞增殖分析 ΔT/C% (dT/C%) was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula is 100×(T-BL)/(C-BL), where T and C are the average endpoint tumor volumes in the treatment group or control group, respectively. Baseline (BL) is the total mean of the tumor volumes of all groups on the baseline (randomization) day. The percentage of regression (regression %) was calculated when the endpoint volume was below baseline. The formula is 100×(T-BL)/BL. Example 12 In vitro cell proliferation analysis of single-agent activity in T47D , T47D ESR1 mutant, T47D abemaciclib-resistant, and T47D abemaciclib plus fulvestrant-resistant cell lines
以下活體外抗增殖分析之目的係量測來源於ER+ HER2-乳癌細胞株T47D之四個不同細胞株中回應於測試化合物A、CDK4/6抑制劑阿貝西利、雌激素受體降解劑(SERD)氟維司群及伊魯司群之細胞生長減少。 The purpose of the following in vitro antiproliferative assays was to measure the reduction in cell growth in four different cell lines derived from the ER+ HER2- breast cancer cell line T47D in response to test compound A, the CDK4/6 inhibitor abemaciclib, and the estrogen receptor degraders (SERDs) fulvestrant and ilulosetran.
為量測化合物A對活體外T47D親本、ESR1突變型、阿貝西利抗性及阿貝西利加氟維司群抗性癌細胞之抗增殖效應，將細胞與增加濃度之抑制劑一起培育2次細胞倍增時間。在處理4或5天之後，固定細胞且藉由在Cell Insight CX7 (Thermo Scientific)上成像對細胞數目進行計數。T47D親本細胞株(ATCC-HTB-133)係獲自美國典型培養物保藏中心(Manassas，VA)。藉由特定ESR1突變對偶基因之CrispR基因嵌入對T47D ESR1突變細胞株(非靶向對照、Y537N+/+、D538G+/+、D538G-/+)進行工程改造。藉由隨時間推移在生長之細胞株中增加化合物之濃度製得T47D阿貝西利抗性及阿貝西利+氟維司群抗性細胞株。藉由向生長培養基中添加1 μM阿貝西利或1 μM阿貝西利加1 μM氟維司群維持抗性細胞株。所有細胞維持在補充有10%胎牛血清(Hyclone #SH30071.03)之RPMI 1640 (gibco #A10491) 中。培養物維持於含濕氣培育箱中37℃下5% CO 2/95%空氣下。 To measure the antiproliferative effect of Compound A on T47D parental, ESR1 mutant, abemaciclib-resistant, and abemaciclib plus fulvestrant-resistant cancer cells in vitro, cells were incubated with increasing concentrations of inhibitor for 2 cell doubling times. After 4 or 5 days of treatment, cells were fixed and cell numbers were counted by imaging on a Cell Insight CX7 (Thermo Scientific). The T47D parental cell line (ATCC-HTB-133) was obtained from the American Type Culture Collection (Manassas, VA). T47D ESR1 mutant cell lines (non-targeted control, Y537N+/+, D538G+/+, D538G-/+) were engineered by CrispR gene insertion of the specific ESR1 mutant allele. T47D abemaciclib-resistant and abemaciclib + fulvestrant-resistant cell lines were generated by increasing the concentration of compound in the growing cell lines over time. Resistant cell lines were maintained by adding 1 μM abemaciclib or 1 μM abemaciclib plus 1 μM fulvestrant to the growth medium. All cells were maintained in RPMI 1640 (gibco #A10491) supplemented with 10% fetal bovine serum (Hyclone #SH30071.03). Cultures were maintained in a humidified incubator at 37°C in 5% CO 2 /95% air.
對於化合物測試，在測試之前使抗性細胞株在無化合物下生長48小時。所有細胞株於150 μl生長培養基中以3,000個細胞/孔之密度接種於黑色透明底96孔盤中。在37℃及5% CO 2下培育盤且在接種後24小時用測試化合物處理。將化合物以10 mM儲備溶液溶解於DMSO中且用聲學液體處置器系統(Tecan D300e)添加至細胞培養盤中，產生1:3稀釋之10點稀釋系列。在整個培養盤中以DMSO進行正規化。當添加化合物時，將第1行固定在PREFER (Anatech Ltd.)中，且培養基替換為PBS。將細胞培養盤返回至培育箱且生長2次細胞倍增時間。將細胞培養盤固定在3.7%甲醛中，細胞用0.1% Triton X-100滲透，且細胞核用2 mg/ml Hoechst 33342染料於PBS中之1:5000稀釋液染色。藉由在Cell Insight CX7上成像來評估細胞增殖且藉由TargetActivation V.4 Bioapplication (Thermo Scientific)分析。使用下式以平均細胞/視野計算抑制%，其中DMSO為DMSO對照孔之平均細胞計數，測試為所關注化合物之細胞計數，且第0天為來自第1行之細胞計數： 抑制% = ((DMSO-測試)/(DMSO-第0天))×100 絕對IC 50值係使用GraphPad Prism 7 (GraphPad Software, Inc)自log(抑制劑)對比反應--可變斜率(四參數)之內插X平均值計算。 For compound testing, resistant cell lines were grown for 48 hours without compound prior to testing. All cell lines were seeded in black clear bottom 96-well plates at a density of 3,000 cells/well in 150 μl growth medium. Plates were incubated at 37°C and 5% CO2 and treated with test compounds 24 hours after seeding. Compounds were dissolved in DMSO as a 10 mM stock solution and added to the cell culture plates using an acoustic liquid handler system (Tecan D300e), generating a 10-point dilution series of 1:3 dilutions. Normalization was performed with DMSO throughout the plate. When compounds were added, row 1 was fixed in PREFER (Anatech Ltd.) and the medium was replaced with PBS. The cell culture plates were returned to the incubator and grown for 2 cell doubling times. The cell culture plates were fixed in 3.7% formaldehyde, cells were permeabilized with 0.1% Triton X-100, and nuclei were stained with 2 mg/ml Hoechst 33342 dye at a 1:5000 dilution in PBS. Cell proliferation was assessed by imaging on a Cell Insight CX7 and analyzed by TargetActivation V.4 Bioapplication (Thermo Scientific). % Inhibition was calculated as mean cells/field using the following formula, where DMSO is the mean cell count of DMSO control wells, Test is the cell count of the compound of interest, and Day 0 is the cell count from row 1: % Inhibition = ((DMSO-Test)/(DMSO-Day 0))×100 Absolute IC50 values were calculated from the interpolated X-average of log(inhibitor) vs. response--variable slope (four parameters) using GraphPad Prism 7 (GraphPad Software, Inc).
表11展示IC
50值在0.7 nM至3.1 nM範圍內之化合物A抗增殖活性。
表11. T47D、T47D ESR1突變型、T47D阿貝西利抗性及T47D阿貝西利及氟維司群抗性細胞株中細胞增殖分析之絕對IC50的概述
由於腫瘤異質性及對內分泌療法之獲得性抗性，組合療法已在ER陽性晚期/轉移性乳癌中變得必不可少。此外，三陰性乳癌(TNBC)之有效且持久治療的缺乏鑑別臨床未滿足之需求的區域。本文提供之組合療法可提供改善之反應持續時間及耐受性。本文提供之組合療法可使用減少劑量的與歸因於毒性之狹窄治療窗相關之經批准療法。 Combination therapy has become essential in ER-positive advanced/metastatic breast cancer due to tumor heterogeneity and acquired resistance to endocrine therapy. Furthermore, the lack of effective and durable treatments for triple-negative breast cancer (TNBC) identifies an area of clinical unmet need. The combination therapies provided herein may provide improved duration of response and tolerability. The combination therapies provided herein may allow the use of reduced doses of approved therapies associated with a narrow therapeutic window due to toxicity.
在活體外及活體內T47D (ER+HER2-細胞株)、T47D ESR1突變型、T47D阿貝西利抗性細胞株中評估化合物A與CDK4/6抑制劑阿貝西利在有/無雌激素受體降解劑(SERD)氟維司群或伊魯司群下的組合，且在活體外及活體內三陰性乳癌(TNBC)細胞株(CAL-148)中評估化合物A與微管穩定劑太平洋紫杉醇之組合。亦在活體外T47D (ER+ HER2-)、T47D ESR1突變型、T47D阿貝西利抗性中評估化合物A與mTORC1/2抑制劑依維莫司，且在活體內T47D (ER+ HER2)中評估化合物A與臨床等效及較低劑量之mTORC1/2抑制劑依維莫司在有或無雌激素受體降解劑(SERD)氟維司群下的作用。在HER2陽性乳癌模型(HCC-1954)中測試化合物A與RTK抑制劑阿法替尼及來那替尼，在肺腺癌(NCI-H1048)中測試化合物A與DNA破壞劑順鉑，且在活體外卵巢(SKOV-3)模型中測試化合物A與微管穩定劑太平洋紫杉醇。在針對PIK3CA H1047R突變、MCF7-H1047R及EFM19-H1047R進行工程改造之ER+ HER2-乳癌細胞模型中進一步測試化合物A與氟維司群的組合。 實例 13 用於組合研究之活體外細胞增殖分析 The combination of Compound A and the CDK4/6 inhibitor abemaciclib in the presence or absence of the estrogen receptor degraders (SERDs) fulvestrant or ilurostran was evaluated in T47D (ER+HER2- cell line), T47D ESR1 mutant, and T47D abemaciclib-resistant cell lines in vitro and in vivo, and the combination of Compound A and the microtubule stabilizer paclitaxel was evaluated in triple-negative breast cancer (TNBC) cell line (CAL-148) in vitro and in vivo. Compound A was also evaluated with the mTORC1/2 inhibitor everolimus in T47D (ER+ HER2-), T47D ESR1 mutant, T47D abemaciclib resistance in vitro, and with clinically equivalent and lower doses of the mTORC1/2 inhibitor everolimus in T47D (ER+ HER2) in vivo with or without the estrogen receptor degrader (SERD) fulvestrant. Compound A was tested with the RTK inhibitors afatinib and neratinib in a HER2-positive breast cancer model (HCC-1954), with the DNA destructor cisplatin in lung adenocarcinoma (NCI-H1048), and with the microtubule stabilizer paclitaxel in an in vitro ovarian (SKOV-3) model. The combination of Compound A and Fulvestrant was further tested in ER+ HER2- breast cancer cell models engineered for PIK3CA H1047R mutation, MCF7-H1047R and EFM19-H1047R. Example 13 In vitro cell proliferation assay for combination studies
細胞於20 μL體積培養基中以適當密度接種至透明底384孔細胞培養盤中；如表12中所指示，在96孔盤中100 μl培養基中分析所選細胞株。各細胞株之接種密度及培養基細節描述於表12中。接著在37℃及5% CO
2下培育盤且在接種後24小時用測試化合物處理。
表12.細胞增殖分析細胞株資訊
將化合物製備為10 mM DMSO儲備溶液且用於劑量-反應研究。對於組合療法，兩種化合物一起以固定比率在以下最高起始濃度下測試：化合物A及伊魯司群/氟維司群為10 μM:1 μM；化合物A及阿貝西利為10 μM:10 μM；在CAL-148中化合物A及太平洋紫杉醇為10 μM:0.1 μM；在SKOV-3中化合物A及太平洋紫杉醇為1 μM:0.1 μM；化合物A及依維莫司為10 μM:1 μM；在NCI-H1048中化合物A及順鉑為1 μM:10 μM；且在HCC-1954中化合物A及來那替尼或阿法替尼為10 μM:1 μM；而對於單藥治療，起始濃度為20 μM。對於單一及組合治療兩者，藉由使用聲學液體處置器系統(Echo 550 series instrument, Labcyte)，在10點濃度反應曲線(CRC)中製備1:3連續稀釋液。在將化合物添加至細胞之前，在培養基中產生5X中間化合物盤。用5 μL連續稀釋之化合物處理細胞，得到0.2%之最終DMSO濃度。將星形孢菌素(Staurosporine) 2 µM用作最小信號之參考化合物且將DMSO 0.2%用作最大信號之參考化合物。在37℃及5% CO 2下培育細胞盤。在與化合物一起培育兩次細胞倍增時間後，自培育箱移除培養盤且將65 μL冰冷EtOH 96%添加至各孔中，得到最終EtOH 70%。30分鐘後，移除培養基且每孔添加20 μL含有RNA酶(50 μg/mL)及碘化丙錠(1 μg/mL)之PBS。將培養盤密封且在室溫下培育1小時(避光保存)，且隨後用ACUMEN EXPLORER™ [由TTP LABTECH LTD製造之雷射掃描螢光微孔盤式細胞儀]掃描。對於以聚集物形式生長之此等細胞株，使用總面積群體或總PI強度來評估總細胞數目，否則將對象數目用作標準讀出。對於經工程改造之MCF-7 H1047R及EFM-19 H1047R細胞株中的組合療法，兩種化合物一起以棋盤矩陣格式測試，對應地，化合物A自500 nM起始(經7.5 nM FBS結合調整)且氟維司群自25 nM起始(經250 pM FBS結合調整)。 Compounds were prepared as 10 mM DMSO stock solutions and used in dose-response studies. For combination therapy, the two compounds were tested together in a fixed ratio at the following highest starting concentrations: Compound A and ilulostran/fulvestrant at 10 μM:1 μM; Compound A and abemaciclib at 10 μM:10 μM; Compound A and paclitaxel at 10 μM:0.1 μM in CAL-148; Compound A and paclitaxel at 1 μM:0.1 μM in SKOV-3; Compound A and everolimus at 10 μM:1 μM; Compound A and cisplatin at 1 μM:10 μM in NCI-H1048; and Compound A and neratinib or afatinib at 10 μM:1 μM in HCC-1954; whereas for monotherapy, the starting concentration was 20 μM. For both single and combination treatments, 1:3 serial dilutions were prepared in a 10-point concentration response curve (CRC) by using an acoustic liquid handler system (Echo 550 series instrument, Labcyte). A 5X intermediate compound plate was generated in the culture medium before adding compounds to the cells. Cells were treated with 5 μL of serially diluted compounds to give a final DMSO concentration of 0.2%. Staurosporine 2 μM was used as a reference compound for minimum signal and DMSO 0.2% was used as a reference compound for maximum signal. Cell plates were incubated at 37°C and 5% CO 2 . After incubation with compounds for two cell doubling times, the plates were removed from the incubator and 65 μL of ice-cold EtOH 96% was added to each well to give a final EtOH 70%. After 30 minutes, the medium was removed and 20 μL of PBS containing RNase (50 μg/mL) and propidium iodide (1 μg/mL) was added to each well. The plates were sealed and incubated at room temperature for 1 hour (protected from light) and then scanned with an ACUMEN EXPLORER™ [Laser Scanning Fluorescent Microplate Cytometer manufactured by TTP LABTECH LTD]. For these cell lines growing as aggregates, total area population or total PI intensity was used to assess total cell number, otherwise object number was used as standard readout. For combination therapy in engineered MCF-7 H1047R and EFM-19 H1047R cell lines, both compounds were tested together in a checkerboard matrix format, correspondingly, Compound A starting at 500 nM (adjusted for 7.5 nM FBS binding) and Fulvestrant starting at 25 nM (adjusted for 250 pM FBS binding).
如表13中所示，活體外組合資料表明化合物A與阿貝西利、伊魯司群、氟維司群及依維莫司組合時在ER陽性乳癌細胞株中之協同作用或相加作用(如下所定義)；化合物A與太平洋紫杉醇之組合在TNBC細胞株中之相加作用；化合物A與太平洋紫杉醇之組合在卵巢癌細胞株中之相加作用；化合物A與順鉑之組合在肺癌細胞株中之相加作用；及化合物A與阿法替尼或來那替尼之組合在乳腺癌細胞株中之協同作用。
表13. 細胞增殖分析之組合結果
使用洛維方法(Loewe method)來計算活體外組合作用(L. Zhao等人, Front Biosci, 2010, 2:241-249及L. Zhao等人, Clin Cancer Res, 2004, 10(23):7994-8004)。為鑑別兩種藥物之間的協同或拮抗相互作用，使用定製之Genedata模組按照洛維模型進行曲線移位分析。使用4參數邏輯斯蒂回歸來調整單一藥劑之曲線。用於擬合之準則及限制為(i)將底部＜ (-20)固定為0及(ii)頂部＞120固定為100。若所有觀測結果小於由使用者設定之臨限值，則執行與希爾=0之常數擬合且IC
50視為高於所包括之最大濃度。一旦獲得各單一藥劑之絕對IC
50，則計算單一及組合藥劑在50%活性下之當量濃度。使用此等當量濃度以及所量測之活性重新計算絕對IC
50，在等於1之當量濃度之值下，單一藥劑之曲線將達到50%活性，而協同組合在較低值下將達至50%，從而導致向左移位，且拮抗組合將展示向右移位。等效濃度亦用於計算CI
50(在50%活性下之組合指數)，其中CI
50等於組合曲線之絕對IC
50。可計算CI
50以及不同活性百分比下之其他CI (組合指數) (CI10、CI20、CI30、CI40、CI60、CI70、CI80、CI90)。為計算CInn，計算在不同活性百分比下之等效濃度。對於各活動百分比，計算誤差邊際，其為95%之信賴區間且使用此信賴區間，將上限計算為誤差邊際與CI相加且下限計算為誤差邊際與CI相減。上限=CI+95%信賴區間且下限=CI-95%信賴區間。此等界限值隨後用於解釋結果。
各活性百分比下之統計解釋如下：
以下異種移植腫瘤抑制分析之目的係量測回應於單獨化合物A投與，及化合物A與CDK4/6抑制劑阿貝西利、雌激素受體降解劑(SERD)氟維司群或伊魯司群組合、及化合物A、阿貝西利及氟維司群或伊魯司群之三重組合的腫瘤體積減小及組合作用。The purpose of the following xenograft tumor inhibition analysis is to measure tumor size reduction and combination effects in response to administration of Compound A alone, and in combination with the CDK4/6 inhibitor abemaciclib, the estrogen receptor degrader (SERD) fulvestrant or iluronidase, and the triple combination of Compound A, abemaciclib, and fulvestrant or iluronidase.
T-47D (ATCC #HTB-133)在培養物中擴增，收穫且在雌性NOD scid gamma (NSG)小鼠(The Jackson Laboratory, Inc)之右後側腹皮下注射於1:1 HBSS+MATRIGEL™溶液(200 μL)中之5×10e 6個細胞。在細胞植入前的二十四小時，皮下植入雌激素丸粒(每丸粒0.72 mg，17β雌二醇，釋放90天，Innovative Research)。在植入之後第七天開始每週量測腫瘤生長及體重兩次。當腫瘤尺寸達到250至300 mm 3時，將動物隨機分為5隻動物之組。在適當媒劑(1莫耳當量於去離子水中之1 N NaOH)中製備化合物A且藉由經口管飼投與28天，BID。在適當媒劑(含1% HEC之25 mM磷酸鹽緩衝液，pH 2)中製備CDK4/6抑制劑阿貝西利且藉由經口管飼投與28天，QD。Q7D投與雌激素受體降解劑氟維司群(由供應商調配) 28天。在適當媒劑(1% HEC/0.25% Tween 80/0.05%消泡劑)中製備伊魯司群，且藉由經口管飼投與28天，QD。組及處理示於表14中。在處理期間藉由一週進行兩次腫瘤體積量測來測定腫瘤反應。每當量測腫瘤體積時，將體重量測視為毒性之一般量度。 T-47D (ATCC #HTB-133) were expanded in culture, harvested and injected subcutaneously in the right flank of female NOD scid gamma (NSG) mice (The Jackson Laboratory, Inc) at 5×10e 6 cells in 1:1 HBSS+MATRIGEL™ solution (200 μL). Twenty-four hours prior to cell implantation, estrogen pellets (0.72 mg per pellet, 17β-estradiol, 90-day release, Innovative Research) were implanted subcutaneously. Tumor growth and body weight were measured twice weekly starting on day 7 after implantation. When tumors reached 250 to 300 mm 3 in size, animals were randomized into groups of 5 animals. Compound A was prepared in an appropriate vehicle (1 molar equivalent of 1 N NaOH in deionized water) and administered by oral gavage for 28 days, BID. The CDK4/6 inhibitor abemaciclib was prepared in an appropriate vehicle (25 mM phosphate buffer containing 1% HEC, pH 2) and administered by oral gavage for 28 days, QD. The estrogen receptor degrader fulvestrant (formulated by the supplier) was administered Q7D for 28 days. Ilustra was prepared in an appropriate vehicle (1% HEC/0.25% Tween 80/0.05% antifoam) and administered by oral gavage for 28 days, QD. The groups and treatments are shown in Table 14. Tumor response was assessed by tumor volume measurements twice a week during the treatment period. Body weight was taken whenever tumor volume was measured as a general measure of toxicity.
發現在ER陽性人類乳癌異種移植模型T47D中化合物A與阿貝西利、伊魯司群及/或氟維司群組合時具有改善之腫瘤療效，如表15中所提供。在小鼠之ER陽性人類乳癌異種移植模型中化合物A與阿貝西利、伊魯司群或氟維司群之組合及化合物A與阿貝西利加伊魯司群或加氟維司群之三重組合的統計分析(如由布利斯獨立性(Bliss Independence)方法所定義)表明，化合物A在組合時展示相加作用，如表16中所示。
表14.活體內功效研究：化合物及給藥資訊
對腫瘤體積之分析係基於Log 10及SpatialPower共變異數結構。 Analysis of tumor volume was based on Log 10 and SpatialPower covariate structures.
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C%。式為100×(T-T 0)/(C-C 0)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。T 0及C 0為彼等組中之平均基線腫瘤體積。當終點體積低於基線時，計算消退%。式為100×(T-T 0)/T 0，其中T 0為處理組之平均基線腫瘤體積。使用所有小組相對於基線(隨機化)之總平均值來計算T/C之變化%。EAR為預期相加反應腫瘤體積。 ΔT/C% was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula is 100×(TT 0 )/(CC 0 ), where T and C are the mean endpoint tumor volumes in the treatment or control group, respectively. T 0 and C 0 are the mean baseline tumor volumes in those groups. % regression was calculated when the endpoint volume was below baseline. The formula is 100×(TT 0 )/T 0 , where T 0 is the mean baseline tumor volume in the treatment group. The % change in T/C was calculated using the grand mean of all groups relative to baseline (randomization). EAR is the expected additive response tumor volume.
28天之處理後量測腫瘤體積。
表16.活體內功效研究：成對比較及布利斯獨立性作用
以下異種移植腫瘤抑制分析之目的係量測PIK3CA H1047R/D350G+/-ESR1 D538G+/-乳癌患者來源之異種移植(PDX)模型中回應於化合物A作為單一藥劑投與，及化合物A與CDK4/6抑制劑阿貝西利、雌激素受體降解劑(SERD)氟維司群及伊魯司群組合、及化合物A、阿貝西利及氟維司群或伊魯司群之三重組合的腫瘤體積減小及組合作用。 The purpose of the following xenograft tumor inhibition assays is to measure tumor size reduction and combination effects in response to administration of Compound A as a single agent, and in combination with the CDK4/6 inhibitor abemaciclib, the estrogen receptor degraders (SERDs) fulvestrant and iluronidase, and in triple combinations of Compound A, abemaciclib, and either fulvestrant or iluronidase in PIK3CA H1047R/D350G+/-ESR1 D538G+/- breast cancer patient-derived xenograft (PDX) models.
向無胸腺裸小鼠之左側腹皮下植入來自模型CTG-1260之腫瘤片段。在腫瘤達到約150-300 mm 3之後，如表17中所定義處理小鼠(n=6/組)。 Tumor fragments from the model CTG-1260 were implanted subcutaneously into the left flank of athymic nude mice. After tumors reached approximately 150-300 mm 3 , mice were treated as defined in Table 17 (n=6/group).
在適當媒劑(1莫耳當量於去離子水中之1 N NaOH)中製備化合物A且藉由經口管飼投與56天，BID。在適當媒劑(含1% HEC之25 mM磷酸鹽緩衝液，pH 2)中製備CDK4/6抑制劑阿貝西利且藉由經口管飼投與56天，QD。QD投與雌激素受體降解劑氟維司群(由供應商調配) 56天。在適當媒劑(1% HEC/0.25% Tween 80/0.05%消泡劑)中製備伊魯司群，且藉由經口管飼投與56天，QD。藉由在處理期間一週兩次進行腫瘤體積量測來測定腫瘤反應，且每當量測腫瘤體積時，將體重評估用作毒性之一般量度。 Compound A was prepared in the appropriate vehicle (1 molar equivalent of 1 N NaOH in deionized water) and administered by oral gavage for 56 days, BID. The CDK4/6 inhibitor abemaciclib was prepared in the appropriate vehicle (25 mM phosphate buffer containing 1% HEC, pH 2) and administered by oral gavage for 56 days, QD. The estrogen receptor degrader fulvestrant (formulated by the supplier) was administered QD for 56 days. Ilustra was prepared in the appropriate vehicle (1% HEC/0.25% Tween 80/0.05% antifoam) and administered by oral gavage for 56 days, QD. Tumor response was determined by measuring tumor volume twice a week during treatment, and body weight assessment was used as a general measure of toxicity whenever tumor volume was measured.
發現在ER陽性人類乳癌患者來源之異種移植模型中化合物A與阿貝西利、伊魯司群或氟維司群組合時具有改善之腫瘤療效，如表18中所提供。在小鼠之ER陽性人類乳癌患者來源之異種移植模型中化合物A與阿貝西利、伊魯司群或氟維司群之組合及化合物A與阿貝西利加伊魯司群或加氟維司群之三重組合的統計分析(如由布利斯獨立性方法所定義)表明，化合物A在組合時展示相加作用，如表19中所示。
表17.活體內功效研究：化合物及給藥資訊
對腫瘤體積之分析係基於Log 10及SpatialPower共變異數結構。 Analysis of tumor volume was based on Log 10 and SpatialPower covariate structures.
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C%。式為100×(T-T 0)/(C-C 0)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。T 0及C 0為彼等組中之平均基線腫瘤體積。當終點體積低於基線時，計算消退%。式為100×(T-T 0)/T 0，其中T 0為處理組之平均基線腫瘤體積。 ΔT/C% was calculated when the endpoint tumor volume in the treatment group was at or above the baseline tumor volume. The formula was 100×(TT 0 )/(CC 0 ), where T and C were the mean endpoint tumor volumes in the treatment or control group, respectively. T 0 and C 0 were the mean baseline tumor volumes in those groups. When the endpoint volume was below baseline, % regression was calculated. The formula was 100×(TT 0 )/T 0 , where T 0 was the mean baseline tumor volume in the treatment group.
使用所有小組相對於基線(隨機化)之總平均值來計算T/C之變化%。EAR為預期相加反應腫瘤體積。 The % change in T/C was calculated using the grand mean of all groups relative to baseline (randomization). EAR is the expected additive response tumor volume.
56天處理後量測腫瘤體積。
表18.活體內功效研究：平均腫瘤體積及反應百分比
以下異種移植腫瘤抑制分析之目的係量測回應於化合物A作為單一藥劑及與太平洋紫杉醇組合投與的腫瘤體積減小。 The purpose of the following xenograft tumor inhibition assays is to measure the reduction in tumor size in response to Compound A administered as a single agent and in combination with paclitaxel.
CAL-148腫瘤細胞株活體外呈單層培養物維持在DMEM + 20% FBS + 0.01 μg/mL EGF中37℃下含5% CO 2之空氣氛圍中。收穫在指數生長期中生長之細胞，且計數以用於腫瘤接種。各小鼠(雌性NOD SCID)在右側腹皮下接種0.1 ml DMEM + 20% FBS + 0.01 μg/mL EGF及基質膠混合物(1:1比率)中之CAL-148腫瘤細胞(1 × 10 7)，用於發展腫瘤。 CAL-148 tumor cell line was maintained in vitro as monolayer culture in DMEM + 20% FBS + 0.01 μg/mL EGF at 37°C in an atmosphere of 5% CO 2. Cells growing in the exponential growth phase were harvested and counted for tumor inoculation. Each mouse (female NOD SCID) was inoculated subcutaneously in the right flank with CAL-148 tumor cells (1 × 10 7 ) in 0.1 ml DMEM + 20% FBS + 0.01 μg/mL EGF and Matrigel mixture (1:1 ratio) for tumor development.
當平均腫瘤體積達到約150-200 mm 3時開始分組及處理。基於腫瘤體積，將小鼠分配至各別組以使得各處理組之平均起始腫瘤尺寸及體重相同。研究組及每組動物數目展示於表20中。在適當媒劑(去離子水 + 1莫耳當量NaOH)中製備化合物A且藉由經口管飼投與14天，BID。太平洋紫杉醇預調配購得(Beijing SL Pharmaceutical CO., LTD)且藉由靜脈內每週投與(QW)。 Grouping and treatment were initiated when the mean tumor volume reached approximately 150-200 mm 3. Based on tumor volume, mice were assigned to individual groups so that the mean initial tumor size and weight of each treatment group were the same. The study groups and the number of animals in each group are shown in Table 20. Compound A was prepared in appropriate vehicle (deionized water + 1 molar equivalent of NaOH) and administered by oral gavage for 14 days, BID. Paclitaxel was purchased pre-formulated (Beijing SL Pharmaceutical CO., LTD) and administered intravenously weekly (QW).
藉由在處理期間一週兩次進行腫瘤體積量測來測定腫瘤反應，且每當量測腫瘤體積時，將體重評估用作毒性之一般量度。 Tumor response was determined by measuring tumor volume twice a week during treatment, and body weight assessment was used as a general measure of toxicity whenever tumor volume was measured.
發現化合物A在與太平洋紫杉醇組合時具有改善之腫瘤功效，如表21中所提供。如表22中所示，此等結果表明，在小鼠中在三陰性乳癌模型中化合物A具有抗腫瘤活性且在與太平洋紫杉醇組合時展示相加作用。
表20.活體內功效研究：化合物及給藥資訊
對腫瘤體積之分析係基於Log 10及SpatialPower共變異數結構。 Analysis of tumor volume was based on Log 10 and SpatialPower covariate structures.
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C%。式為100×(T-T
0)/(C-C
0)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。T
0及C
0為彼等組中之平均基線腫瘤體積。當終點體積低於基線時，計算消退%。式為100×(T-T
0)/T
0，其中T
0為處理組之平均基線腫瘤體積。使用所有小組相對於基線(隨機化)之總平均值來計算T/C之變化%。14天處理後量測腫瘤體積。
表22.活體內功效研究：成對比較及布利斯獨立性作用
以下異種移植腫瘤抑制分析之目的係量測回應於測試化合物化合物A單獨投與及與雌激素受體降解劑(SERD)氟維司群及mTORC1/2抑制劑依維莫司組合的腫瘤體積減小及組合作用。The purpose of the following xenograft tumor inhibition analysis was to measure tumor size reduction and combination effects in response to administration of the test compound Compound A alone and in combination with the estrogen receptor degrader (SERD) fulvestrant and the mTORC1/2 inhibitor everolimus.
T-47D (ATCC #HTB-133)在培養物中擴增，收穫且在雌性NOD scid gamma (NSG)小鼠(The Jackson Laboratory, Inc)之右後側腹皮下注射於1:1 HBSS+MATRIGEL™溶液(200 μL)中之5×10e 6個細胞。在細胞植入前的二十四小時，皮下植入雌激素丸粒(每丸粒0.72 mg，17β雌二醇，釋放90天，Innovative Research)。在植入之後第七天開始每週量測腫瘤生長及體重兩次。當腫瘤尺寸達到250至300 mm 3時，將動物隨機分為5隻動物之組。在適當媒劑(1莫耳當量於去離子水中之1 N NaOH)中製備測試化合物化合物A且藉由經口管飼投與28天，BID。在適當媒劑(含15%右旋糖之無菌水劑)中製備依維莫司，且藉由經口管飼投與28天，QD。Q7D投與雌激素受體降解劑氟維司群(由供應商調配) 28天。組及治療展示於表23中。在處理期間藉由一週進行兩次腫瘤體積量測來測定腫瘤反應。每當量測腫瘤體積時，將體重量測視為毒性之一般量度。 T-47D (ATCC #HTB-133) were expanded in culture, harvested and injected subcutaneously in the right flank of female NOD scid gamma (NSG) mice (The Jackson Laboratory, Inc) at 5×10e 6 cells in 1:1 HBSS+MATRIGEL™ solution (200 μL). Twenty-four hours prior to cell implantation, estrogen pellets (0.72 mg per pellet, 17β-estradiol, 90-day release, Innovative Research) were implanted subcutaneously. Tumor growth and body weight were measured twice weekly starting on day 7 after implantation. When tumors reached 250 to 300 mm 3 in size, animals were randomized into groups of 5 animals. The test compound Compound A was prepared in an appropriate vehicle (1 molar equivalent of 1 N NaOH in deionized water) and administered by oral gavage for 28 days, BID. Everolimus was prepared in an appropriate vehicle (sterile water containing 15% dextrose) and administered by oral gavage for 28 days, QD. The estrogen receptor degrader Fulvestrant (formulated by the supplier) was administered Q7D for 28 days. The groups and treatments are shown in Table 23. Tumor response was determined by tumor volume measurements twice a week during the treatment period. Body weight was taken as a general measure of toxicity whenever tumor volume was measured.
發現在ER陽性人類乳癌異種移植模型T47D中化合物A與依維莫司在有或無氟維司群下組合時具有改善之腫瘤療效，如以下表24中所提供。在小鼠之ER陽性人類乳癌異種移植模型中化合物A化合物與依維莫司或氟維司群之組合及化合物A之化合物與依維莫司加氟維司群之三重組合的統計分析(如由布利斯獨立性方法所定義)表明，化合物A在組合時展示相加作用，如表25中所示。
表23.活體內功效研究：化合物及給藥資訊
對腫瘤體積之分析係基於Log 10及SpatialPower共變異數結構。 Analysis of tumor volume was based on Log 10 and SpatialPower covariate structures.
當處理組中之終點腫瘤體積處於或高於基線腫瘤體積時計算ΔT/C%。式為100×(T-T
0)/(C-C
0)，其中T及C分別為處理組或對照組中之平均終點腫瘤體積。T
0及C
0為彼等組中之平均基線腫瘤體積。當終點體積低於基線時，計算消退%。式為100×(T-T
0)/T
0，其中T
0為處理組之平均基線腫瘤體積。使用所有小組相對於基線(隨機化)之總平均值來計算T/C之變化%。EAR為預期相加反應腫瘤體積
28天處理後量測腫瘤體積。
表25.活體內功效研究：成對比較及布利斯獨立性作用
布利斯獨立性方法係用於估計腫瘤體積組合治療作用。使用先前已描述之RM ANOVA模型且添加以下形式之雙因子相互作用對比來分析對照組、單一藥劑1組、單一藥劑2組以及單一藥劑1及2之組合之組的log 10轉化腫瘤體積資料，以估計布利斯作用： 其中 • 為治療 t之平均腫瘤體積 The Bliss independence method was used to estimate the tumor volume combination treatment effect. The log 10-transformed tumor volume data for the control group, the single agent 1 group, the single agent 2 group, and the combination of single agents 1 and 2 were analyzed using the previously described RM ANOVA model with the addition of a two-way interaction contrast of the following form to estimate the Bliss effect: in• The average tumor volume for the treatment of t
假定腫瘤體積理論上或實際上可達到零(完全消退)，當在對數標度上分析腫瘤體積時，此方法在數學上等效於布利斯獨立性方法。 Assuming that tumor volume can theoretically or practically reach zero (complete regression), this method is mathematically equivalent to the Bliss independence method when tumor volume is analyzed on a logarithmic scale.
若組合作用精確地為相加的，則根據布利斯獨立性之定義，雙因子相互作用對比估計值等於零。若對比估計值在統計上不同於零 ，則在所觀測到之組合平均體積分別小於或大於預期相加反應腫瘤體積( )之情況下，組合作用大於(協同)或小於(拮抗)相加。 If the combined effects are exactly additive, then the two-way interaction contrast estimate is equal to zero, as defined by Bliss independence. If the contrast estimate is statistically different from zero , then the observed combined mean volume is smaller or larger than the expected sum of the tumor volumes ( ) the combined effect is greater (synergistic) or less (antagonistic) than their sum.
使用以下等式來估計 ： Use the following equation to estimate :
若對照與各單一藥劑處理組相對於組合處理組之間的相互作用對比測試及所有成對比較皆在統計上顯著(p ≤ 0.05)，且觀測到之組合平均體積小於EAR體積，則宣告組合作用大於相加(協同)。 If the interaction comparison tests and all pairwise comparisons between the control and each single agent treatment group versus the combination treatment group were statistically significant (p ≤ 0.05), and the observed combined mean volume was less than the EAR volume, the combination effect was declared greater than additive (synergistic).
若相互作用對比測試在統計上顯著(p ≤ 0.05)且觀測到之組合平均體積大於EAR體積，則不管成對比較結果如何，均宣告組合作用小於相加(拮抗)。 If the interaction comparison test is statistically significant (p ≤ 0.05) and the observed combined mean volume is greater than the EAR volume, the combined effect is declared less than additive (antagonistic) regardless of the pairwise comparison results.
若相互作用測試在統計上並不顯著(p ≥ 0.05)，但相對於組合組之所有成對比較皆顯著(p ≤ 0.05)，則宣告組合作用為相加，否則組合作用不確定(無作用)。 If the interaction test is not statistically significant (p ≥ 0.05), but all pairwise comparisons relative to the combined group are significant (p ≤ 0.05), the combined effect is declared additive, otherwise the combined effect is indeterminate (no effect).
用於組合分析及報導輸出之LS平均值係自RM ANOVA模型估計，該模型僅由與各組合相關之4個組(亦即，對照、單一藥劑1、單一藥劑2及組合)組成，而並非如腫瘤生長抑制分析所進行的那樣藉由分別擬合各組來估計。雖然估計值類似，但其可能並不精確匹配。 三重組合分析 LS means used for combination analyses and reported outputs were estimated from RM ANOVA models consisting of only the 4 groups associated with each combination (i.e., control, single agent 1, single agent 2, and combination) and not by fitting each group separately as was done for the tumor growth inhibition analysis. Although the estimates are similar, they may not match exactly. Triple Combination Analysis
腫瘤生長抑制布利斯獨立性三重組合分析遵循與先前Zeus組合分析之文件中所描述相同的通用方法。使用先前已描述於Zeus腫瘤生長抑制分析之文件中的RM ANOVA模型來分析 對照、 單一藥劑 1、 單一藥劑 2、 單一藥劑 3及三種單一藥劑之 三重組合的log 10轉化腫瘤體積資料。藉由以下形式之對比表述來估計布利斯作用： 其中 • 為治療 t之平均腫瘤體積 Tumor Growth Inhibition Bliss independent triple combination analysis followed the same general approach as previously described in the Zeus combination analysis paper. The log 10 transformed tumor volume data for control , single agent 1 , single agent 2 , single agent 3 , and triple combinations of the three single agents were analyzed using the RM ANOVA model previously described in the Zeus tumor growth inhibition analysis paper. Bliss effects were estimated by contrast expression of the form: in• The average tumor volume for the treatment of t
假定腫瘤體積理論上或實際上可達到零(完全消退)，當在對數標度上分析腫瘤體積時，此方法在數學上等效於布利斯獨立性方法。 Assuming that tumor volume can theoretically or practically reach zero (complete regression), this method is mathematically equivalent to the Bliss independence method when tumor volume is analyzed on a logarithmic scale.
若組合作用精確地為相加的，則根據布利斯獨立性之定義，對比估計值等於零。若對比估計值在統計上不同於零 ，則在所觀測到之組合平均體積分別小於或大於預期相加反應腫瘤體積( )之情況下，組合作用 大於 ( 協同 )或 小於 ( 拮抗 ) 相加。使用以下等式計算三重組合 ： If the combined effects are exactly additive, then the contrast estimate is equal to zero by the definition of Bliss independence. If the contrast estimate is statistically different from zero , then the observed combined mean volume is smaller or larger than the expected sum of the tumor volumes ( ), the combination effect is greater ( synergistic ) or less ( antagonistic ) than the sum of the two. The triple combination was calculated using the following equation :
若對照與各單一藥劑處理組相對於組合處理組之間的對比在統計上不同於零 且所有成對比較皆為統計顯著 ，且觀測到之組合平均體積小於 ，則宣告組合作用 大於相加 ( 協同 )。 If the comparison between the control and each single agent treatment group relative to the combined treatment group is statistically different from zero All pairwise comparisons were statistically significant , and the observed combined mean volume is less than , then the combination is declared to be greater than addition ( synergy ) .
若對比在統計上不同於零 且觀測到之組合平均體積大於EAR體積，則不管成對比較結果如何，均宣告組合作用 小於相加 ( 拮抗 )。 If the contrast is statistically different from zero If the observed combined mean volume is greater than the EAR volume, the combined effect is declared less than additive ( antagonistic ) regardless of the pairwise comparison results.
若相互作用測試並非統計上顯著 而相對於組合組之所有成對比較皆顯著 ，則宣告組合作用為 相加。否則，組合作用不確定(無作用)。用於組合分析及報導輸出之LS平均值係自RM ANOVA模型估計，該模型僅由與各組合相關之5個組(亦即， 對照、單一藥劑 1 、單一藥劑 2 、 單一藥劑 3及 三重組合)組成，而並非如腫瘤生長抑制分析所進行的那樣藉由分別擬合各組來估計。雖然估計值類似，但其可能並不精確匹配。 實例 18 化合物 A 緩血酸胺錠劑調配物 If the interaction test is not statistically significant All pairwise comparisons were significant relative to the combined group. , then the combination effect is declared to be additive . Otherwise, the combination effect is indeterminate (no effect). The LS means used for the combination analysis and reported outputs are estimated from the RM ANOVA model, which consists only of the 5 groups associated with each combination (i.e., control, single agent 1 , single agent 2 , single agent 3 , and triple combination ), rather than by fitting each group separately as was done for the tumor growth inhibition analysis. Although the estimates are similar, they may not match exactly. Example 18 Compound A sedative tablet formulation
例示性化合物A緩血酸胺鹽形式A錠劑定量調配物列於表26中。化合物A緩血酸胺鹽形式A錠劑(50 mg及200 mg)之例示性批料配方提供於表27中。例示性製造步驟如下：1)分配化合物A緩血酸胺鹽原料藥、微晶纖維素、甘露糖醇、交聯羧甲基纖維素鈉、膠態二氧化矽、滑石及硬脂醯反丁烯二酸鈉。2)用適當篩網篩選微晶纖維素及膠態二氧化矽之顆粒內部分，且與化合物A緩血酸胺鹽原料藥在合適尺寸摻合器中摻合。3)將微晶纖維素、甘露糖醇、交聯羧甲基纖維素鈉及滑石與步驟2材料在適合尺寸摻合器中摻合。4)使用適合篩網研磨來自步驟3之摻合物。5)在適合尺寸摻合器中摻合來自步驟4之經研磨材料。6)使用適當篩網篩選硬脂醯反丁烯二酸鈉，且使用合適摻合器與步驟5材料摻合。7)滾筒壓實步驟6顆粒內摻合物。8)用適當篩網篩選微晶纖維素、交聯羧甲基纖維素鈉及膠態二氧化矽之顆粒外部分且使用合適尺寸之摻合器與步驟7顆粒摻合。9)使用適當篩網篩選硬脂醯反丁烯二酸鈉，且使用合適摻合器與步驟8材料摻合。10)使用等效於50 mg及200 mg物質之適合尺寸之工具將來自步驟9之最終摻合物壓製成錠劑。11)使用適合尺寸鍋包衣機用Opadry QX 321A120059 Yellow包衣步驟10核心錠劑。12)將成品封裝至具有乾燥劑之HDPE瓶中。
表26. 化合物A緩血酸胺鹽形式A錠劑成分
首次在人類中進行的1a/1b期臨床試驗(NCT05307705)旨在評估作為單藥療法及與抗癌療法組合投與患有晚期乳癌及具有PIK3CA H1047R突變之其他實體腫瘤的患者的化合物A或其醫藥學上可接受之鹽。主要目標係鑑別在有或無其他抗癌療法下化合物A之最大耐受劑量(MTD)/推薦2期劑量(RP2D)。The first-in-human Phase 1a/1b clinical trial (NCT05307705) is designed to evaluate Compound A or its pharmaceutically acceptable salt as a monotherapy and in combination with anticancer therapy in patients with advanced breast cancer and other solid tumors with PIK3CA H1047R mutation. The primary objective is to identify the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of Compound A with or without other anticancer therapy.
在此1a/1b期研究中招收之患者將接受化合物A或其醫藥學上可接受之鹽，作為單藥療法與多種抗癌劑組合，如下表中所示。所有標準護理藥劑將根據其標記劑量投與。
表28. 1a期給藥及投與模式
各1b期部分B隊列(隊列B1、B2及B3)中之患者將接受阿貝西利+芳香酶抑制劑(AI) (隊列B1)、單獨阿貝西利(隊列B2)或阿貝西利 + 伊魯司群(隊列B3)之7天治療引入(C1D -7至C1D -1)。在此引入之最後一天(C1D -1)，患者將進行PK取樣。在C1D1時，患者將開始各隊列之完全方案。 Patients in each Phase 1b Part B cohort (cohorts B1, B2, and B3) will receive a 7-day treatment lead-in (C1D -7 to C1D -1) of abemaciclib + aromatase inhibitor (AI) (cohort B1), abemaciclib alone (cohort B2), or abemaciclib + ilurostran (cohort B3). On the last day of this lead-in (C1D -1), patients will undergo PK sampling. On C1D1, patients will start the full regimen for each cohort.
在開始與太平洋紫杉醇之組合療法(在C1D8)之前，1b期部分D中之患者將接受化合物A單藥療法之7天治療引入(C1D1至C1D7)以評估化合物A暴露。 Patients in Phase 1b Part D will receive a 7-day treatment lead-in (C1D1 to C1D7) of Compound A monotherapy to assess Compound A exposure prior to starting combination therapy with paclitaxel (on C1D8).
太平洋紫杉醇將在C1D8、C1D15、C1D22給出，且隨後在所有後續週期之D1、D8、D15及D22給出。除C1以外，在研究者判斷下D22為視情況選用的。 Paclitaxel will be given on C1D8, C1D15, C1D22, and subsequently on D1, D8, D15, and D22 of all subsequent cycles. In addition to C1, D22 is optional at the discretion of the investigator.
部分F中之患者將在與批准劑量之氟維司群組合的化合物A或其醫藥學上可接受之鹽的多個劑量隊列(開放標記)中1:1隨機化。
合格準則： 納入準則 各患者必須符合以下所有納入準則，才有資格參與該研究：
年齡及性別1)在篩選時必須≥18歲或若根據地方法規更高，則為成年。
2)患者可為男性或女性。
患者類型及疾病特徵3)藉由在腫瘤或血液樣品中偵測之分子測試測定，存在PIK3CA H1047R突變(或除H1047R突變外，其他經贊助者及SRC批准之活化PIK3CA突變)。
4)具有分配至以下研究部分中之一者所需的診斷及先前治療史：
a) 1a 期： i) 劑量遞增及回填患者 ：(1)晚期實體腫瘤，其中標準治癒性或姑息性措施不再有效或在研究人員看來認為不適當或安全。
(2)患者可能先前已針對晚期疾病進行多達5種方案。
b) 1b 期： i) 部分 A ：(1) ER+/HER2-晚期乳癌
(2)患者可能先前已針對晚期疾病進行多達5種方案。
(a)需要先前週期蛋白依賴性激酶(CDK) 4/6抑制劑療法。
ii) 部分 B ：(1) ER+/HER2-晚期乳癌
(2)患者可能先前已針對晚期疾病進行多達2種方案。
iii) 部分 C ：(1) ER+/HER2-晚期乳癌
(2)患者可能先前已針對晚期疾病進行多達5種方案。
(a)需要先前CDK4/6抑制劑療法。
(3)診斷出2型糖尿病，且
(a)已進行穩定糖尿病治療方案，且在研究治療之第一次給藥之前3個月期間未進行胰島素治療
(b)在進入研究時血紅素A1c (HbA1c) ≤ 8%
iv) 部分 D ：(1)晚期乳癌
(2)患者可能先前已針對晚期疾病進行多達5種方案。
v) 部分 E ：(1)晚期實體腫瘤
(2)患者可能先前已針對晚期疾病進行多達3種方案。
vi) 部分 F ：(1) ER+/HER2-晚期乳癌
(2)患者可能先前已針對晚期疾病進行多達5種方案。
(a)需要先前CDK4/6抑制劑療法。
c) 藥效學生物標記物子研究患者： i)ER+/HER2-晚期乳癌
ii)患者必須具有可接近之軟組織(非中樞神經系統及非骨)腫瘤病變，其允許安全重複生檢。
5)對於乳癌患者，在呈現復發性或轉移性疾病時，自所取之最近組織切片評估ER及HER2狀態。
a)為滿足地方測試對ER+疾病之要求，根據相關American Society of Clinical Oncology (ASCO)/CAP指南中所定義，藉由免疫組織化學，乳癌必須表現ER(Allison KH, Hammond EH, Dowsett M等人, Estrogen and progesterone receptor testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists guideline update [2020年1月13日線上公開]. Arch Pathol Lab Med.)。
b)為滿足HER2-疾病之要求，根據相關ASCO/CAP指南中所定義，在初始診斷時或在後續生檢時，藉由免疫組織化學(IHC)或原位雜交，乳癌不可展現HER2之過表現(Wolff AC, Hammond MEH, Allison KH等人, Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018年11月;142(11):1364-1382)。儘管不需要作為方案程序，但若臨床上指示，則在進入研究之前，應儘可能藉由生檢再次評估HER2狀態，考慮患有新轉移性病灶之患者。
6)對於患有ER+乳癌診斷之患者：
a)若為女性，則必須為停經後：
i)若女性及停經後狀態歸因於卵巢功能之天然停止、手術或治療輻射，則患者必須符合以下準則中之至少1者以證明停經後狀態：
(1)先前兩側卵巢切除，或
(2)年齡≥60歲，或
(3)年齡＜60歲，閉經至少12個月(在無化學療法、他莫昔芬、托瑞米芬或卵巢遏制存在下)，及促卵泡激素(FSH)及雌二醇含量在停經後範圍內。
ii)若女性及停經後狀態歸因於使用促性腺激素釋放激素(GnRH)促效劑，諸如戈舍瑞林(goserelin)或亮丙立德(leuprolide) (每月接受且在第1週期第1天之前至少28天開始)進行卵巢功能遏制(OFS)，則患者必須在基線處(在治療之前14天內)具有陰性血清妊娠測試，且同意使用高度有效、經醫學批准之防護措施以防止在研究期間及在最後一次劑量研究治療之後6個月內懷孕。
b)若為男性，必須同意使用以下：
i)使用促性腺激素釋放激素促效劑，諸如戈舍瑞林或亮丙立德進行激素遏制(每月接受且在第1週期第1天之前至少28天開始)。
c)若研究人員認為具有足夠激素遏制，則將允許患者建立不太頻繁(亦即3個月或6個月) GnRH促效劑投與時程。
7)病灶之可量測性：
a)根據實體腫瘤反應評價準則(RECIST) v1.1所定義，患者必須具有以下中之一者(Eisenhauer EA, Therasse P, Bogaerts J等人, New response evaluation criteria in solid tumours: revised RECIST guideline (版本1.1). Eur J Cancer. 2009年1月;45(2):228-47)：
i)可量測疾病
(1)患有非乳房腫瘤類型之患者必須具有至少1個使用RECIST v1.1之標準技術可評定之可量測病灶(Eisenhauer等人 2009)。
ii)僅乳癌患者中不可量測之骨骼疾病(至少一個骨骼病灶)其可以包括以下：
(1)母細胞性骨骼病灶
(2)無可量測軟組織組分之溶解性骨骼病灶
(3)無可量測軟組織組分之混合溶解性-母細胞性骨骼病灶。
8)可獲得足夠歸檔腫瘤組織樣品，或若腫瘤樣品不可獲得，則經贊助者批准入選。較佳地，若組織用於鑑別PIK3CA H1047R (或其他限定)突變，則在可獲得情況下應提供對應於同一集合之樣品。若腫瘤組織不可獲得或腫瘤組織不用於PIK3CA測試，則應提供最近獲得之生檢(非骨樣品)。若無法提供足夠數量或品質之組織，則在根據活動時程開始治療之前，患者應在醫學上可行的情況下進行新的腫瘤生檢。在入選之前，無法安全地進行新腫瘤生檢之不可獲得腫瘤樣品的患者須與贊助者討論。
a)藥效學生物標記物子研究患者必須能夠且願意安全地進行軟組織(非中樞神經系統及非骨)腫瘤病灶之強制性成對研究生檢(治療前及治療前)。將在確定合格性之後且在開始研究治療之前收集預處理生檢。
9)根據美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group，ECOG)量表具有0或1之體能狀態(Oken MM, Creech RH, Tormey DC等人 Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982年12月;5(6):649-55)。
10)估計預期壽命≥12週。
11)須具有足夠的器官功能，如下文所定義：
表30.納入準則之實驗室值
圖1為結晶化合物A形式A之XRPD圖。 Figure 1 is the XRPD pattern of crystalline compound A form A.
圖2為結晶化合物A形式B之XRPD圖。 Figure 2 is the XRPD pattern of crystalline compound A form B.
圖3為結晶化合物A形式C之圖。 Figure 3 is a diagram of crystalline compound A form C.
圖4為結晶化合物A緩血酸胺鹽(tromethamine salt)形式A之XRPD圖。 Figure 4 is the XRPD pattern of crystalline compound A tromethamine salt form A.
圖5為結晶化合物A緩血酸胺鹽形式C之XRPD圖。 Figure 5 is the XRPD pattern of crystalline compound A sulphate amine salt form C.
圖6為結晶化合物A緩血酸胺鹽形式D之XRPD圖。 Figure 6 is the XRPD pattern of crystalline compound A sulphate amine salt form D.
圖7為結晶化合物A特丁胺鹽(erbumine salt)之XRPD圖。FIG. 7 is an XRPD pattern of crystalline compound A erbumine salt.
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| TWI863667B true TWI863667B (en) | 2024-11-21 |
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| JP4291696B2 (en) | 2002-01-22 | 2009-07-08 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | 2- (Pyridin-2-ylamino) -pyrido [2,3-d] pyrimidin-7-one |
| JP4053073B2 (en) | 2003-07-11 | 2008-02-27 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | Isethionate, a selective CDK4 inhibitor |
| AU2007297286A1 (en) | 2006-09-08 | 2008-03-20 | Pfizer Products Inc. | Synthesis of 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-ones |
| PA8852901A1 (en) | 2008-12-22 | 2010-07-27 | Lilly Co Eli | PROTEIN CINASE INHIBITORS |
| US20120115878A1 (en) | 2010-11-10 | 2012-05-10 | John Vincent Calienni | Salt(s) of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CA2900322C (en) | 2013-02-21 | 2019-03-26 | Pfizer Inc. | Solid forms of the selective cdk4/6 inhibitor compound acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8h-pyrido[2,3-d]pyrimidin-7-one |
| TWI702219B (en) | 2018-07-12 | 2020-08-21 | 美商美國禮來大藥廠 | Selective estrogen receptor degraders |
| MX2023013080A (en) * | 2021-05-03 | 2023-11-16 | Petra Pharma Corp | Allosteric chromenone inhibitors of phosphoinositide 3-kinase (pi3k) for the treatment of disease. |
| KR20250004897A (en) * | 2022-04-29 | 2025-01-08 | 페트라 파마 코포레이션 | Allosteric chromenone inhibitors of phosphoinositide 3-kinase (PI3K) for the treatment of diseases |
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Non-Patent Citations (1)
| Title |
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| 期刊 Vitale et al. PI3K inhibition in breast cancer: Identifying and overcoming different flavors of resistance Critical Reviews in Oncology / Hematology 162 2021 103334 |
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| KR20250105413A (en) | 2025-07-08 |
| TW202432102A (en) | 2024-08-16 |
| AU2023373671A1 (en) | 2025-05-15 |
| JP2024067010A (en) | 2024-05-16 |
| EP4611739A1 (en) | 2025-09-10 |
| WO2024097206A1 (en) | 2024-05-10 |
| CN120456897A (en) | 2025-08-08 |
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