TWI751516B - 類鐸受體調節劑之固體形式 - Google Patents
類鐸受體調節劑之固體形式 Download PDFInfo
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- TWI751516B TWI751516B TW109110763A TW109110763A TWI751516B TW I751516 B TWI751516 B TW I751516B TW 109110763 A TW109110763 A TW 109110763A TW 109110763 A TW109110763 A TW 109110763A TW I751516 B TWI751516 B TW I751516B
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Abstract
本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之固體形式、溶劑合物及水合物，以及製造方法。
Description
本申請案大體上係關於類鐸受體調節劑化合物，包括二胺基吡啶并[3,2-d
]嘧啶化合物及醫藥組合物，其尤其調節類鐸受體(例如TLR-8)；以及製造及使用其之方法。
類鐸受體(TLR)家族在先天性免疫之病原體識別及活化中起重要作用。類鐸受體8 (TLR-8)主要由骨髓免疫細胞表現，且此受體之活化刺激廣泛的免疫反應。TLR-8促效劑活化骨髓樹突狀細胞、單核球、單核球衍生之樹突狀細胞及庫普弗細胞(Kupffer cell)，導致產生促炎性細胞介素及趨化因子，諸如介白素-18 (IL-18)、介白素-12 (IL-12)、腫瘤壞死因子-α (TNF-α)及干擾素-γ (IFN-γ)。此類促效劑亦促進共刺激分子(諸如CD8+
細胞)、主要組織相容性複合體分子(MAIT、NK細胞)及趨化因子受體之表現增加。
總體而言，此等先天免疫反應及適應性免疫反應之活化誘發免疫反應，且在包括自體免疫、炎症、過敏、氣喘、移植排斥反應、移植物抗宿主疾病(GvHD)、感染、癌症及免疫缺乏之各種病狀中提供治療益處。舉例而言，對於B型肝炎，TLR8在專職性抗原呈現細胞(pAPC)及其他肝內免疫細胞上之活化與IL-12及促炎性細胞介素之誘發相關，預期該誘發可增強HBV特異性T細胞反應，活化肝內NK細胞且驅動抗病毒免疫復原。參見例如Wille-Reece, U.等人J Exp Med 203
, 1249-1258 (2006)；Peng, G.等人Science 309
, 1380-1384 (2005)；Jo, J.等人PLoS Pathogens 10
, e1004210 (2014)及Watashi, K.等人,J Biol Chem 288
, 31715-31727 (2013)。
鑒於治療各種疾病之潛力，仍需要類鐸受體(例如TLR-8)之新穎調節劑。脫靶傾向之可能性降低的有效且具選擇性之TLR-8調節劑係特別理想的。
在一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇龍膽酸之結晶形式：
其特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含三個或更多個峰的X射線粉末繞射(XRPD)圖案，化合物I龍膽酸。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇馬尿酸之結晶形式：
其特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I馬尿酸。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
其特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，磷酸鹽形式I。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
其特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，磷酸鹽形式II。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇丁二酸之結晶形式：
其特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I丁二酸。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
其特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I乙二磺酸形式I。
在另一個實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
其特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I乙二磺酸形式II。
相關申請案之交叉引用
本申請案主張2019年4月17日申請的美國臨時申請案第62/835,359號之益處，該臨時申請案之全部內容以全文引用之方式併入本文中。I. 通則
本發明係由意外地發現(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇(化合物I)之固體形式以及其鹽、溶劑合物或共晶體產生：
。
化合物I可採用多種結晶形式，包括(但不限於)結晶化合物I龍膽酸、結晶化合物I馬尿酸、結晶化合物I磷酸形式I、結晶化合物I磷酸形式II、結晶化合物I丁二酸、結晶化合物I乙二磺酸形式I及結晶化合物I乙二磺酸形式II。化合物I可形成兩種或更多種結晶形式之混合物，或形成實質上不含其他結晶形式之單晶形式。
本文提供之(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇(化合物I)之固體形式的X射線粉末繞射(XRPD)圖案係使用Cu Kα
輻射收集。II. 定義
如本說明書中所用，以下字詞及片語一般意欲具有如在下文中闡述之含義，使用其之上下文另外指示的方面除外。
「水合物」係指由化合物I與水組合而形成之複合物。該術語包括化學計量以及非化學計量水合物。
「溶劑合物」係指由化合物I與溶劑組合而形成之複合物。
「去溶劑化」係指作為如本文所述之溶劑合物且已自其中部分或完全地移除溶劑分子的化合物I形式。產生去溶劑化形式之去溶劑化技術包括(但不限於)使化合物I形式(溶劑合物)暴露於真空，使溶劑合物經歷高溫，使溶劑合物暴露於氣流，諸如空氣或氮氣，或者其任何組合。因此，去溶劑化化合物I形式可為無水(亦即完全不含溶劑分子)，或部分地去溶劑化，其中溶劑分子以化學計量或非化學計量量存在。
「醇」係指具有羥基之溶劑。代表性醇可具有任何適合數目之碳原子，諸如C1
-C6
，及任何適合數目之羥基，諸如1-3個。例示性醇包括(但不限於)甲醇、乙醇、正丙醇、異丙醇等。
「治療有效量」係指當投與需要此類治療之哺乳動物時如下所定義足以實現治療的量。治療有效量將視所治療之個體、個體之體重及年齡、疾病病狀之嚴重程度、投與方式及其類似因素而變化，容易由一般熟習此項技術者確定。
「實質上不含化合物I之其他結晶形式」係指含有少於10%之化合物I之其他結晶形式的化合物I之結晶形式。舉例而言，實質上不含可指含有少於9%、8%、7%、6%、5%、4%、3%、2%或1%之化合物I之其他結晶形式的化合物I之結晶形式。較佳地，實質上不含係指含有少於5%之化合物I之其他結晶形式的化合物I之結晶形式。較佳地，實質上不含係指含有少於1%之化合物I之其他結晶形式的化合物I之結晶形式。III. 化合物 I 之固體形式
本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇(化合物I；參見美國專利第9,670,205號)之固體形式，包括結晶形式，以及鹽、溶劑合物或共晶形式。在一些實施例中，本發明提供具有以下結構之化合物I之結晶形式：
及其鹽、溶劑合物或共晶體。
化合物I可採用多種結晶形式，包括(但不限於)結晶化合物I龍膽酸、結晶化合物I馬尿酸、結晶化合物I磷酸形式I、結晶化合物I磷酸形式II、結晶化合物I丁二酸、結晶化合物I乙二磺酸形式I及結晶化合物I乙二磺酸形式II。化合物I可形成兩種或更多種結晶形式之混合物，或形成實質上不含其他結晶形式之單晶形式。
在一些實施例中，本發明提供選自由以下組成之群的化合物：(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇龍膽酸；(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇馬尿酸；(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸形式I；(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸形式II；(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇丁二酸；(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸形式I；以及(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸形式II。形式 I
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為形式I。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇(化合物I)之結晶形式：
其特徵在於在10.9°、11.5°、13.2°、14.7°、15.5°、21.4°、21.9°、23.2°及24.9° 2θ (± 0.2° 2θ)處包含峰的X射線粉末繞射(XRPD)圖案。在一些實施例中，形式I之特徵在於如藉由單晶X射線結晶學所測定之具有以下尺寸之單位晶胞：a = 8.0344 (2) Å；b = 8.0344 (2) Å；c = 23.7871 (7) Å；α = 90°；β = 90°；以及γ = 90°。在一些實施例中，形式I之特徵在於實質上如圖1中所示之XRPD圖案。龍膽酸
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇龍膽酸鹽之結晶形式，其中結晶形式為龍膽酸鹽。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I龍膽酸共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇龍膽酸之結晶形式：
其特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含三個或更多個峰的X射線粉末繞射(XRPD)圖案，化合物I龍膽酸。
在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°及14.9° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°及26.3° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I龍膽酸之特徵在於在12.9°、24.8°及25.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、17.3°、19.5°或26.3° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°或26.3° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°或26.3° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°或26.3° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°或26.3° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°及26.3° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、24.8°或25.7° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、24.8°或25.7° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、24.8°或25.7° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、24.8°及25.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，化合物I龍膽酸之特徵在於在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°及26.3° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於實質上如圖2中所示之XRPD圖案。在一些實施例中，化合物I龍膽酸之特徵在於在約178℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I龍膽酸之特徵在於實質上如圖3中所示之DSC熱分析圖。
在一些實施例中，化合物I龍膽酸之特徵在於：(a)在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°及26.3° 2θ (± 0.2° 2θ)處包含峰之XRPD圖案；以及(b)在約178℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I龍膽酸之特徵在於：(a)實質上如圖2中所示之XRPD圖案；以及(b)實質上如圖3中所示之DSC熱分析圖。
在一些實施例中，化合物I龍膽酸實質上不含化合物I形式I。馬尿酸
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇馬尿酸鹽之結晶形式，其中結晶形式為馬尿酸鹽。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I馬尿酸共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇馬尿酸之結晶形式：
其特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I馬尿酸。
在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、17.6°、19.0°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，化合物I馬尿酸之特徵在於在5.0°、12.6°及25.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°或28.5° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°或28.5° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°或28.5° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°或28.5° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°或28.5° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在2.9°、7.6°、10.4°、17.6°、19.0°及28.5° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、7.6°及19.0° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°或28.5° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.0°、10.4°、12.6°、17.6°、25.2°及28.5° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I馬尿酸之特徵在於在2.9°、5.0°、7.6°、10.4°、12.6°、19.0°、17.6°、25.2°及28.5° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於實質上如圖6中所示之XRPD圖案。在一些實施例中，化合物I馬尿酸之特徵在於在約127℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I馬尿酸之特徵在於實質上如圖7中所示之DSC熱分析圖。
在一些實施例中，化合物I馬尿酸之特徵在於：(a)在2.9°、5.0°、7.6°、10.4°、12.6°、19.0°、17.6°、25.2°及28.5° 2θ (± 0.2° 2θ)處包含峰之XRPD圖案；以及(b)在約127℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I馬尿酸之特徵在於：(a)實質上如圖6中所示之XRPD圖案；以及(b)實質上如圖7中所示之DSC熱分析圖。
在一些實施例中，化合物I馬尿酸實質上不含化合物I形式I。磷酸形式 I
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸鹽之結晶形式，其中結晶形式為磷酸鹽形式I。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I磷酸形式I共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
其特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，磷酸鹽形式I。
在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°及7.1° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在12.1°、14.2°、21.6°、24.0°、27.4°及28.2° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，磷酸鹽形式I之特徵在於在14.2°、27.4°及28.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°或24.0° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°或24.0° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°或24.0° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°或24.0° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°或24.0° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在3.7°、6.1°、7.1°、12.1°、21.6°及24.0° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、14.2°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、14.2°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、14.2°、27.4°或28.2° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、14.2°、27.4°及28.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，磷酸鹽形式I之特徵在於在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°及28.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於實質上如圖10中所示之XRPD圖案。在一些實施例中，磷酸鹽形式I之特徵在於在約43℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，DSC熱分析圖在約118℃下開始第二次吸熱。在一些實施例中，DSC熱分析圖在約202℃下開始第三次吸熱。在一些實施例中，磷酸鹽形式I之特徵在於在約43℃、約118℃及約202℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，磷酸鹽形式I之特徵在於實質上如圖11中所示之DSC熱分析圖。
在一些實施例中，磷酸鹽形式I之特徵在於：(a)在3.7°、6.1°、7.1°、12.1°、14.2°、21.6°、24.0°、27.4°及28.2° 2θ (± 0.2° 2θ)處包含峰之XRPD圖案；以及(b)在約43℃、約118℃及約202℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，磷酸鹽形式I之特徵在於：(a)實質上如圖10中所示之XRPD圖案；以及(b)實質上如圖11中所示之DSC熱分析圖。
在一些實施例中，化合物I磷酸形式I實質上不含化合物I形式I。磷酸形式 II
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸鹽之結晶形式，其中結晶形式為磷酸鹽形式II。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I磷酸形式II共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
其特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，磷酸鹽形式II。
在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°及26.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°或27.4° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°或27.4° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°或27.4° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°或27.4° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°或27.4° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在15.8°、18.1°、18.9°、20.6°、24.1°及27.4° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，磷酸鹽形式II之特徵在於在15.8°、18.1°及18.9° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°或27.4° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.4°、6.3°、20.6°、24.1°、26.7°及27.4° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°或26.7° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°或26.7° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°或26.7° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°及26.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，磷酸鹽形式II之特徵在於在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°及27.4° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於實質上如圖13中所示之XRPD圖案。在一些實施例中，磷酸鹽形式II之特徵在於在約42℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，DSC熱分析圖在約95℃下開始第二次吸熱。在一些實施例中，磷酸鹽形式II之特徵在於在約42℃及約95℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，磷酸鹽形式II之特徵在於實質上如圖14中所示之DSC熱分析圖。
在一些實施例中，磷酸鹽形式II之特徵在於：(a)在5.4°、6.3°、15.8°、18.1°、18.9°、20.6°、24.1°、26.7°及27.4° 2θ (± 0.2° 2θ)處包含峰之XRPD圖案；以及(b)在約42℃及約95℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，磷酸鹽形式II之特徵在於：(a)實質上如圖13中所示之XRPD圖案；以及(b)實質上如圖14中所示之DSC熱分析圖。
在一些實施例中，化合物I磷酸形式II實質上不含化合物I形式I。丁二酸
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇丁二酸鹽之結晶形式，其中結晶形式為丁二酸鹽。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I丁二酸共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇丁二酸之結晶形式：
其特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I丁二酸。
在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°及9.3° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°或27.0° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在13.2°、17.5°、18.7°、19.0°、25.7°及27.0° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I丁二酸之特徵在於在18.7°、19.0°及25.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°或27.0° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°或27.0° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°或27.0° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°或27.0° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°或27.0° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.6°、6.8°、9.3°、13.2°、17.5°及27.0° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、18.7°、19.0°或25.7° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、18.7°、19.0°或25.7° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、18.7°、19.0°或25.7° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、18.7°、19.0°及25.7° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，化合物I丁二酸之特徵在於在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°及27.0° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於實質上如圖16中所示之XRPD圖案。在一些實施例中，化合物I丁二酸之特徵在於在約96℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，DSC熱分析圖在約115℃下開始第二次吸熱。在一些實施例中，化合物I丁二酸之特徵在於在約96℃及約115℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I丁二酸之特徵在於實質上如圖17中所示之DSC熱分析圖。
在一些實施例中，化合物I丁二酸之特徵在於：(a)在4.6°、6.8°、9.3°、13.2°、17.5°、18.7°、19.0°、25.7°及27.0° 2θ (± 0.2° 2θ)處包含峰之XRPD圖案；以及(b)在約96℃及約115℃下開始吸熱之差示掃描熱量測定(DSC)熱分析圖。在一些實施例中，化合物I丁二酸之特徵在於：(a)實質上如圖16中所示之XRPD圖案；以及(b)實質上如圖17中所示之DSC熱分析圖。
在一些實施例中，化合物I丁二酸實質上不含化合物I形式I。乙二磺酸形式 I
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸鹽之結晶形式，其中結晶形式為乙二磺酸鹽形式I。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I乙二磺酸形式I共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
其特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I乙二磺酸形式I。
在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、8.7°及22.1° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°或26.0° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°或26.0° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°或26.0° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°或26.0° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°或26.0° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在7.9°、13.0°、16.6°、20.6°、21.1°及26.0° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I乙二磺酸形式I之特徵在於在7.9°、13.0°及21.1° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°或26.0° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.4°、8.7°、16.6°、20.6°、22.1°及26.0° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、21.1°或22.1° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、21.1°或22.1° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、21.1°或22.1° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、21.1°和22.1° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，化合物I乙二磺酸形式I之特徵在於在4.4°、7.9°、8.7°、13.0°、16.6°、20.6°、21.1°、22.1°及26.0° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式I之特徵在於實質上如圖20中所示之XRPD圖案。
在一些實施例中，化合物I乙磺酸形式I實質上不含化合物I形式I。乙二磺酸形式 II
在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸鹽之結晶形式，其中結晶形式為乙二磺酸鹽形式II。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇之結晶形式，其中結晶形式為化合物I乙二磺酸形式II共晶體。在一些實施例中，本發明提供(R
)-2-((2-胺基-7-氟吡啶并[3,2-d
]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
其特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案，化合物I乙二磺酸形式II。
在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含六個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含七個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含八個或更多個峰的XRPD圖案。
在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、8.4°及22.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°或18.3° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°或18.3° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°或18.3° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°或18.3° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°或18.3° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在5.6°、12.9°、13.4°、16.6°、17.9°及18.3° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I乙二磺酸形式II之特徵在於在12.9°、13.4°及16.6° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含一或多個額外峰。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含兩個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含三個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含四個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°或22.2° 2θ (± 0.2° 2θ)處包含五個或更多個額外峰。在一些實施例中，XRPD圖案進一步在4.5°、5.6°、8.4°、17.9°、18.3°及22.2° 2θ (± 0.2° 2θ)處包含額外峰。
在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、8.4°、12.9°、13.4°、16.6°或22.2° 2θ (± 0.2° 2θ)處包含三個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、8.4°、12.9°、13.4°、16.6°或22.2° 2θ (± 0.2° 2θ)處包含四個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、8.4°、12.9°、13.4°、16.6°或22.2° 2θ (± 0.2° 2θ)處包含五個或更多個峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、8.4°、12.9°、13.4°、16.6°及22.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。
在一些實施例中，化合物I乙二磺酸形式II之特徵在於在4.5°、5.6°、8.4°、12.9°、13.4°、16.6°、17.9°、18.3°及22.2° 2θ (± 0.2° 2θ)處包含峰的XRPD圖案。在一些實施例中，化合物I乙二磺酸形式II之特徵在於實質上如圖21中所示之XRPD圖案。
在一些實施例中，化合物I乙二磺酸形式II實質上不含化合物I形式I。IV. 製備化合物 I 之固體形式之方法
化合物I之固體形式可藉由多種方法製備。舉例而言，化合物I可溶解於單一溶劑系統中且使其結晶。或者，可藉由使化合物I溶解於溶劑中且接著添加反溶劑至混合物，引起化合物I結晶而使化合物I自雙溶劑系統中結晶。
溶劑可為適合於形成溶液之任何溶劑。通常溶劑可為極性溶劑，在一些實施例中，其為質子溶劑。其他合適溶劑包括非極性溶劑。合適溶劑包括(但不限於)水、烷烴(諸如庚烷、己烷及環己烷)、石油醚、C1
-C3
醇(甲醇、乙醇、丙醇、異丙醇)、乙二醇及聚乙二醇(諸如PEG400)、烷酸酯(諸如乙酸乙酯、乙酸丙酯、乙酸異丙酯及乙酸丁酯)、乙腈、烷酮(諸如丙酮、丁酮、甲基乙基酮(MEK)、甲基丙基酮(MPK)及甲基異丁基酮(MIBK))、醚(諸如乙醚、甲基-第三丁基醚、四氫呋喃、甲基-四氫呋喃、1,2-二甲氧基乙烷及1,4-二噁烷)、芳族化合物(諸如苯及甲苯)、鹵化溶劑(諸如二氯甲烷、氯仿及四氯化碳)、二甲亞碸(DMSO)及二甲基甲醯胺(DMF)。合適溶劑亦包括(但不限於)鹵化C1
-C3
醇(三氟甲醇、三氟乙醇(TFE)、六氟異丙醇(HFIPA))。舉例而言，溶劑可為極性非質子溶劑，尤其諸如二氯甲烷、N-甲基吡咯啶酮、四氫呋喃、乙酸乙酯、丙酮、甲基乙基酮、二甲基甲醯胺(DMF)、乙腈(AcCN)、二甲亞碸(DMSO)。溶劑亦可為極性質子溶劑，尤其諸如第三丁醇、正丙醇、異丙醇、乙醇、甲醇、乙酸、水。溶劑亦可為非極性溶劑，諸如己烷、戊烷、石油醚、苯、甲苯、乙醚、甲基-第三丁基醚、四氫呋喃、甲基-四氫呋喃、1,2-二甲氧基乙烷及1,4-二噁烷、氯仿及四氯化碳。
在溶劑混合物中兩種或更多種溶劑可以任何合適之比率使用。舉例而言，第一溶劑與第二溶劑之比率可為10:1至約1:10(體積/體積)，或約10:1至1:5或10:1至1:1或10:1至5:1或5:1至1:5或5:1至1:1或4:1至1:1或3:1至1:1或2:1至1:1。其他溶劑比率包括約10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9或約1:10(體積/體積)。
製備化合物I之固體形式之方法可在任何合適之反應條件下進行。舉例而言，製備化合物I之結晶形式之方法可在任何合適之溫度下，諸如(但不限於)在低於室溫下，在室溫下或在超過室溫下進行。在一些實施例中，溫度可為約-78℃至約100℃，或約0℃至約50℃，或約10℃至約30℃。舉例而言，反應混合物在約20℃或25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃或約100℃的溫度下。反應混合物亦可在約20℃、15℃、10℃、5℃、0℃、-5℃、-10℃、-20℃、-30℃、-40℃、-50℃、-60℃、-70℃或約-78℃的溫度下。在一些實施例中，溫度可為方法中所用之特定溶劑的回流溫度。在其它實施例中，化合物I之結晶形式可加熱至超過約100℃，使得化合物I之一種結晶形式形成化合物I之第二種結晶形式。
製備化合物I之固體形式之方法可包括多個其他步驟。舉例而言，溶劑可蒸發，晶種可添加至混合物中，混合物可單次或重複加熱及冷卻等。舉例而言，方法可包括將反應混合物加熱至約20℃或25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、65℃、70℃、75℃、80℃、85℃、90℃、95℃或約100℃之溫度。方法亦可包括冷卻反應混合物至約20℃、15℃、10℃、5℃、0℃、-5℃、-10℃、-20℃、-30℃、-40℃、-50℃、-60℃、-70℃或約-78℃之溫度。反應混合物之溫度可以任何合適之速率改變。舉例而言，溫度改變速率可為約0.1℃/min至約10℃/min。
製備化合物I之結晶形式之方法可進行任何合適之時間。舉例而言，時間可為數分鐘、數小時或數天。在一些實施例中，時間可為若干小時，諸如隔夜。製備化合物I之結晶形式之方法可為在任何合適之壓力下進行。舉例而言，壓力可低於大氣壓，在約大氣壓下，或超過大氣壓。
可藉由此項技術中已知之方法，例如藉由機械方式，諸如用例如玻璃棒刮擦或摩擦反應容器之接觸表面來誘發結晶。視情況飽和或過飽和溶液可用晶種接種。製備化合物I之固體形式之方法亦可包括結晶化合物I之晶種。
期望結晶形式之分離可藉由移除溶劑且使晶體自溶劑沈澱來實現。一般地，此係藉由已知方法，諸如過濾、抽濾、傾析或離心進行。可藉由用熟習此項技術者已知之方法，如例如施加真空和/或藉由加熱自結晶形式移除任何過量溶劑來達成進一步分離。形式 I
結晶化合物I形式I可藉由多種方法製備。在一些實施例中，本發明提供一種製備本發明之結晶化合物I形式I之方法，其包括在適合於製備形式I之條件下形成本發明之化合物I與溶劑之混合物。在一些實施例中，使化合物I溶解於溶劑中。
在一些實施例中，溶劑可為乙酸乙酯。
製備化合物I形式I之方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約85℃之溫度。在一些實施例中，該方法包括冷卻反應混合物至約20℃之溫度。在一些實施例中，製備化合物I形式I之方法亦包括加熱混合物以溶解化合物I，且冷卻混合物。在一些實施例中，製備化合物I形式I之方法包括形成化合物I與乙酸乙酯之混合物，加熱混合物以溶解化合物I，且冷卻混合物，因此形成化合物形式I。龍膽酸
結晶化合物I龍膽酸可由化合物I形式I藉由使化合物I形式I溶解於具有龍膽酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I龍膽酸之方法，其包括在適合於製備化合物I龍膽酸之條件下形成化合物I形式I、龍膽酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性非質子溶劑。在一些實施例中，溶劑可為乙腈。
該方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約50℃之溫度。在一些實施例中，反應混合物可冷卻至周圍溫度。在一些實施例中，反應混合物可冷卻至約10℃之溫度。在一些實施例中，該方法可包括多個加熱及冷卻步驟。馬尿酸
結晶化合物I馬尿酸可由化合物I形式I藉由使化合物I形式I溶解於具有馬尿酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I馬尿酸之方法，其包括在適合於製備化合物I馬尿酸之條件下形成化合物I形式I、馬尿酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性非質子溶劑。在一些實施例中，溶劑可為丙酮。
該方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約50℃之溫度。在一些實施例中，反應混合物可冷卻至周圍溫度。在一些實施例中，反應混合物可冷卻至約10℃之溫度。在一些實施例中，該方法可包括多個加熱及冷卻步驟。磷酸形式 I
結晶化合物I磷酸形式I可由化合物I形式I藉由使化合物I形式I溶解於具有磷酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I磷酸之方法，其包括在適於製備形式I之條件下形成化合物I形式I、磷酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性非質子溶劑。在一些實施例中，溶劑可為丙酮。
該方法可包括多個其他步驟。在一些實施例中，反應混合物可用乙腈與異丙醇之溶劑混合物濕磨。磷酸形式 II
結晶化合物I磷酸形式II可由化合物I形式I藉由使化合物I形式I溶解於具有磷酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I磷酸形式II之方法，其包括在適於製備化合物I磷酸形式II之條件下形成化合物I形式I、磷酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性質子溶劑。在一些實施例中，溶劑可為第三丁醇、正丙醇、異丙醇、乙醇或甲醇。在一些實施例中，溶劑可為異丙醇。
製備化合物I磷酸形式II之方法可包括多個其他步驟。舉例而言，反應混合物可用乙腈與異丙醇之溶劑混合物濕磨。該方法亦可包括在二乙醚中形成漿液且添加化合物I磷酸形式I之晶種。丁二酸
結晶化合物I丁二酸可由化合物I形式I藉由使化合物I形式I溶解於具有丁二酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I丁二酸之方法，其包括在適於製備化合物I丁二酸之條件下形成化合物I形式I、丁二酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性質子溶劑。在一些實施例中，溶劑可為第三丁醇、正丙醇、異丙醇、乙醇或甲醇。在一些實施例中，溶劑可為異丙醇。
該方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約60℃之溫度。在一些實施例中，反應混合物可冷卻至周圍溫度。在一些實施例中，反應混合物可冷卻至約5℃之溫度。在一些實施例中，該方法可包括多個加熱及冷卻步驟。乙二磺酸形式 I
結晶化合物I乙二磺酸形式I可由化合物I形式I藉由使化合物I形式I溶解於具有乙二磺酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I乙二磺酸之方法，其包括在適於製備化合物I乙二磺酸形式I之條件下形成化合物I形式I、乙二磺酸及溶劑之混合物。在一些實施例中，使化合物I形式I溶解於溶劑中。在一些實施例中，溶劑可為極性非質子溶劑。在一些實施例中，溶劑可為丙酮。
該方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約50℃之溫度。在一些實施例中，反應混合物可冷卻至周圍溫度。在一些實施例中，反應混合物可冷卻至約10℃之溫度。在一些實施例中，該方法可包括多個加熱及冷卻步驟。乙二磺酸形式 II
結晶化合物I乙二磺酸形式II可藉由使化合物I乙二磺酸形式I在溶劑中形成漿液來製備。在一些實施例中，本發明提供一種製備結晶化合物I乙二磺酸形式II之方法，其包括在適於製備化合物I乙二磺酸形式II之條件下形成化合物I乙二磺酸形式I與溶劑之混合物。在一些實施例中，溶劑可為二氯甲烷。
或者，結晶化合物I乙二磺酸形式I可由化合物I形式I藉由使化合物I形式I溶解於具有乙二磺酸之溶劑中來製備。在一些實施例中，本發明提供一種製備結晶化合物I乙二磺酸形式II之方法，其包括在適於製備化合物I乙二磺酸形式II之條件下形成本發明之化合物I形式I、乙二磺酸及溶劑之混合物。在一些實施例中，使化合物I乙二磺酸形式II溶解於溶劑中。在一些實施例中，溶劑可為極性非質子溶劑。在一些實施例中，溶劑可為丙酮。
該方法可包括多個其他步驟。在一些實施例中，可將反應混合物加熱至約60℃之溫度。在一些實施例中，反應混合物可冷卻至約20℃之溫度。
V.醫藥組合物
本文提供之化合物I之固體形式可呈醫藥組合物形式投與。本發明提供醫藥組合物，其含有作為活性成分的所述化合物I之固體形式或其醫藥學上可接受之鹽或酯中之一或多者及一或多種醫藥學上可接受之賦形劑、載劑(包括惰性固體稀釋劑及填充劑)、稀釋劑(包括無菌水溶液及多種有機溶劑)、滲透增強劑、增溶劑及佐劑。醫藥組合物可單獨或與其他治療劑(如以下組合療法部分中所指示)組合投與。此類組合物以醫藥技術中熟知之方式製備(參見例如Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 第17版 (1985))；及Modern Pharmaceutics, Marcel Dekker, Inc. 第3版 (G.S. Banker & C.T. Rhodes編輯)。
醫藥組合物可藉由具有類似效用之藥劑的公認投與模式中之任一者，例如如以引用之方式併入的彼等專利及專利申請案中所述，包括直腸、經頰、鼻內及經皮途徑、藉由動脈內注射、靜脈內、腹膜內、非經腸、肌肉內、皮下、經口、表面、以吸入劑形式或經由浸漬或塗佈裝置，諸如支架，例如或經動脈插入之圓柱形聚合物，以單一或多個劑量形式投與。
一種投與模式為非經腸，尤其藉由注射。新穎本發明之組合物可併入以藉由注射來投與的形式包括水性或油懸浮液或乳液，具有芝麻油、玉米油、棉籽油或花生油以及酏劑、甘露糖醇、右旋糖或無菌水溶液及類似醫藥媒劑。鹽水溶液亦習知用於注射，但在本發明之上下文中不太較佳。亦可採用乙醇、甘油、丙二醇、液體聚乙二醇及其類似物(及其適合混合物)、環糊精衍生物及植物油。適當流動性可例如藉由使用諸如卵磷脂之包衣、藉由在分散液之情況下維持所需粒度及藉由使用界面活性劑來維持。可藉由各種抗菌劑及抗真菌劑，例如對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞及其類似物預防微生物作用。
無菌可注射溶液藉由將需要量之根據本發明之化合物併入具有如上方列舉之視需要之多種其他成分的合適溶劑中，接著過濾殺菌製備。一般而言，分散液藉由將多種滅菌活性成分併入含有基本分散介質及來自上文所列之彼等成分之所需其他成分的無菌媒劑中來製備。在用於製備無菌可注射溶液之無菌粉末之情況下，一般製備方法為真空乾燥及冷凍乾燥技術，由其先前無菌過濾溶液產生活性成分加任何額外所需成分之粉末。
經口投藥係根據本發明之化合物之另一投與途徑。投與可經由膠囊或包覆腸衣之錠劑或其類似物。在製造包括至少一種本文所述之化合物的醫藥組合物中，活性成分通常藉由賦形劑稀釋及/或密封於此類載劑內，其可呈膠囊、藥囊、紙或其他容器形式。當賦形劑充當稀釋劑時，其可呈固體、半固體或液體材料(如上所述)形式，其充當活性成分之媒劑、載劑或介質。因此，組合物可呈以下形式：錠劑、丸劑、散劑、口含錠、藥囊、扁囊劑、酏劑、懸浮液、乳液、溶液、糖漿、氣霧劑(呈固體形式或於液體介質中)、含有例如高達10重量%之活性化合物之軟膏、軟及硬明膠膠囊、無菌可注射溶液及無菌包裝粉末。
合適賦形劑之一些實例包括乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、澱粉、阿拉伯膠、磷酸鈣、海藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、無菌水、糖漿及甲基纖維素。調配物可另外包括：潤滑劑，諸如滑石、硬脂酸鎂及礦物油；濕潤劑；乳化劑及懸浮劑；防腐劑，諸如羥基苯甲酸甲酯及羥基苯甲酸丙酯；甜味劑；以及調味劑。
可調配本發明之組合物以便在藉由採用此項技術中已知之程序投與患者之後，提供活性成分之快速、持續或延遲釋放。用於經口投藥之控制釋放藥物遞送系統包括含有經聚合物塗佈之儲集囊或藥物-聚合物基質調配物之滲透泵系統及溶解系統。控制釋放系統之實例在美國專利第3,845,770號、第4,326,525號、第4,902,514號及第5,616,345號中給出。用於本發明之方法中之另一調配物採用經皮遞送裝置(「貼片」)。此類經皮貼片可用於提供本發明之化合物以控制量連續或不連續輸注。用於遞送藥劑之經皮貼片之構造及用法為此項技術中所熟知。參見例如美國專利第5,023,252號、第4,992,445號及第5,001,139號。此類貼片可經構造以持續、脈衝式或按需求遞送藥劑。
在一些實施例中，組合物調配成單位劑型。術語「單位劑型」係指適用作針對人類個體及其他哺乳動物之單位劑量的物理離散單元，各單元含有經計算以產生所需治療效果的預定量之活性物質，與合適醫藥賦形劑(例如錠劑、膠囊、安瓿)結合。化合物通常以醫藥有效量投與。在一些實施例中，各劑量單元含有1 mg至2 g本文所述之化合物，且對於非經腸投藥，在一些實施例中，0.1至700 mg本文所述之化合物。然而，應瞭解，實際上投與之化合物之量將由醫師根據相關情況來確定，包括待治療之病狀、所選投與途徑、實際投與活性劑及其相對活性、個別患者之年齡、體重及反應以及患者症狀之嚴重性及類似情況。
為了製備固體組合物(諸如錠劑)，將主要活性成分與醫藥賦形劑混合以形成含有本發明化合物之均勻混合物的固體預調配組合物。當提及此等預調配組合物為均質時，意謂活性成分均勻分散在整個組合物中，使得組合物可易於再分為同等有效之單位劑型，諸如錠劑、丸劑及膠囊。
本發明之錠劑或丸劑可包覆包衣或以其他方式混配以提供得到長期作用或免受胃之酸性條件影響之優點的劑型。舉例而言，錠劑或丸劑可包含內部劑量及外部劑量組分，後者呈包覆前者之包膜形式。兩種組分可由腸溶層隔開，該腸溶層用以防止在胃中崩解且允許內部組分完整進入十二指腸或釋放延遲。各種材料可用於該等腸溶層或包衣，此類材料包括多種聚合酸及聚合酸與諸如蟲膠、鯨蠟醇及乙酸纖維素之材料的混合物。
用於吸入或吹入之組合物包括醫藥學上可接受之水性或有機溶劑或其混合物中之溶液及懸浮液，以及散劑。液體或固體組合物可含有如上文所描述之適合的醫藥學上可接受之賦形劑。在一些實施例中，藉由經口或經鼻呼吸道途徑投與組合物以用於局部或全身性作用。於較佳醫藥學上可接受之溶劑中之組合物可藉由使用惰性氣體進行霧化。霧化溶液可直接自霧化裝置吸入或霧化裝置可連接至面罩或間歇性正壓呼吸機。溶液、懸浮液或粉末組合物可自以適當方式遞送調配物之裝置，在一些實施例中經口或經鼻投與。
在一個實施例中，本發明係關於一種醫藥組合物，其包含醫藥學上可接受之賦形劑或載劑及治療有效量的如上所述之化合物I之化合物或其醫藥學上可接受之鹽、酯、前藥、立體異構體或水合物。
VI.使用方法
可藉由熟習此項技術者已知且如上文所詳述之任一公認投與模式，以單次或多次劑量向罹患諸如(但不限於)B型肝炎病毒(HBV)、C型肝炎病毒(HCV)及人類免疫缺乏病毒(HIV)之病毒感染的個體投與本文所述之化合物I之固體形式。
如本文所用，「促效劑」為刺激其結合搭配物(通常受體)之物質。刺激係在特定分析之背景下定義，或在文獻中自本文中在與熟習此項技術者所瞭解實質上類似之情況下與公認為特定結合搭配物之「促效劑」或「拮抗劑」之因子或物質進行比較的論述可顯而易見。刺激可相對於由促效劑或部分促效劑與結合搭配物之相互作用誘發且可包括異位效應之特定效應或功能的增加來定義。
如本文所用，「拮抗劑」為刺激其結合搭配物(通常受體)之物質。抑制係在特定分析之背景下定義，或在文獻中自本文中在與熟習此項技術者所瞭解實質上類似之情況下與公認為特定結合搭配物之「促效劑」或「拮抗劑」之因子或物質進行比較的論述可顯而易見。抑制可相對於由拮抗劑與結合搭配物之相互作用誘發且可包括異位效應之特定效應或功能的減少來定義。
如本文所用，「部分促效劑」或「部分拮抗劑」為對結合搭配物分別提供分別為不充分或不完全促效或拮抗之刺激或抑制程度的物質。應認識到，刺激且因此抑制係固有地針對被定義為促效劑、拮抗劑或部分促效劑之任何物質或物質類別來定義。
如本文所用，「固有活性」或「功效」係關於結合搭配物複合物之生物有效性的一定量測。關於受體藥理學，應定義固有活性或功效之情形將視結合搭配物(例如，受體/配位體)複合物之情形及考慮與特定生物結果有關之活性而定。舉例而言，在一些情況下，固有活性可視所涉及之特定第二信使系統而變化。一般技術者將顯而易見此類上下文特定評估何處相關及其在本發明之上下文中如何可能相關。
如本文所用，受體之調節包括受體之促效作用、部分促效作用、拮抗作用、部分拮抗作用或反向促效作用。
如熟習此項技術者將瞭解，當治療諸如HCV、HBV或HIV之病毒感染時，可以多種方式表徵此類治療且藉由多個終點量測。本發明之範疇意欲涵蓋所有此類表徵。
在一個實施例中，該方法可用於在人類中誘發針對病毒感染之多個抗原決定基的免疫反應。針對病毒感染之免疫反應的誘發可使用熟習此項技術者已知用於判定免疫反應是否已發生之任何技術來評估。本發明之偵測免疫反應之適合方法尤其包括偵測個體之血清中的病毒負荷或抗原之減少，偵測IFN-γ分泌肽特異性T細胞，及偵測一或多種肝酶，諸如丙胺酸轉移酶(ALT)及天冬胺酸轉移酶(AST)之含量的增加。在一個實施例中，偵測IFN-γ分泌肽特異性T細胞係使用ELISPOT分析實現。另一實施例包括降低與HBV感染相關之病毒負荷，包括如藉由PCR測試所量測之降低。
在一些實施例中，本發明提供一種治療病毒感染之方法，其包含向有需要之人類投與治療有效量之化合物I之結晶形式或本發明之醫藥組合物。在一些實施例中，本發明提供用於治療病毒感染之化合物I之結晶形式，其包含投與治療有效量之化合物I之結晶形式或本發明之醫藥組合物。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於治療病毒感染。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於製造供治療病毒感染用之藥劑。
在另一態樣中，本發明提供用於治療B型肝炎病毒感染或C型肝炎病毒感染之方法，其中該等方法各包括向感染B型肝炎病毒或C型肝炎病毒之人類個體投與治療有效量之化合物I之結晶形式的步驟。通常，人類個體罹患慢性B型肝炎感染或慢性C型肝炎感染，但治療急性感染HCV之人係在本發明之範疇內。
在一些實施例中，本發明提供化合物I之結晶形式，其用於治療B型肝炎病毒感染或C型肝炎病毒感染。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於製造供治療B型肝炎病毒感染或C型肝炎病毒感染用之藥劑。
在一些實施例中，本發明提供化合物I之結晶形式，其用於治療B型肝炎病毒感染。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於製造供治療B型肝炎病毒感染用之藥劑。
根據本發明之治療通常分別刺激感染HBV或HCV之人類中針對HBV或HCV之免疫反應，隨之降低感染個人中HBV或HCV之病毒負荷。免疫反應之實例包括產生抗體(例如IgG抗體)及/或產生調節免疫系統活性之細胞介素(諸如干擾素)。免疫系統反應可為新誘發之反應，或可為現有免疫反應之強化。特定言之，免疫系統反應可為針對一或多個HBV或HCV抗原之血清轉化。
可藉由量測血液中存在之HBV DNA或HCV DNA之量來確定病毒負荷。舉例而言，血清HBV DNA可使用Roche COBAS Amplicor Monitor PCR分析(2.0版；定量下限，300複本/毫升[57 IU/mL])及Quantiplex bDNA分析(定量下限，0.7 MEq/mL；Bayer Diagnostics，以前為Chiron Diagnostics, Emeryville, CA)定量。可使用諸如酶聯免疫分析及酶聯免疫吸附分析之此項技術中公認之技術，量測抗體針對特定HBV或HCV抗原(例如B型肝炎表面抗原(HBsAG))之量。舉例而言，可使用Abbott AxSYM微米粒子酶免疫分析系統(Abbott Laboratories, North Chicago, IL)量測抗體針對特定HBV或HCV抗原之量。
化合物I可藉由任何適用途徑及方式，諸如藉由經口或非經腸(例如靜脈內)投與來投與。化合物I之治療有效量為每日每公斤體重約0.00001 mg至每日每公斤體重約10 mg，諸如每日每公斤體重約0.0001 mg至每日每公斤體重約10 mg，或諸如每日每公斤體重約0.001 mg至每日每公斤體重約1 mg，或諸如每日每公斤體重約0.01 mg至每日每公斤體重約1 mg，或諸如每日每公斤體重約0.05 mg至每日每公斤體重約0.5 mg，或諸如每日約0.3 μg至約30 mg，或諸如每日約30 μg至約300 μg。
化合物I之治療有效量亦為每劑約0.01 mg至每劑約1000 mg，諸如每劑約0.01 mg至每劑約100 mg，或諸如每劑約0.1 mg至每劑約100 mg，或諸如每劑約1 mg至每劑約100 mg，或諸如每劑約1 mg至每劑約10 mg。化合物I之其他治療有效量為每劑約1 mg、每劑1.5 mg、每劑2 mg、每劑2.5 mg、每劑3 mg或每劑3.5 mg或每劑約2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或約100 mg。化合物I之其他治療有效量為每劑約100 mg，或每劑約125、150、175、200、225、250、275、300、350、400、450或約500 mg。可每小時、每日或每週投與單次劑量。舉例而言，單次劑量可每隔1小時、2小時、3小時、4小時、6小時、8小時、12小時、16小時投與一次或每隔24小時投與一次。單次劑量亦可每隔1天、2天、3天、4天、5天、6天投與一次或每隔7天投與一次。單次劑量亦可每隔1週、2週、3週投與一次，或每隔4週投與一次。單次劑量亦可每月投與一次。
化合物I之給藥頻率將由個別患者之需要確定，且可為例如每天一次或兩次或每天更多次。化合物I之投與持續治療HBV或HCV感染所必需的時長。舉例而言，可向感染HBV或HCV之人類投與化合物I持續20天至180天之時段，或例如20天至90天之時段，或例如30天至60天之時段。
投與可為間歇性的，其中在數天或更多天之時段期間患者接受日劑量之化合物I，隨後在數天或更多天之時段期間患者不接受日劑量之化合物I。舉例而言，患者可每隔一天或每週三次接受一劑化合物I。再次舉例而言，患者可每日接受一劑化合物I達1天至14天之時段，隨後在7天至21天之時段期間患者不接受一劑化合物I，隨後在後續時段(例如1天至14天)期間患者再次接受日劑量之化合物I。可視治療患者之臨床需要來重複交替時段之化合物I投與、接著化合物I不投與。
如本文中更充分地描述，化合物I之結晶形式可與一或多種額外治療劑一起投與感染B型肝炎病毒或C型肝炎病毒之人類。額外治療劑可與化合物I之結晶形式同時，或在化合物I之結晶形式投與之前或之後投與感染人類。在一些實施例中，本發明提供化合物I之結晶形式，其用於治療或預防B型肝炎病毒感染之方法中，其中化合物I之結晶形式與一或多種用於治療B型肝炎病毒感染之額外治療劑同時、分開或相繼投與。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於製造供治療B型肝炎病毒感染用之藥劑，其中化合物I之結晶形式與一或多種用於治療B型肝炎病毒感染之額外治療劑同時、分開或相繼投與。
在另一態樣中，本發明提供一種用於改善與HBV感染或HCV感染相關聯之症狀之方法，其中該方法包含向感染B型肝炎病毒或C型肝炎病毒之人類個體投與治療有效量之化合物I之結晶形式，其中治療有效量足夠改善與HBV感染或HCV感染相關聯之症狀。此類症狀包括血液中存在HBV病毒粒子(或HCV病毒粒子)、肝炎症、黃疸、肌肉疼痛、虛弱及疲勞。
在一些實施例中，本發明提供化合物I之結晶形式，其用於改善與HBV感染或HCV感染相關聯之症狀，其中該方法包含向感染B型肝炎病毒或C型肝炎病毒之人類個體投與治療有效量之化合物I之結晶形式，其中治療有效量足夠改善與HBV感染或HCV感染相關聯之症狀。在一些實施例中，本發明提供化合物I之結晶形式之用途，其用於製造供改善與HBV感染或HCV感染相關聯之症狀用之藥劑，其中該方法包含向感染B型肝炎病毒或C型肝炎病毒之人類個體投與治療有效量之化合物I之結晶形式，其中治療有效量足夠改善與HBV感染或HCV感染相關聯之症狀。
在另一態樣中，本發明提供一種用於降低人類中B型肝炎病毒感染或C型肝炎病毒感染之進展速率之方法，其中該方法包含向感染B型肝炎病毒或C型肝炎病毒之人類個體投與治療有效量之化合物I或其醫藥學上可接受之鹽，其中治療有效量足夠降低B型肝炎病毒感染或C型肝炎病毒感染之進展速率。感染之進展速率可藉由量測血液中HBV病毒粒子或HCV病毒粒子之量來追蹤。
在另一態樣中，本發明提供一種用於降低與HBV感染或HCV感染相關聯之病毒負荷之方法，其中該方法包含向感染HBV或HCV之人類投與治療有效量之化合物I或其醫藥學上可接受之鹽，其中治療有效量足夠降低人類中之HBV病毒負荷或HCV病毒負荷。
在另一態樣中，本發明提供一種誘發或增強人類中針對B型肝炎病毒或C型肝炎病毒之免疫反應的方法，其中該方法包含向人類投與治療有效量之化合物I或其醫藥學上可接受之鹽，其中誘發人類中新的針對B型肝炎病毒或C型肝炎病毒之免疫反應或增強人類中預先存在的針對B型肝炎病毒或C型肝炎病毒之免疫反應。可在個體中誘發關於HBV或HCV之血清轉化。免疫反應之實例包括產生抗體(諸如IgG抗體分子)，及/或產生調節人類免疫系統之一或多種組分之活性的細胞介素分子。
誘發長期感染此等病毒中之任一者之患者中針對HCV或HBV之血清轉化係化合物I之意外特性。在臨床實踐中，將HBV患者或HCV患者用單獨或與一或多種其他治療劑組合之化合物I治療，直至誘發或增強針對HBV或HCV之免疫反應且降低HBV或HCV之病毒負荷。隨後，雖然HBV或HCV病毒可呈潛伏形式存留於患者體內，但可停止用化合物I治療，且患者自身免疫系統能夠遏制進一步病毒複製。在根據本發明治療且已接受用抑制HBV病毒或HCV病毒複製之抗病毒劑治療的患者中，在用抗病毒劑治療期間在患者體內可存在很少或沒有可偵測之病毒粒子。在此等患者中，當抗病毒劑不再投與患者且HBV或HCV之病毒負荷不增加時，血清轉化將為明顯的。
在本發明實踐中，誘發針對HBV或HCV之一或多種抗原的免疫反應。舉例而言，可誘發針對HBV表面抗原(HBsAg)，或針對小形式之HBV表面抗原(小S抗原)，或針對中等形式之HBV表面抗原(中等S抗原)或針對其組合的免疫反應。再次藉助於實例，可誘發針對HBV表面抗原(HBsAg)以及針對其他HBV衍生之抗原(諸如核心聚合酶或x-蛋白)的免疫反應。
可使用熟習此項技術者已知用於判定免疫反應是否已發生之任何技術評估誘發針對HCV或HBV之免疫反應。本發明之偵測免疫反應之合適方法尤其包括諸如藉由使用PCR分析量測個體血液中HBV DNA或HCV DNA之量及/或藉由使用諸如ELISA之方法量測個體血液中抗HBV抗體或抗HCV抗體之量來偵測個體血清中病毒負荷之降低。
另外，本發明之化合物可用於治療癌症或腫瘤(包括發育不良，諸如子宮發育不良)。此等包括血液科惡性疾病、口腔癌(例如唇、舌或咽)、消化器官(例如食道、胃、小腸、結腸、大腸或直腸)、肝及膽道、胰臟、呼吸系統(諸如喉或肺) (小細胞及非小細胞)、骨、結締組織、皮膚(例如黑色素瘤)、乳房、生殖器官(子宮、子宮頸、睾丸、卵巢或前列腺)、泌尿道(例如膀胱或腎)、腦及內分泌腺(諸如甲狀腺)。概言之，本發明化合物用於治療任何贅瘤，不僅包括血液科惡性疾病，且亦包括各種實體腫瘤。
血液科惡性疾病廣泛定義為血細胞及/或其前驅細胞之增生性病症，其中此等細胞以不受控制的方式增生。在解剖學上，血液科惡性疾病分為兩個主要組：淋巴瘤，即淋巴細胞之惡性腫塊，主要但非排他地位於淋巴結中；及白血病，即通常來源於淋巴或骨髓細胞且主要影響骨髓及周邊血液之贅瘤。淋巴瘤可再分成霍奇金氏病(Hodgkin's Disease)及非霍奇金氏淋巴瘤(NHL)。後一組包含幾個不同實體，其可在臨床上(例如高度進展性淋巴瘤、和緩性淋巴瘤)、組織學上(例如濾泡性淋巴瘤、套細胞淋巴瘤)或基於惡性細胞之來源(例如B淋巴細胞、T淋巴細胞)加以區分。白血病及相關惡性疾病包括急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、急性淋巴母細胞性白血病(ALL)及慢性淋巴細胞性白血病(CLL)。其他血液科惡性疾病包括漿細胞病，包括多發性骨髓瘤及骨髓發育不良症候群。VII. 組合療法
在某些實施例中，提供一種用於治療或預防患有感染性疾病、病毒感染、B型肝炎感染、HIV感染、癌症或過度增生性疾病或處於患該疾病之風險下之人類的該疾病之方法，其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑組合。在一實施例中，提供一種用於治療患有感染性疾病、病毒感染、B型肝炎感染、HIV感染、癌症或過度增生性疾病或處於患該疾病之風險下之人類的該疾病之方法，其包含向該人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑組合。
在某些實施例中，本發明提供一種用於治療病毒感染之方法，其包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)適用於治療病毒感染之額外治療劑組合。在一些實施例中，病毒感染為B型肝炎感染。在一些實施例中，病毒感染為HIV感染。
在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與一種、兩種、三種、四種或更多種額外治療劑組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與兩種額外治療劑組合。在其他實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與三種額外治療劑組合。在另外實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與四種額外治療劑組合。一種、兩種、三種、四種或更多種額外治療劑可為選自相同類別之治療劑的不同治療劑，及/或其可選自不同類別之治療劑。組合療法之投藥
在某些實施例中，本文所揭示之化合物與一或多種額外治療劑一起投與。本文所揭示之化合物與一或多種額外治療劑之共同投與通常係指同時或依序投與本文所揭示之化合物及一或多種額外治療劑，使得個體體內存在治療有效量之本文所揭示之化合物及一或多種額外治療劑。當依序投與時，組合可以兩次或更多次投與形式投與。
本文所揭示之化合物與一或多種額外治療劑共投與通常係指同時或依序投與本文所揭示之化合物及一或多種額外治療劑，使得患者體內存在治療有效量之各藥劑。
在某些實施例中，如本文所揭示之化合物可以化合物之任何劑量(例如10 mg至1000 mg化合物)與一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑組合。
共投與包括在投與單位劑量之一或多種額外治療劑之前或之後投與單位劑量之本文所揭示之化合物。本文所揭示之化合物可在投與一或多種額外治療劑之數秒、數分鐘或數小時內投與。舉例而言，在一些實施例中，首先投與單位劑量之本文所揭示之化合物，隨後在數秒或數分鐘內投與單位劑量之一或多種額外治療劑。或者，在其他實施例中，首先投與單位劑量之一或多種額外治療劑，隨後在數秒或數分鐘內投與單位劑量本文所揭示之化合物。在一些實施例中，首先投與單位劑量之本文所揭示之化合物，隨後在數小時(例如1至12小時)之時段之後投與單位劑量之一或多種額外治療劑。在其他實施例中，首先投與單位劑量之一或多種額外治療劑，然後在數小時(例如1至12小時)之時段之後投與單位劑量之本文所揭示之化合物。
在某些實施例中，本文所揭示之化合物與一或多種額外治療劑組合成單一劑型，同時投與個體，例如用於口服投與之固體劑型。
在某些實施例中，如本文所述之化合物調配為錠劑，其可視情況含有一或多種可用於治療所治療之疾病之其他化合物。在某些實施例中，錠劑可含有用於治療病毒性疾病(例如B型肝炎病毒或HIV)之另一活性成分。
在某些實施例中，此類錠劑適用於每天一次給藥。
在一個實施例中，提供包含本文所揭示之化合物或其醫藥學上可接受之鹽與一或多種(例如一種、兩種、三種、一或兩種或一至三種)額外治療劑組合及醫藥學上可接受之載劑、稀釋劑或賦形劑的醫藥組合物。
在一個實施例中，提供套組，其包含本文所揭示之化合物或其醫藥學上可接受之鹽與一或多種(例如一種、兩種、三種、四種、一或兩種或一至三種或一至四種)額外治療劑組合。病毒性組合療法
本文所述之化合物可與一或多種抗病毒劑一起使用或組合，該等抗病毒劑包括阿巴卡韋(abacavir)、阿昔洛韋(aciclovir)、阿德福韋(adefovir)、金剛胺(amantadine)、安普那韋(amprenavir)、阿比朵爾(arbidol)、阿紮那韋(atazanavir)、立普妥(atripla)、溴夫定(brivudine)、西多福韋(cidofovir)、可比韋(combivir)、依度尿苷(edoxudine)、依法韋侖(efavirenz)、恩曲他濱(emtricitabine)、恩夫韋地(enfuvirtide)、恩替卡韋(entecavir)、弗維森(fomvirsen)、夫沙那韋(fosamprenavir)、膦甲酸(foscarnet)、膦乙醇(fosfonet)、更昔洛韋(ganciclovir)、加德西(gardasil)、伊巴他濱(ibacitabine)、英木洛韋(immunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韋(indinavir)、肌苷、整合酶抑制劑、干擾素(包括III型干擾素、II型干擾素、I型干擾素)、拉米夫定(lamivudine)、洛匹那韋(lopinavir)、洛韋胺(loviride)、MK-0518、馬拉韋羅(maraviroc)、嗎啉脒胍(moroxydine)、奈非那韋(nelfinavir)、奈韋拉平(nevirapine)、多吉美(nexavir)、核苷類似物、奧司他韋(oseltamivir)、噴昔洛韋(penciclovir)、帕拉米韋(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、蛋白酶抑制劑、逆轉錄酶抑制劑、利巴韋林(ribavirin)、金剛乙胺(rimantadine)、利托那韋(ritonavir)、沙奎那韋(saquinavir)、司他夫定(stavudine)、替諾福韋(tenofovir)、替諾福韋二吡呋酯(tenofovir disoproxil)、替拉那韋(tipranavir)、曲氟尿苷(trifluridine)、曲利志韋(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada)、纈更昔洛韋(valganciclovir)、維克韋羅(vicriviroc)、阿糖腺苷(vidarabine)、偉拉咪定(viramidine)、紮西他濱(zalcitabine)、紮那米韋(zanamivir)、齊多夫定(zidovudine)及其組合。
在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與5-30 mg反丁烯二酸替諾福韋艾拉酚胺(tenofovir alafenamide fumarate)、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與5-10 mg、5-15 mg、5-20 mg、5-25 mg、25-30 mg、20-30 mg、15-30 mg或10-30 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與10 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與25 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。如本文所揭示之化合物可以任何化合物劑量(例如50 mg至500 mg化合物)與本文所提供之藥劑組合，如同各劑量組合具體且個別地列出一般。
在某些實施例中，本文中所揭示之化合物或其醫藥學上可接受之鹽與100-400 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯組合。在某些實施例中，本文中所揭示之化合物或其醫藥學上可接受之鹽與100-150、100-200、100-250、100-300、100-350、150-200、150-250、150-300、150-350、150-400、200-250、200-300、200-350、200-400、250-350、250-400、350-400或300-400 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯組合。在某些實施例中，本文中所揭示之化合物或其醫藥學上可接受之鹽與300 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯組合。在某些實施例中，本文中所揭示之化合物或其醫藥學上可接受之鹽與250 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯組合。在某些實施例中，本文中所揭示之化合物或其醫藥學上可接受之鹽與150 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯組合。如所揭示之化合物可以任何化合物劑量(例如50 mg至500 mg化合物)與本文所提供之藥劑組合，如同各劑量組合具體且個別地列出一般。HIV 組合療法
在某些實施例中，提供一種用於治療或預防患有HIV感染或具有患HIV感染之風險之人類或動物的感染的方法，其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、一或兩種或一至三種)額外治療劑組合。在一個實施例中，提供一種用於治療患有HIV感染或具有患HIV感染之風險之人類或動物的感染的方法，其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、一或兩種或一至三種)額外治療劑組合。
在某些實施例中，本發明提供一種用於治療HIV感染之方法，其包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種適用於治療HIV感染之額外治療劑組合。
在某些實施例中，本文所揭示之化合物調配成錠劑，其可視情況含有一或多種適用於治療HIV之其他化合物。在某些實施例中，錠劑可含有另一種用於治療HIV之活性成分，諸如HIV蛋白酶抑制劑、HIV非核苷或非核苷酸逆轉錄酶抑制劑、HIV核苷或核苷酸逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、藥物動力學增強劑及其組合。
在某些實施例中，此類錠劑適用於每天一次給藥。
在上述實施例中，額外治療劑可為抗HIV劑。在一些實施例中，額外治療劑係選自由以下組成之群：HIV組合藥物、HIV蛋白酶抑制劑、HIV非核苷或非核苷酸逆轉錄酶抑制劑、HIV核苷或核苷酸逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、HIV進入抑制劑、HIV成熟抑制劑、免疫調節劑、免疫治療劑、抗體-藥物結合物、基因調節劑、基因編輯因子(諸如CRISPR/Cas9、鋅指核酸酶、歸巢核酸酶、合成核酸酶、TALEN)、細胞療法(諸如嵌合抗原受體T細胞，CAR-T及經工程改造之T細胞受體，TCR-T)、潛伏逆轉劑、靶向HIV衣殼之化合物(包括衣殼抑制劑)、基於免疫之療法、磷脂醯肌醇3-激酶(PI3K)抑制劑、α-4/β-7拮抗劑、HIV抗體、雙特異性抗體及「抗體樣」治療性蛋白質、HIV p17基質蛋白抑制劑、IL-13拮抗劑、肽基-脯胺醯基順式-反式異構酶A調節劑、蛋白質二硫鍵異構酶抑制劑、補體C5a受體拮抗劑、DNA甲基轉移酶抑制劑、HIV vif基因調節劑、Vif二聚拮抗劑、HIV-1病毒感染性因子抑制劑、TAT蛋白抑制劑、HIV-1 Nef調節劑、Hck酪胺酸激酶調節劑、混合譜系激酶-3 (MLK-3)抑制劑、HIV-1剪接抑制劑、Rev蛋白抑制劑、整合素拮抗劑、核蛋白抑制劑、剪接因子調節劑、含有COMM結構域之蛋白1調節劑、HIV核糖核酸酶H抑制劑、逆細胞週期素調節劑、CDK-9抑制劑、樹突狀ICAM-3捕獲非整合素1抑制劑、HIV GAG蛋白抑制劑、HIV POL蛋白抑制劑、補體因子H調節劑、泛素連接酶抑制劑、去氧胞苷激酶抑制劑、細胞週期素依賴性激酶抑制劑、前蛋白轉化酶PC9刺激劑、ATP依賴性RNA解螺旋酶DDX3X抑制劑、逆轉錄酶激活複合抑制劑、G6PD及NADH-氧化酶抑制劑、藥物動力學增強劑、HIV基因療法、HIV疫苗及其他HIV治療劑及其組合。
在一些實施例中，額外治療劑係選自由以下組成之群：用於HIV之組合藥物、用於治療HIV之其他藥物、HIV蛋白酶抑制劑、HIV逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、HIV侵入(融合)抑制劑、HIV成熟抑制劑、潛伏逆轉劑、衣殼抑制劑、基於免疫之療法、PI3K抑制劑、HIV抗體、及雙特異性抗體、及「抗體樣」治療性蛋白質、及其組合。HIV 組合藥物
組合藥物之實例包括ATRIPLA®
(依法韋侖、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；COMPLERA®
(EVIPLERA®；利匹韋林(rilpivirine)、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；STRIBILD®
(埃替格韋(elvitegravir)、考比西他(cobicistat)、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；TRUVADA®
(反丁烯二酸替諾福韋二吡呋酯及恩曲他濱；TDF+FTC)；DESCOVY® (替諾福韋艾拉酚胺及恩曲他濱)；ODEFSEY® (替諾福韋艾拉酚胺、恩曲他濱及利匹韋林)；GENVOYA® (替諾福韋艾拉酚胺、恩曲他濱、考比西他及埃替格韋)；BIKTARVY® (比替拉韋(bictegravir)、恩曲他濱、替諾福韋艾拉酚胺)；地瑞那韋(darunavir)、半反丁烯二酸替諾福韋艾拉酚胺、恩曲他濱及考比西他；依法韋侖、拉米夫定及反丁烯二酸替諾福韋二吡呋酯；拉米夫定及反丁烯二酸替諾福韋二吡呋酯；替諾福韋及拉米夫定；替諾福韋艾拉酚胺及恩曲他濱；半反丁烯二酸替諾福韋艾拉酚胺及恩曲他濱；半反丁烯二酸替諾福韋艾拉酚胺、恩曲他濱及利匹韋林；半反丁烯二酸替諾福韋艾拉酚胺、恩曲他濱、考比西他及埃替格韋；COMBIVIR®
(齊多夫定及拉米夫定；AZT+3TC)；EPZICOM®
(LIVEXA®；硫酸阿巴卡韋(abacavir sulfate)及拉米夫定；ABC+3TC)；KALETRA®
(ALUVIA®；洛匹那韋及利托那韋)；TRIUMEQ®
(都魯拉韋、阿巴卡韋及拉米夫定)；TRIZIVIR®
(硫酸阿巴卡韋、齊多夫定及拉米夫定；ABC+AZT+3TC)；阿紮那韋及考比西他；硫酸阿紮那韋及考比西他；硫酸阿紮那韋及利托那韋；地瑞那韋及考比西他；都魯拉韋(dolutegravir)及利匹韋林；都魯拉韋及鹽酸利匹韋林；都魯拉韋、硫酸阿巴卡韋及拉米夫定；拉米夫定、奈韋拉平及齊多夫定；雷特格韋(raltegravir)及拉米夫定；多拉韋林(doravirine)、拉米夫定及反丁烯二酸替諾福韋二吡呋酯；多拉韋林、拉米夫定及替諾福韋二吡呋酯；都魯拉韋+拉米夫定、拉米夫定+阿巴卡韋+齊多夫定、拉米夫定+阿巴卡韋、拉米夫定+反丁烯二酸替諾福韋二吡呋酯、拉米夫定+齊多夫定+奈韋拉平、洛匹那韋+利托那韋；洛匹那韋+利托那韋+阿巴卡韋+拉米夫定、洛匹那韋+利托那韋+齊多夫定+拉米夫定、替諾福韋+拉米夫定；及反丁烯二酸替諾福韋二吡呋酯+恩曲他濱+鹽酸利匹韋林；洛匹那韋、利托那韋、齊多夫定及拉米夫定；Vacc-4x及羅米地辛(romidepsin)；及APH-0812。HIV 蛋白酶抑制劑
HIV蛋白酶抑制劑之實例包括安普那韋、阿紮那韋、貝卡那韋(brecanavir)、達盧那韋、夫沙那韋、夫沙那韋鈣、茚地那韋、硫酸茚地那韋、咯匹那韋、奈非那韋、甲磺酸奈非那韋、利托那韋、沙奎那韋、甲磺酸沙喹那韋、替拉那韋、DG-17、TMB-657 (PPL-100)、T-169、BL-008及TMC-310911。HIV 逆轉錄酶抑制劑
HIV非核苷或非核苷酸逆轉錄酶抑制劑之實例包括達匹韋林(dapivirine)、地拉韋啶(delavirdine)、甲磺酸地拉韋啶、多拉韋林、依法韋侖、依曲韋林(etravirine)、香菇多醣(lentinan)、奈韋拉平、利匹韋林、ACC-007、AIC-292、KM-023、PC-1005及VM-1500。
HIV核苷或核苷酸逆轉錄酶抑制劑之實例包括阿德福韋、阿德福韋酯(adefovir dipivoxil)、阿茲夫定(azvudine)、恩曲他濱、替諾福韋、替諾福韋艾拉酚胺、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替諾福韋二吡呋酯、反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯、VIDEX®
及VIDEX EC®
(地達諾新(didanosine)，ddl)、阿巴卡韋、硫酸阿巴卡韋、阿洛夫定(alovudine)、阿普瑞西他濱(apricitabine)、森沙戊定(censavudine)、地達諾新、艾夫他濱(elvucitabine)、非替那韋(festinavir)、氟沙定替酯(fosalvudine tidoxil)、CMX-157、達匹韋林、多拉韋林、依曲韋林、OCR-5753、乳清酸替諾福韋二吡呋酯、福齊夫定替酯(fozivudine tidoxil)、拉米夫定、福斯非茲(phosphazid)、司他夫定、紮西他濱、齊多夫定、GS-9131、GS-9148、MK-8504及KP-1461。HIV 整合酶抑制劑
HIV整合酶抑制劑之實例包括埃替格韋、薑黃素、薑黃素之衍生物、菊苣酸、菊苣酸之衍生物、3,5-二咖啡醯奎寧酸、3,5-二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、槲皮素、槲皮素之衍生物、雷特格韋、都魯拉韋、JTK-351、比替拉韋、AVX-15567、卡伯拉韋(cabotegravir) (長效可注射)、二酮喹啉-4-1衍生物、整合酶-LEDGF抑制劑、ledgin、M-522、M-532、NSC-310217、NSC-371056、NSC-48240、NSC-642710、NSC-699171、NSC-699172、NSC-699173、NSC-699174、二苯乙烯二磺酸、T-169及卡伯拉韋。
HIV非催化位點或異位整合酶抑制劑(NCINI)之實例包括CX-05045、CX-05168及CX-14442。HIV 進入抑制劑
HIV進入(融合)抑制劑之實例包括森尼韋羅(cenicriviroc)、CCR5抑制劑、gp41抑制劑、CD4附接抑制劑、gp120抑制劑及CXCR4抑制劑。
CCR5抑制劑之實例包括阿普韋羅(aplaviroc)、維克韋羅(vicriviroc)、馬拉韋羅(maraviroc)、森尼韋羅、PRO-140、艾達他韋(adaptavir) (RAP-101)、尼非韋羅(nifeviroc) (TD-0232)、抗GP120/CD4或CCR5雙特異性抗體、B-07、MB-66、多肽C25P、TD-0680及vMIP(海米普(Haimipu))。
gp41抑制劑之實例包括艾博韋地(albuvirtide)、恩夫韋地、BMS-986197、恩夫韋地生物更佳藥、恩夫韋地生物類似藥、HIV-1融合抑制劑(P26-Bapc)、ITV-1、ITV-2、ITV-3、ITV-4、PIE-12三聚體及西夫韋地(sifuvirtide)。
CD4連接抑制劑之實例包括伊利祖單抗(ibalizumab)及CADA類似物。
gp120抑制劑之實例包括Radha-108 (瑞西普托(receptol)) 3B3-PE38、BanLec、基於膨潤土之奈米藥物、福斯薩維緩血酸胺(fostemsavir tromethamine)、IQP-0831及BMS-663068。
CXCR4抑制劑之實例包括普樂沙福(plerixafor)、ALT-1188、N15肽及vMIP (海米普)。HIV 成熟抑制劑
HIV成熟抑制劑之實例包括BMS-955176及GSK-2838232。潛伏逆轉劑
潛伏逆轉劑之實例包括組蛋白去乙醯基酶(HDAC)抑制劑、諸如萬珂(velcade)之蛋白酶體抑制劑、蛋白質激酶C (PKC)活化劑、Smyd2抑制劑、BET-溴結構域4 (BRD4)抑制劑、離子黴素、PMA、SAHA (辛二醯苯胺異羥肟酸，或辛二醯基、苯胺，及氧肟酸)、AM-0015、ALT-803、NIZ-985、NKTR-255、IL-15調節抗體、JQ1、二硫龍、兩性黴素B，及諸如拉格唑拉類似物(largazole analog)之泛素抑制劑，及GSK-343。
HDAC抑制劑之實例包括羅米地辛、伏立諾他(vorinostat)及帕比諾他(panobinostat)。
PKC活化劑之實例包括吲哚拉坦(indolactam)、普羅斯坦(prostratin)、巨大戟醇B及DAG-內酯。衣殼抑制劑
衣殼抑制劑之實例包括衣殼聚合抑制劑或衣殼分裂化合物、諸如偶氮二甲醯胺之HIV核衣殼p7 (NCp7)抑制劑、HIV p24衣殼蛋白質抑制劑、AVI-621、AVI-101、AVI-201、AVI-301及AVI-CAN1-15系列。基於免疫之療法
基於免疫之療法之實例包括類鐸受體調節劑，諸如TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13；計劃性細胞死亡蛋白1 (Pd-1)調節劑；計劃性死亡配位體1 (Pd-L1)調節劑；IL-15促進劑；德瑪韋(DermaVir)；介白素-7；氯奎寧(plaquenil)(羥基氯奎)；普留淨(proleukin)(阿地介白素(aldesleukin)，IL-2)；干擾素α；干擾素α-2b；干擾素α-n3；聚乙二醇化干擾素α；干擾素γ；羥基脲；黴酚酸嗎啉乙酯(MPA)及其酯衍生物黴酚酸嗎啉乙酯(MMF)；利巴韋林；瑞他立德(rintatolimod)、聚合物聚乙二亞胺(PEI)；吉朋(gepon)；瑞他立德；IL-12；WF-10；VGV-1；MOR-22；BMS-936559；CYT-107、介白素-15/Fc融合蛋白、normferon、聚乙二醇化干擾素α-2a、聚乙二醇化干擾素α-2b、重組型介白素-15、RPI-MN、GS-9620、STING調節劑、RIG-I調節劑、NOD2調節劑及IR-103。
TLR8調節劑之實例包括莫托莫特(motolimod)、雷西莫特(resiquimod)、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463以及以下中所揭示之彼等TLR8調節劑：US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、US20140350031 (Janssen)、WO2014/023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (VentirxPharma)、US20140275167 (Novira therapeutics)、US20130251673 (Novira therapeutics)、美國專利第9670205號(Gilead Sciences Inc.)、US20160289229 (Gilead Sciences Inc.)、美國專利申請案第15/692161號(Gilead Sciences Inc.)及美國專利申請案第15/692093號(Gilead Sciences Inc.)。磷脂醯肌醇 3- 激酶 (PI3K) 抑制劑
PI3K抑制劑之實例包括艾德昔布(idelalisib)、阿培昔布(alpelisib)、布帕昔布(buparlisib)、CAI乳清酸鹽、考班昔布(copanlisib)、杜維昔布(duvelisib)、吉達昔布(gedatolisib)、來那替尼(neratinib)、帕努昔布(panulisib)、哌立福新(perifosine)、皮克昔布(pictilisib)、皮拉昔布(pilaralisib)、甲磺酸普喹替尼(puquitinib mesylate)、瑞戈替布(rigosertib)、瑞戈替布鈉、索諾昔布(sonolisib)、泰尼昔布(taselisib)、AMG-319、AZD-8186、BAY-1082439、CLR-1401、CLR-457、CUDC-907、DS-7423、EN-3342、GSK-2126458、GSK-2269577、GSK-2636771、INCB-040093、LY-3023414、MLN-1117、PQR-309、RG-7666、RP-6530、RV-1729、SAR-245409、SAR-260301、SF-1126、TGR-1202、UCB-5857、VS-5584、XL-765及ZSTK-474。α-4/β-7 拮抗劑
整合素α-4/β-7拮抗劑之實例包括PTG-100、TRK-170、阿布里單抗(abrilumab)、艾托珠單抗(etrolizumab)、卡洛斯特甲基(carotegrast methyl)及維多珠單抗(vedolizumab)。HIV 抗體、雙特異性抗體及「抗體樣」治療性蛋白質
HIV抗體、雙特異性抗體及「抗體樣」治療性蛋白質之實例包括DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物、bnAB (廣譜中和HIV-1抗體)、BMS-936559、TMB-360及靶向HIV gp120或gp41之抗體、靶向HIV之抗體募集分子、抗CD63單株抗體、抗GB病毒C抗體、抗GP120/CD4、CCR5雙特異性抗體、抗nef單域抗體、抗Rev抗體、駱駝衍生之抗CD18抗體、駱駝衍生之抗ICAM-1抗體、DCVax-001、靶向gp140之抗體、基於gp41之HIV治療性抗體、人類重組型mAb (PGT-121)、伊利祖單抗、Immuglo及MB-66。
以此方式靶向HIV之抗體之實例包括巴維昔單抗(bavituximab)、UB-421、C2F5、2G12、C4E10、C2F5+C2G12+C4E10、8ANC195、3BNC117、3BNC60、10-1074、PGT145、PGT121、PGT-151、PGT-133、MDX010 (伊派利單抗)、DH511、N6、VRC01 PGDM1400、A32、7B2、10E8、10E8v4、CAP256-VRC26.25、DRVIA7、VRC-07-523、VRC-HIVMAB080-00-AB、VRC-HIVMAB060-00-AB、MGD-014及VRC07。HIV雙特異性抗體之實例包括MGD014。藥物動力學增強劑
藥物動力學增強劑之實例包括考比西他及利托那韋。HIV 疫苗
HIV疫苗之實例包括肽疫苗、重組次單位蛋白疫苗、活載體疫苗、DNA疫苗、CD4衍生之肽疫苗、疫苗組合、rgp120 (AIDSVAX)、ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144)、單體gp120 HIV-1亞型C疫苗、Remune、ITV-1、Contre Vir、Ad5-ENVA-48、DCVax-001 (CDX-2401)、Vacc-4x、Vacc-C5、VAC-3S、多進化枝DNA重組腺病毒-5 (rAd5)、Pennvax-G、Pennvax-GP、HIV-TriMix-mRNA疫苗、HIV-LAMP-vax、Ad35、Ad35-GRIN、NAcGM3/VSSP ISA-51、聚-ICLC為佐劑之疫苗、TatImmune、GTU-multiHIV (FIT-06)、gp140[δ]V2.TV1+MF-59、rVSVIN HIV-1 gag疫苗、SeV-Gag疫苗、AT-20、DNK-4、ad35-Grin/ENV、TBC-M4、HIVAX、HIVAX-2、NYVAC-HIV-PT1、NYVAC-HIV-PT4、DNA-HIV-PT123、rAAV1-PG9DP、GOVX-B11、GOVX-B21、TVI-HIV-1、Ad-4 (Ad4-env進化枝C+Ad4-mGag)、EN41-UGR7C、EN41-FPA2、PreVaxTat、AE-H、MYM-V101、CombiHIVvac、ADVAX、MYM-V201、MVA-CMDR、DNA-Ad5 gag/pol/nef/nev (HVTN505)、MVATG-17401、ETV-01、CDX-1401、rcAD26.MOS1.HIV-Env、Ad26.Mod.HIV疫苗、AGS-004、AVX-101、AVX-201、PEP-6409、SAV-001、ThV-01、TL-01、TUTI-16、VGX-3300、IHV-001及病毒樣顆粒疫苗(諸如假病毒粒子疫苗)、CombiVICHvac、LFn-p24 B/C融合疫苗、基於GTU之DNA疫苗、HIV gag/pol/nef/env DNA疫苗、抗TAT HIV疫苗、結合多肽疫苗、樹突狀細胞疫苗、基於gag之DNA疫苗、GI-2010、gp41 HIV-1疫苗、HIV疫苗(PIKA佐劑)、I i-key/MHC II類抗原決定基雜合肽疫苗、ITV-2、ITV-3、ITV-4、LIPO-5、多進化枝Env疫苗、MVA疫苗、Pennvax-GP、pp71-缺陷HCMV載體HIV gag疫苗、重組肽疫苗(HIV感染)、NCI、rgp160 HIV疫苗、RNActive HIV疫苗、SCB-703、Tat Oyi疫苗、TBC-M4、治療HIV疫苗、UBI HIV gp120、Vacc-4x +羅米地辛、變異gp120多肽疫苗、rAd5 gag-pol env A/B/C疫苗、DNA.HTI及MVA.HTI。其他 HIV 治療劑
額外治療劑之實例包括揭示於以下中之化合物：WO 2004/096286 (Gilead Sciences)、WO 2006/015261 (Gilead Sciences)、WO 2006/110157 (Gilead Sciences)、WO 2012/003497 (Gilead Sciences)、WO 2012/003498 (Gilead Sciences)、WO 2012/145728 (Gilead Sciences)、WO 2013/006738 (Gilead Sciences)、WO 2013/159064 (Gilead Sciences)、WO 2014/100323 (Gilead Sciences)、US 2013/0165489 (University of Pennsylvania)、US 2014/0221378 (Japan Tobacco)、US 2014/0221380 (Japan Tobacco)、WO 2009/062285 (Boehringer Ingelheim)、WO 2010/130034 (Boehringer Ingelheim)、WO 2013/006792 (Pharma Resources)、US 20140221356 (Gilead Sciences)、US 20100143301 (Gilead Sciences)及WO 2013/091096 (Boehringer Ingelheim)。
用於治療HIV之其他藥物之實例包括乙醯嗎喃(acemannan)、阿拉泊韋(alisporivir)、BanLec、去鐵酮(deferiprone)、格瑪木因(Gamimune)、米特法林(metenkefalin)、納曲酮(naltrexone)、普拉斯汀(Prolastin)、REP 9、RPI-MN、VSSP、H1viral、SB-728-T、1,5-二咖啡醯奎寧酸、rHIV7-shl-TAR-CCR5RZ、AAV-eCD4-Ig基因療法、MazF基因療法、BlockAide、ABX-464、AG-1105、APH-0812、BIT-225、CYT-107、HGTV-43、HPH-116、HS-10234、IMO-3100、IND-02、MK-1376、MK-8507、MK-8591、NOV-205、PA-1050040 (PA-040)、PGN-007、SCY-635、SB-9200、SCB-719、TR-452、TEV-90110、TEV-90112、TEV-90111、TEV-90113、RN-18、Immuglo及VIR-576。基因療法及細胞療法
基因療法及細胞療法包括用於使基因沉默之基因修飾；用於直接殺死感染細胞之基因方法；輸注經設計以替換個體之大部分自身免疫系統以增強對感染細胞之免疫反應，或活化個體之自身免疫系統以殺死感染細胞，或尋找且殺死感染細胞之免疫細胞；用於改變細胞活性以進一步改變針對感染之內源性免疫反應性之基因方法。
樹突狀細胞療法之實例包括AGS-004。基因編輯器
基因編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統。
靶向HIV之CRISPR/Cas9系統之實例包括EBT101。CAR-T 細胞療法
CAR-T細胞療法包括經工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞之群體，其中CAR包含HIV抗原結合域。HIV抗原包括HIV包膜蛋白或其部分、gp120或其部分、gp120上之CD4結合位點、gp120上之CD4誘導之結合位點、gp120上之N聚醣、gp120之V2、gp41上之近膜區域。免疫效應細胞為T細胞或NK細胞。在一些實施例中，T細胞為CD4+ T細胞、CD8+ T細胞或其組合。
HIV CAR-T之實例包括VC-CAR-T。TCR-T 細胞療法
TCR-T細胞療法包括經工程改造以靶向經病毒感染之細胞之表面上存在的HIV衍生之肽的T細胞。
熟習此項技術者應瞭解，上文所列之額外治療劑可包括於上文所列之類別中之超過一者中。特定類別不欲限制彼等類別中所列之彼等化合物的功能。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑及HIV非核苷逆轉錄酶抑制劑組合。在另一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑及HIV蛋白酶抑制化合物組合。在另一實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑、HIV非核苷逆轉錄酶抑制劑及藥物動力學增強劑組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與至少一種HIV核苷逆轉錄酶抑制劑、整合酶抑制劑及藥物動力學增強劑組合。在另一實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與兩種HIV核苷或核苷酸逆轉錄酶抑制劑組合。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與一種、兩種、三種、四種或更多種選自以下之額外治療劑組合：ATRIPLA®
(依法韋侖、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；COMPLERA®
(EVIPLERA®
；利匹韋林、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；STRIBILD®
(埃替格韋、考比西他、反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；TRUVADA®
(反丁烯二酸替諾福韋二吡呋酯及恩曲他濱；TDF +FTC)；DESCOVY® (替諾福韋艾拉酚胺及恩曲他濱)；ODEFSEY® (替諾福韋艾拉酚胺、恩曲他濱及利匹韋林)；GENVOYA® (替諾福韋艾拉酚胺、恩曲他濱、考比西他及埃替格韋)；BIKTARVY® (比替拉韋、恩曲他濱、替諾福韋艾拉酚胺)；阿德福韋；阿德福韋酯；考比西他；恩曲他濱；替諾福韋；替諾福韋二吡呋酯；反丁烯二酸替諾福韋二吡呋酯；替諾福韋艾拉酚胺；半反丁烯二酸替諾福韋艾拉酚胺；TRIUMEQ®
(都魯拉韋、阿巴卡韋及拉米夫定)；都魯拉韋、硫酸阿巴卡韋及拉米夫定；雷特格韋；雷特格韋及拉米夫定；馬拉維若；恩夫韋地；ALUVIA®
(KALETRA®
；咯匹那韋及利托那韋)；COMBIVIR®
(齊多夫定及拉米夫定；AZT+3TC)；EPZICOM®
(LIVEXA®
；硫酸阿巴卡韋及拉米夫定；ABC+3TC)；TRIZIVIR®
(硫酸阿巴卡韋、齊多夫定及拉米夫定；ABC+AZT+3TC)；利匹韋林；鹽酸利匹韋林；硫酸阿紮那韋及考比西他；阿紮那韋及考比西他；地瑞那韋及考比西他；阿紮那韋；硫酸阿紮那韋；都魯拉韋；埃替格韋；利托那韋；硫酸阿紮那韋及利托那韋；地瑞那韋；拉米夫定；普拉斯汀；夫沙那韋；夫沙那韋鈣依法韋侖；依曲韋林；奈非那韋；甲磺酸奈非那韋；干擾素；地達諾新；司他夫定；茚地那韋；硫酸茚地那韋；替諾福韋及拉米夫定；齊多夫定；奈韋拉平；沙奎那韋；甲磺酸沙喹那韋；阿地介白素；紮西他濱；替拉那韋；安普那韋；地拉韋定；甲磺酸地拉韋定；Radha-108 (瑞西普托)；拉米夫定及反丁烯二酸替諾福韋二吡呋酯；依法韋侖；拉米夫定及反丁烯二酸替諾福韋二吡呋酯；福斯非茲；拉米夫定；奈韋拉平及齊多夫定；阿巴卡韋；以及硫酸阿巴卡韋。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合：硫酸阿巴卡韋、替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋雙索酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或比替拉韋。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合：替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋二吡呋酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或比替拉韋。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合：選自由硫酸阿巴卡韋、替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋二吡呋酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺及比替拉韋組成之群的第一額外治療劑；及選自由恩曲他濱及拉米夫定組成之群的第二額外治療劑。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合：選自由替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋二吡呋酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺及比替拉韋組成之群的第一額外治療劑；及第二額外治療劑，其中第二額外治療劑為恩曲他濱。
在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與5-30 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg恩曲他濱組合。在某些實施例中，將本文所揭示之化合物或其醫藥學上可接受之鹽與5至10 mg、5至15 mg、5至20 mg、5至25 mg、25至30 mg、20至30 mg、15至30 mg或10至30 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg恩曲他濱組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與10 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg恩曲他濱組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與25 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg恩曲他濱組合。如本文所揭示之化合物可以任何化合物劑量(例如1 mg至500 mg化合物)與本文所提供之藥劑組合，如同各劑量組合具體且個別地列出一般。
在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與200-400 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯及200 mg恩曲他濱組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與200 mg至250 mg、200 mg至300 mg、200 mg至350 mg、250 mg至350 mg、250 mg至400 mg、350 mg至400 mg、300 mg至400 mg或250 mg至400 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯及200 mg恩曲他濱組合。在某些實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與300 mg反丁烯二酸替諾福韋二吡呋酯、半反丁烯二酸替諾福韋二吡呋酯或替諾福韋二吡呋酯及200 mg恩曲他濱組合。如本文所揭示之化合物可以任何化合物劑量(例如1 mg至500 mg化合物)與本文所提供之藥劑組合，如同各劑量組合具體且個別地列出一般。HBV 組合療法
在某些實施例中，提供一種用於治療或預防具有HBV感染或處於HBV感染風險下之人類的感染的方法，該方法包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑的組合。在一個實施例中，提供一種用於治療具有HBV感染或處於HBV感染風險下之人類之感染的方法，其包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑的組合。
在某些實施例中，本發明提供一種用於治療HBV感染之方法，該方法包含向有需要之患者投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、四種、一或兩種、一至三種或一至四種)適用於治療HBV感染之額外治療劑的組合。
本文所述之化合物可與以下中之一或多者一起使用或組合：化學治療劑、免疫調節劑、免疫治療劑、治療性抗體、治療性疫苗、雙特異性抗體及「抗體樣」治療性蛋白質(諸如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗體-藥物結合物(ADC)、基因調節劑或基因編輯劑(諸如CRISPR Cas9、鋅指核酸酶、歸巢核酸內切酶、合成核酸酶、TALEN)、細胞療法(諸如CAR-T (嵌合抗原受體T細胞)及TCR-T (經工程改造之T細胞受體)藥劑)或其任何組合。
在某些實施例中，本文所述之化合物調配為錠劑，其可視情況含有一或多種可用於治療HBV之其他化合物。在某些實施例中，錠劑可含有另一種用於治療HBV之活性成分，諸如3-雙加氧酶(IDO)抑制劑、脂蛋白元A1調節劑、精胺酸酶抑制劑、B及T淋巴細胞衰減因子抑制劑、布魯東氏酪胺酸激酶(Bruton's tyrosine kinase，BTK)抑制劑、CCR2趨化因子拮抗劑、CD137抑制劑、CD160抑制劑、CD305抑制劑、CD4促效劑及調節劑、靶向HBcAg之化合物、靶向B型肝炎核心抗原(HBcAg)之化合物、核心蛋白變構調節劑、共價閉合環狀DNA (cccDNA)抑制劑、親環素抑制劑、細胞毒性T淋巴細胞相關蛋白4 (ipi4)抑制劑、DNA聚合酶抑制劑、核酸內切酶調節劑、表觀遺傳調節劑、法尼酯X受體促效劑、HBsAg抑制劑、HBsAg分泌或組裝抑制劑、HBV DNA聚合酶抑制劑、HBV複製抑制劑、HBV RNA酶抑制劑、HBV病毒進入抑制劑、HBx抑制劑、B型肝炎大包膜蛋白調節劑、B型肝炎大包膜蛋白刺激劑、B型肝炎結構蛋白調節劑、B型肝炎表面抗原(HBsAg)抑制劑、B型肝炎表面抗原(HBsAg)分泌或組裝抑制劑、B型肝炎病毒E抗原抑制劑、B型肝炎病毒複製抑制劑、肝炎病毒結構蛋白抑制劑、HIV-1逆轉錄酶抑制劑、玻尿酸酶抑制劑、IAPs抑制劑、IL-2促效劑、IL-7促效劑、免疫調節劑、吲哚胺-2抑制劑、核糖核苷酸還原酶抑制劑、介白素-2配位體、ipi4抑制劑、離胺酸去甲基酶抑制劑、組蛋白去甲基酶抑制劑、KDM1抑制劑、KDM5抑制劑、殺手細胞凝集素樣受體亞家族G成員1抑制劑、淋巴細胞活化基因3抑制劑、淋巴毒素β受體活化劑、Axl調節劑、B7-H3調節劑、B7-H4調節劑、CD160調節劑、CD161調節劑、CD27調節劑、CD47調節劑、CD70調節劑、GITR調節劑、HEVEM調節劑、ICOS調節劑、Mer調節劑、NKG2A調節劑、NKG2D調節劑、OX40調節劑、SIRPα調節劑、TIGIT調節劑、Tim-4調節劑、Tyro調節劑、牛磺膽酸Na+共輸送多肽(NTCP)抑制劑、自然殺手細胞受體2B4抑制劑、NOD2基因刺激劑、核蛋白抑制劑、核蛋白調節劑、PD-1抑制劑、PD-L1抑制劑、肽基脯胺醯異構酶抑制劑、磷脂醯肌醇-3激酶(PI3K)抑制劑、視黃酸誘導性基因1刺激劑、逆轉錄酶抑制劑、核糖核酸酶抑制劑、RNA DNA聚合酶抑制劑、SLC10A1基因抑制劑、SMAC模擬物、Src酪胺酸激酶抑制劑、干擾素基因刺激蛋白(STING)促效劑、NOD1刺激劑、T細胞表面醣蛋白CD28抑制劑、T細胞表面醣蛋白CD8調節劑、胸腺素促效劑、胸腺素α 1配位體、Tim-3抑制劑、TLR-3促效劑、TLR-7促效劑、TLR-9促效劑、TLR9基因刺激劑、類鐸受體(TLR)調節劑、病毒核糖核苷酸還原酶抑制劑及其組合。HBV 組合藥物
用於治療HBV之組合藥物的實例包括TRUVADA®
(反丁烯二酸替諾福韋二吡呋酯及恩曲他濱)；ABX-203、拉米夫定及PEG-IFN-α；ABX-203阿德福韋及PEG-IFNα；以及INO-1800 (INO-9112及RG7944)。其他 HBV 藥物
用於治療HBV之其他藥物的實例包括α-羥基環庚三烯酚酮(alpha-hydroxytropolones)、胺多索韋(amdoxovir)、β-羥基胞嘧啶核苷、AL-034、CCC-0975、艾夫他濱、依澤替米貝(ezetimibe)、環孢素A、龍膽苦苷(gentiopicrin/gentiopicroside)、JNJ-56136379、硝唑尼特(nitazoxanide)、比林納潘特(birinapant)、NJK14047、NOV-205 (莫里克桑(molixan)，BAM-205)、寡苷酸、米沃替酯(mivotilate)、菲隆(feron)、GST-HG-131、左旋咪唑(levamisole)、卡舒寧(Ka Shu Ning)、阿洛菲隆(alloferon)、WS-007、Y-101 (替芬泰(Ti Fen Tai))、rSIFN-co、PEG-IIFNm、KW-3、BP-Inter-014、齊墩果酸(oleanolic acid)、HepB-nRNA、cTP-5 (rTP-5)、HSK-II-2、HEISCO-106-1、HEISCO-106、赫普巴納(Hepbarna)、IBPB-006IA、和普印芬(Hepuyinfen)、DasKloster 0014-01、ISA-204、將安泰(Jiangantai)(肝西康(Ganxikang))、MIV-210、OB-AI-004、PF-06、胡黃連苷(picroside)、DasKloster-0039、荷普蘭太(hepulantai)、IMB-2613、TCM-800B、還原麩胱甘肽、RO-6864018、RG-7834、UB-551及ZH-2N，及US20150210682、(Roche)、US 2016/0122344 (Roche)、WO2015173164、WO2016023877、US2015252057A (Roche)、WO16128335A1 (Roche)、WO16120186A1 (Roche)、US2016237090A (Roche)、WO16107833A1 (Roche)、WO16107832A1 (Roche)、US2016176899A (Roche)、WO16102438A1 (Roche)、WO16012470A1 (Roche)、US2016220586A (Roche)及US2015031687A (Roche)中所揭示之化合物。HBV 疫苗
HBV疫苗包括預防性及治療性疫苗。HBV預防性疫苗之實例包括Vaxelis、Hexaxim、Heplisav、Mosquirix、DTwP-HBV疫苗、Bio-Hep-B、D/T/P/HBV/M (LBVP-0101；LBVW-0101)、DTwP-Hepb-Hib-IPV疫苗、Heberpenta L、DTwP-HepB-Hib、V-419、CVI-HBV-001、Tetrabhay、B型肝炎預防性疫苗(Advax Super D)、Hepatrol-07、GSK-223192A、ENGERIX B®
、重組型B型肝炎疫苗(肌肉內，Kangtai Biological Products)、重組型B型肝炎疫苗(漢遜多形酵母(Hansenual polymorpha yeast)，肌肉內，Hualan Biological Engineering)、重組型B型肝炎表面抗原疫苗、Bimmugen、Euforavac、Eutravac、anrix-DTaP-IPV-Hep B、HBAI-20、Infanrix-DTaP-IPV-Hep B-Hib、Pentabio Vaksin DTP-HB-Hib、Comvac 4、Twinrix、Euvax-B、Tritanrix HB、Infanrix Hep B、Comvax、DTP-Hib-HBV疫苗、DTP-HBV疫苗、Yi Tai、Heberbiovac HB、Trivac HB、GerVax、DTwP-Hep B-Hib疫苗、Bilive、Hepavax-Gene、SUPERVAX、Comvac5、Shanvac-B、Hebsulin、Recombivax HB、Revac B mcf、Revac B+、Fendrix、DTwP-HepB-Hib、DNA-001、Shan5、Shan6、rhHBsAG疫苗、HBI五價疫苗、LBVD、Infanrix HeXa及DTaP-rHB-Hib疫苗。
HBV治療性疫苗之實例包括HBsAG-HBIG複合物、ARB-1598、Bio-Hep-B、NASVAC、abi-HB (靜脈內)、ABX-203、Tetrabhay、GX-110E、GS-4774、肽疫苗(εPA-44)、Hepatrol-07、NASVAC (NASTERAP)、IMP-321、BEVAC、Revac B mcf、Revac B+、MGN-1333、KW-2、CVI-HBV-002、AltraHepB、VGX-6200、FP-02、FP-02.2、TG-1050、NU-500、HBVax、im/TriGrid/抗原疫苗、Mega-CD40L為佐劑之疫苗、HepB-v、RG7944 (INO-1800)、重組型基於VLP之治療性疫苗(HBV感染，VLP Biotech)、AdTG-17909、AdTG-17910、AdTG-18202、ChronVac-B、TG-1050及Lm HBV。HBV DNA 聚合酶抑制劑
HBV DNA聚合酶抑制劑之實例包括阿德福韋(HEPSERA®
)、恩曲他濱(EMTRIVA®
)、反丁烯二酸替諾福韋二吡呋酯(VIREAD®
)、替諾福韋艾拉酚胺、替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替諾福韋酯(tenofovir dipivoxil)、反丁烯二酸替諾福韋酯、替諾福韋十八烷氧基乙酯、CMX-157、拜斯福韋(besifovir)、恩替卡韋(BARACLUDE®
)、順丁烯二酸恩替卡韋、替比夫定(telbivudine) (TYZEKA®
)、非洛西韋(filocilovir)、帕拉德福韋(pradefovir)、克來夫定(clevudine)、利巴韋林、拉米夫定(EPIVIR-HBV®
)、疊氮膦(phosphazide)、泛昔洛韋(famciclovir)、弗索林(fusolin)、美他卡韋(metacavir)、SNC-019754、FMCA、AGX-1009、AR-II-04-26、HIP-1302、天冬胺酸替諾福韋二吡呋酯、乳清酸替諾福韋二吡呋酯及HS-10234。免疫調節劑
免疫調節劑之實例包括瑞他立德、鹽酸艾咪朵爾(imidol hydrochloride)、因加容(ingaron)、德瑪韋、氯奎寧(羥氯喹)、普留淨、羥脲、黴酚酸嗎啉乙酯(MPA)及其酯衍生物黴酚酸嗎啉乙酯(MMF)、JNJ-440、WF-10、AB-452、利巴韋林、IL-12、INO-9112、聚合物聚伸乙亞胺(PEI)、Gepon、VGV-1、MOR-22、CRV-431、JNJ-0535、TG-1050、ABI-H2158、BMS-936559、RO-7011785、RG-7854、AB-506、RO-6871765、AIC-649及IR-103。類鐸 受體 (TLR) 調節劑
TLR調節劑包括TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13之調節劑。TLR3調節劑之實例包括瑞他立德、聚ICLC、RIBOXXON®、阿伯辛(Apoxxim)、RIBOXXIM®、IPH-33、MCT-465、MCT-475及ND-1.1。
TLR7調節劑之實例包括GS-9620、GSK-2245035、咪喹莫特、雷西莫特、DSR-6434、DSP-3025、IMO-4200、MCT-465、MEDI-9197、3M-051、SB-9922、3M-052、Limtop、D、特拉莫德(telratolimod)、SP-0509、TMX-30X、TMX-202、RG-7863、RG-7795、LHC-165、RG-7854及US20100143301 (Gilead Sciences)、US20110098248 (Gilead Sciences)及US20090047249 (Gilead Sciences)中揭示之化合物。
TLR8調節劑之實例包括莫托莫特、雷西莫特、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463以及以下中所揭示之化合物：US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、US20140350031 (Janssen)、WO2014/023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (Ventirx Pharma)、US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics)、美國專利第9670205號、US20160289229、美國專利申請案第15/692161號及美國專利申請案第15/692093號。
TLR9調節劑之實例包括BB-001、BB-006、CYT-003、IMO-2055、IMO-2125、IMO-3100、IMO-8400、IR-103、IMO-9200、阿托莫特(agatolimod)、DIMS-9054、DV-1079、DV-1179、AZD-1419、利福莫特(leftolimod) (MGN-1703)、利騰莫特(litenimod)及CYT-003-QbG10。
TLR7、TLR8及TLR9調節劑之實例包括以下中所揭示之化合物：WO2017047769 (Teika Seiyaku)、WO2015014815 (Janssen)、WO2018045150(Gilead Sciences Inc)、WO2018045144 (Gilead Sciences Inc)、WO2015162075(Roche)、WO2017034986 (University of Kansas)、WO2018095426 (Jiangsu Hengrui Medicine Co Ltd)、WO2016091698(Roche)、WO2016075661 (GlaxoSmithKline Biologicals)、WO2016180743 (Roche)、WO2018089695 (Dynavax Technologies)、WO2016055553 (Roche)、WO2015168279 (Novartis)、WO2016107536 (Medshine Discovery)、WO2018086593 (Livo (Shanghai) Pharmaceutical)、WO2017106607(Merck)、WO2017061532 (Sumitomo Dainippon Pharma)、WO2016023511 (Chia Tai Tianqing Pharmaceutical)、WO2017076346 (Chia Tai Tianqing Pharmaceutical)、WO2017046112(Roche)、WO2018078149(Roche)、WO2017040233 (3M Co)、WO2016141092 (Gilead Sciences)、WO2018049089 (Bristol Myers Squibb)、WO2015057655 (Eisai Co Ltd)、WO2017001307 (Roche)、WO2018005586 (Bristol Myers Squibb)、WO201704023(3M Co)、WO2017163264 (Council of Scientific and Industrial Research (India))、WO2018046460 (GlaxoSmithKline Biologicals)、WO2018047081 (Novartis)、WO2016142250 (Roche)、WO2015168269 (Novartis)、WO201804163 (Roche)、WO2018038877 (3M Co)、WO2015057659 (Eisai Co Ltd)、WO2017202704 (Roche)、WO2018026620 (Bristol Myers Squibb)、WO2016029077 (Janus Biotherapeutics)、WO201803143 (Merck)、WO2016096778 (Roche)、WO2017190669 (Shanghai De Novo Pharmatech)、US09884866 (University of Minnesota)、WO2017219931 (Sichuan KelunBiotech Biopharmaceutical)、WO2018002319 (Janssen Sciences)、WO2017216054(Roche)、WO2017202703 (Roche)、WO2017184735 (IFM Therapeutics)、WO2017184746 (IFM Therapeutics)、WO2015088045 (Takeda Pharmaceutical)、WO2017038909 (Takeda Pharmaceutical)、WO2015095780 (University of Kansas)、WO2015023958 (University of Kansas)。干擾素 α 受體配位體
干擾素α受體配位體之實例包括干擾素α-2b (INTRON A®
)、聚乙二醇化干擾素α-2a (PEGASYS®
)、聚乙二醇化干擾素α-1b、干擾素α 1b (HAPGEN®
)、Veldona、Infradure、Roferon-A、YPEG-干擾素α-2a (YPEG-rhIFNα-2a)、P-1101、Algeron、Alfarona、Ingaron (干擾素γ)、rSIFN-co (重組超化合物干擾素)、Ypeg干擾素α-2b (YPEG-rhIFNα-2b)、MOR-22、peg干擾素α-2b (PEG-INTRON®
)、Bioferon、Novaferon、Inmutag (Inferon)、MULTIFERON®、干擾素α-n1(HUMOFERON®
)、干擾素β-1a (AVONEX®
)、Shaferon、干擾素α-2b (Axxo)、Alfaferone、干擾素α-2b (BioGeneric Pharma)、干擾素-α 2 (CJ)、Laferonum、VIPEG、BLAUFERON-A、BLAUFERON-B、Intermax Alpha、Realdiron、Lanstion、Pegaferon、PDferon-B、干擾素α-2b (IFN，Laboratorios Bioprofarma)、α干擾素2b、Kalferon、Pegnano、Feronsure、PegiHep、干擾素α 2b (Zydus-Cadila)、干擾素α 2a、Optipeg A、Realfa 2B、Reliferon、干擾素α-2b (Amega)、干擾素α-2b (Virchow)、ropeg干擾素α-2b、rHSA-IFN α-2a (重組人血清白蛋白干擾素α 2a融合蛋白)、rHSA-IFN α 2b、重組人干擾素α-(1b、2a、2b)、peg干擾素α-2b (Amega)、peg干擾素α-2a、Reaferon-EC、Proquiferon、Uniferon、Urifron、干擾素α-2b (Changchun Institute of Biological Products)、Anterferon、Shanferon、Layfferon、Shang Sheng Lei Tai、INTEFEN、SINOGEN、Fukangtai、Pegstat、rHSA-IFN α-2b、SFR-9216及Interapo (Interapa)。玻尿酸酶抑制劑
玻尿酸酶抑制劑之實例包括阿斯君默(astodrimer)。B 型肝炎表面抗原 (HBsAg) 抑制劑
HBsAg抑制劑之實例包括HBF-0259、PBHBV-001、PBHBV-2-15、PBHBV-2-1、REP-9AC、REP-9C、REP-9、REP-2139、REP-2139-Ca、REP-2165、REP-2055、REP-2163、REP-2165、REP-2053、REP-2031及REP-006及REP-9AC'。
HBsAg分泌抑制劑之實例包括BM601。細胞毒性 T 淋巴細胞相關蛋白 4 (ipi4) 抑制劑
細胞毒性T淋巴細胞相關蛋白4 (ipi4)抑制劑之實例包括AGEN-2041、AGEN-1884、伊匹魯密單抗(ipilumimab)、貝拉西普(belatacept)、PSI-001、PRS-010、Probody mAb、曲美單抗(tremelimumab)及JHL-1155。親環素抑制劑
親環素抑制劑之實例包括CPI-431-32、EDP-494、OCB-030、SCY-635、NVP-015、NVP-018、NVP-019、STG-175及以下中所揭示之化合物：US8513184 (Gilead Sciences)、US20140030221 (Gilead Sciences)、US20130344030 (Gilead Sciences)及US20130344029 (Gilead Sciences)。HBV 病毒進入抑制劑
HBV病毒進入抑制劑之實例包括米魯德西B (Myrcludex B)。靶向病毒 mRNA 之反義寡核苷酸
靶向病毒mRNA之反義寡核苷酸之實例包括ISIS-HBVRx、IONIS-HBVRx、IONIS-GSK6-LRx、GSK-3389404、RG-6004。短干擾 RNA (siRNA) 及 ddRNAi
siRNA之實例包括TKM-HBV (TKM-HepB)、ALN-HBV、SR-008、HepB-nRNA和ARC-520、ARC-521、ARB-1740、ARB-1467。
DNA定向RNA干擾(ddRNAi)之實例包括BB-HB-331。核酸內切酶調節劑
核酸內切酶調節劑之實例包括PGN-514。核糖核苷酸還原酶抑制劑
核糖核苷酸還原酶抑制劑之實例包括曲美多斯(Trimidox)。HBV E 抗原抑制劑
HBV E抗原抑制劑之實例包括漢黃芩素(wogonin)。共價閉合 環狀 DNA (cccDNA) 抑制劑
cccDNA抑制劑之實例包括BSBI-25及CHR-101。法尼酯 X 受體促效劑
法尼酯X受體促效劑之實例諸如EYP-001、GS-9674、EDP-305、MET-409、曲匹氟索(Tropifexor)、AKN-083、RDX-023、BWD-100、LMB-763、INV-3、NTX-023-1、EP-024297及GS-8670。HBV 抗體
靶向B型肝炎病毒表面抗原之HBV抗體的實例包括GC-1102、XTL-17、XTL-19、KN-003、IV Hepabulin SN及全人類單株抗體療法(B型肝炎病毒感染，Humabs BioMed)。
包括單株抗體及多株抗體之HBV抗體的實例包括Zutectra、上生甘迪(Shang Sheng Gan Di)、Uman Big (B型肝炎高免疫)、Omri-Hep-B、Nabi-HB、Hepatect CP、HepaGam B、igantibe、Niuliva、CT-P24、B型肝炎免疫球蛋白(靜脈內，pH4，HBV感染，Shanghai RAAS Blood Products)及Fovepta (BT-088)。
全人類單株抗體包括HBC-34。CCR2 趨化因子拮抗劑
CCR2趨化因子拮抗劑之實例包括丙帕鍺(propagermanium)。胸腺素促效劑
胸腺素促效劑之實例包括胸腺法新(Thymalfasin)，亦即重組胸腺素α 1 (GeneScience)。細胞介素
細胞介素之實例包括重組IL-7、CYT-107、介白素-2 (IL-2，Immunex)、重組人類介白素-2 (Shenzhen Neptunus)、IL-15、IL-21、IL-24及西莫介白素(celmoleukin)。核蛋白調節劑
核蛋白調節劑可為HBV核心或衣殼蛋白抑制劑。核蛋白調節劑之實例包括GS-4882、AB-423、AT-130、GLS4、NVR-1221、NVR-3778、AL-3778、BAY 41-4109、甲磺酸莫非賽定(morphothiadine mesilate)、ARB-168786、ARB-880、JNJ-379、RG-7907、HEC-72702、AB-506、ABI-H0731、JNJ-440、ABI-H2158及DVR-23。
衣殼抑制劑之實例包括以下中所揭示之化合物：US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics)、US20140343032 (Roche)、WO2014037480 (Roche)、US20130267517 (Roche)、WO2014131847 (Janssen)、WO2014033176 (Janssen)、WO2014033170 (Janssen)、WO2014033167 (Janssen)、WO2015/059212 (Janssen)、WO2015118057(Janssen)、WO2015011281 (Janssen)、WO2014184365 (Janssen)、WO2014184350 (Janssen)、WO2014161888 (Janssen)、WO2013096744 (Novira)、US20150225355 (Novira)、US20140178337 (Novira)、US20150315159 (Novira)、US20150197533 (Novira)、US20150274652 (Novira)、US20150259324、(Novira)、US20150132258 (Novira)、US9181288 (Novira)、WO2014184350 (Janssen)、WO2013144129 (Roche)、WO2017198744(Roche)、US 20170334882(Novira)、US 20170334898 (Roche)、WO2017202798(Roche)、WO2017214395(Enanta)、WO2018001944 (Roche)、WO2018001952(Roche)、WO2018005881(Novira)、WO2018005883(Novira)、WO2018011100(Roche)、WO2018011160(Roche)、WO2018011162(Roche)、WO2018011163(Roche)、WO2018036941(Roche)、WO2018043747(Kyoto Univ)、US20180065929 (Janssen)、WO2016168619 (Indiana University)、WO2016195982 (The Penn State Foundation)、WO2017001655 (Janssen)、WO2017048950 (Assembly Biosciences)、WO2017048954 (Assembly Biosciences)、WO2017048962 (Assembly Biosciences)、US20170121328 (Novira)、US20170121329 (Novira)。
轉錄物抑制劑之實例包括以下中所揭示之化合物：WO2017013046 (Roche)、WO2017016960 (Roche)、WO2017017042 (Roche)、WO2017017043 (Roche)、WO2017061466 (Toyoma chemicals)、WO2016177655 (Roche)、WO2016161268 (Enanta). WO2017001853 (Redex Pharma)、WO2017211791 (Roche)、WO2017216685 (Novartis)、WO2017216686 (Novartis)、WO2018019297 (Ginkgo Pharma)、WO2018022282 (Newave Pharma)、US20180030053 (Novartis)、WO2018045911 (Zhejiang Pharma)。視黃酸誘發型基因 1 刺激劑
視黃酸誘發型基因1刺激劑之實例包括SB-9200、SB-40、SB-44、ORI-7246、ORI-9350、ORI-7537、ORI-9020、ORI-9198及ORI-7170、RGT-100。NOD2 刺激劑
NOD2刺激劑之實例包括SB-9200。磷脂醯肌醇 3- 激酶 (PI3K) 抑制劑
PI3K抑制劑之實例包括艾德昔布、ACP-319、AZD-8186、AZD-8835、布帕昔布、CDZ-173、CLR-457、皮克昔布、來那替尼、瑞戈替布、瑞戈替布鈉、EN-3342、TGR-1202、阿培昔布、杜維昔布、IPI-549、UCB-5857、泰尼昔布、XL-765、吉達昔布、ME-401、VS-5584、考班昔布、乳清酸CAI、哌立福新、RG-7666、GSK-2636771、DS-7423、帕努昔布、GSK-2269557、GSK-2126458、CUDC-907、PQR-309、INCB-40093、皮拉昔布、BAY-1082439、甲磺酸普喹替尼、SAR-245409、AMG-319、RP-6530、ZSTK-474、MLN-1117、SF-1126、RV-1729、索諾昔布、LY-3023414、SAR-260301、TAK-117、HMPL-689、特納昔布(tenalisib)、沃塔昔布(voxtalisib)及CLR-1401。吲哚胺 -2,3- 雙加氧酶 (IDO) 路徑抑制劑
IDO抑制劑之實例包括艾帕斯塔(epacadostat)(INCB24360)、雷米諾他(resminostat)(4SC-201)、因多莫得(indoximod)、F-001287、SN-35837、NLG-919、GDC-0919、GBV-1028、GBV-1012、NKTR-218，以及US20100015178 (Incyte)、US2016137652 (Flexus Biosciences, Inc.)中所揭示之化合物。PD-1 抑制劑
PD-1抑制劑之實例包括賽咪單抗(cemiplimab)、納武單抗、派姆單抗(pembrolizumab)、皮立珠單抗、BGB-108、STI-A1014、SHR-1210、PDR-001、PF-06801591、IBI-308、GB-226、STI-1110、JNJ-63723283、CA-170、德瓦魯單抗(durvalumab)、阿特珠單抗(atezolizumab)及mDX-400、JS-001、坎立珠單抗(Camrelizumab)、斯迪利單抗(Sintilimab)、斯迪利單抗、緹勒珠單抗(tislelizumab)、BCD-100、BGB-A333、JNJ-63723283、GLS-010 (WBP-3055)、CX-072、AGEN-2034、GNS-1480 (表皮生長因子受體拮抗劑；計劃性細胞死亡配位體1抑制劑)、CS-1001、M-7824 (PD-L1/TGF-β雙功能融合蛋白)、傑諾珠單抗(Genolimzumab)、BMS-936559。PD-L1 抑制劑
PD-L1抑制劑之實例包括阿特珠單抗、阿維魯單抗(avelumab)、AMP-224、MEDI-0680、RG-7446、GX-P2、德瓦魯單抗、KY-1003、KD-033、MSB-0010718C、TSR-042、ALN-PDL、STI-A1014、GS-4224、CX-072及BMS-936559。
PD-1抑制劑之實例包括以下中所揭示之化合物：WO2017112730 (Incyte Corp)、WO2017087777(Incyte Corp)、WO2017017624、WO2014151634 (Bristol Myers Squibb Co)、WO201317322 (Bristol Myers Squibb Co)、WO2018119286 (Incyte Corp)、WO2018119266 (Incyte Corp)、WO2018119263(Incyte Corp)、WO2018119236 (Incyte Corp)、WO2018119221(Incyte Corp)、WO2018118848 (Bristol Myers Squibb Co)、WO20161266460(Bristol Myers Squibb Co)、WO2017087678 (Bristol Myers Squibb Co)、WO2016149351 (Bristol Myers Squibb Co)、WO2015033299 (Aurigene Discovery Technologies Ltd)、WO2015179615(Eisai Co Ltd；Eisai Research Institute)、WO2017066227(Bristol Myers Squibb Co)、WO2016142886 (Aurigene Discovery Technologies Ltd)、WO2016142852(Aurigene Discovery Technologies Ltd)、WO2016142835 (Aurigene Discovery Technologies Ltd；個體)、WO2016142833 (Aurigene Discovery Technologies Ltd)、WO2018085750 (Bristol Myers Squibb Co)、WO2015033303 (Aurigene Discovery Technologies Ltd)、WO2017205464 (Incyte Corp)、WO2016019232 (3M Co；個體；Texas A&M University System)、WO2015160641 (Bristol Myers Squibb Co)、WO2017079669 (Incyte Corp)、WO2015033301 (Aurigene Discovery Technologies Ltd)、WO2015034820 (Bristol Myers Squibb Co)、WO2018073754 (Aurigene Discovery Technologies Ltd)、WO2016077518 (Bristol Myers Squibb Co)、WO2016057624 (Bristol Myers Squibb Co)、WO2018044783 (Incyte Corp)、WO2016100608 (Bristol Myers Squibb Co)、WO2016100285 (Bristol Myers Squibb Co)、WO2016039749 (Bristol Myers Squibb Co)、WO2015019284 (Cambridge Enterprise Ltd)、WO2016142894 (Aurigene Discovery Technologies Ltd)、WO2015134605 (Bristol Myers Squibb Co)、WO2018051255 (Aurigene Discovery Technologies Ltd)、WO2018051254 (Aurigene Discovery Technologies Ltd)、WO2017222976 (Incyte Corp)、WO2017070089 (Incyte Corp)、WO2018044963 (Bristol Myers Squibb Co)、WO2013144704 (Aurigene Discovery Technologies Ltd)、WO2018013789 (Incyte Corp)、WO2017176608 (Bristol Myers Squibb Co)、WO2018009505 (Bristol Myers Squibb Co)、WO2011161699 (Aurigene Discovery Technologies Ltd)、WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp)、WO2017192961 (Incyte Corp)、WO2017106634 (Incyte Corp)、WO2013132317 (Aurigene Discovery Technologies Ltd)、WO2012168944 (Aurigene Discovery Technologies Ltd)、WO2015036927 (Aurigene Discovery Technologies Ltd)、WO2015044900 (Aurigene Discovery Technologies Ltd)、WO2018026971 (Arising International)。重組胸腺素 α-1
重組胸腺素α-1之實例包括NL-004及聚乙二醇化胸腺素α-1。布魯 東 氏酪胺酸激酶 (BTK) 抑制劑
BTK抑制劑之實例包括ABBV-105、阿卡替尼(acalabrutinib) (ACP-196)、ARQ-531、BMS-986142、達沙替尼、依魯替尼、GDC-0853、PRN-1008、SNS-062、ONO-4059、BGB-3111、ML-319、MSC-2364447、RDX-022、X-022、AC-058、RG-7845、司培替尼(spebrutinib)、TAS-5315、TP-0158、TP-4207、HM-71224、KBP-7536、M-2951、TAK-020、AC-0025及在US20140330015 (Ono Pharmaceutical)、US20130079327 (Ono Pharmaceutical)及US20130217880 (Ono Pharmaceutical)中所揭示之化合物。KDM 抑制劑
KDM5抑制劑之實例包括以下中揭示之化合物：WO2016057924 (Genentech/Constellation Pharmaceuticals)、US20140275092 (Genentech/Constellation Pharmaceuticals)、US20140371195 (Epitherapeutics)及US20140371214 (Epitherapeutics)、US20160102096 (Epitherapeutics)、US20140194469 (Quanticel)、US20140171432、US20140213591 (Quanticel)、US20160039808 (Quanticel)、US20140275084 (Quanticel)、WO2014164708 (Quanticel)。
KDM1抑制劑之實例包括US9186337B2 (Oryzon Genomics)中所揭示之化合物、GSK-2879552及RG-6016。STING 促效劑
STING促效劑之實例包括SB-11285、AdVCA0848、STINGVAX及以下中所揭示之化合物：WO 2018065360 (''Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany)、WO 2018009466 (Aduro Biotech)、WO 2017186711 (InvivoGen)、WO 2017161349 (Immune Sensor)、WO 2017106740 (Aduro Biotech)、US 20170158724 (Glaxo Smithkline)、WO 2017075477 (Aduro Biotech)、US 20170044206 (Merck)、WO 2014179760 (University of California)、WO2018098203 (Janssen)、WO2018118665 (Merck)、WO2018118664 (Merck)、WO2018100558 (Takeda)、WO2018067423 (Merck)、WO2018060323 (Boehringer)。非核苷逆轉錄酶抑制劑 (NNRTI)
NNRTI之實例包括以下中所揭示之化合物：WO2018118826 (Merck)、WO2018080903(Merck)、WO2018119013 (Merck)、WO2017100108 (Idenix)、WO2017027434 (Merck)、WO2017007701 (Merck)、WO2008005555 (Gilead)。HBV 複製抑制劑
B型肝炎病毒複製抑制劑之實例包括異噻氟定(isothiafludine)、IQP-HBV、RM-5038及新甘帖(Xingantie)。精胺酸酶抑制劑
精胺酸酶抑制劑之實例包括CB-1158、C-201及雷米諾他。基因療法及細胞療法
基因療法及細胞療法包括用於使基因沉默之基因修飾；用於直接殺死感染細胞之基因方法；輸注經設計以替換患者之大部分自身免疫系統以增強對感染細胞之免疫反應，或活化患者之自身免疫系統以殺死感染細胞，或尋找且殺死感染細胞的免疫細胞；以及用於改變細胞活性以進一步改變針對感染之內源性免疫反應性之基因方法。基因編輯器
基因組編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統；例如經由靶向裂解進行之cccDNA消除，及改變B型肝炎病毒(HBV)病毒基因中之一或多者。改變(例如基因剔除及/或阻斷基因表現)PreC
、C
、X
、PreSI
、PreS2
、S
、P
或SP
基因係指(1)降低或消除PreC
、C
、X
、PreSI
、PreS2
、S
、P
或SP
基因表現；(2)干擾前核心蛋白(Precore)、核心蛋白(Core)、X蛋白質、長表面蛋白質、中表面蛋白質、S蛋白質(亦稱為HBs抗原及HBsAg)、聚合酶蛋白質及/或B型肝炎剪接蛋白質功能(HBe、HBc、HBx、PreS1、PreS2、S、Pol及/或HBSP)；或(3)減少或消除HBe、HBc、HBx、LHBs、MHBs、SHBs、Pol及/或HBSP蛋白質之細胞內、血清及/或腦實質內含量。阻斷PreC、C、X、PreSI、PreS2、S、P及/或SP基因中之一或多者的基因表現藉由靶向HBV cccDNA及/或整合HBV DNA內之基因來進行。CAR-T 細胞療法
CAR T細胞療法包括經工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞之群體，其中CAR包含HBV抗原結合域。免疫效應細胞為T細胞或NK細胞。在一些實施例中，T細胞為CD4+ T細胞、CD8+ T細胞或其組合。細胞可為自體或同種異體的。TCR-T 細胞療法
TCR T細胞療法包括表現HBV特異性T細胞受體之T細胞。TCR-T細胞經工程改造以靶向在感染病毒細胞之表面上呈現的HBV源性肽。在一些實施例中，T細胞表現HBV表面抗原(HBsAg)特異性TCR。針對HBV之治療的TCR-T療法之實例包括LTCR-H2-1。
在另一個特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合：HBV DNA聚合酶抑制劑；一或兩種選自由以下組成之群的額外治療劑：免疫調節劑、TLR調節劑、HBsAg抑制劑、HBsAg分泌或組裝抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒表面抗原之HBV抗體)以及雙特異性抗體及「抗體樣」治療性蛋白質(諸如DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物或TCR樣抗體)、親環素抑制劑、視黃酸誘發型基因1刺激劑、RIG-I樣受體刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶抑制劑、PI3K抑制劑、IDO抑制劑及NOD2刺激劑；及一或兩種選自由以下組成之群的額外治療劑：HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒表面抗原之HBV抗體、siRNA、miRNA基因治療劑、sshRNA、KDM5抑制劑及核蛋白調節劑(HBV核心或衣殼蛋白調節劑)。
在另一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與HBV DNA聚合酶抑制劑及至少一種選自由以下組成之群的第二額外治療劑組合：免疫調節劑、TLR調節劑、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒表面抗原之HBV抗體)以及雙特異性抗體及「抗體樣」治療性蛋白質(諸如DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物或TCR樣抗體)、親環素抑制劑、視黃酸誘發型基因1刺激劑、RIG-I樣受體刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶抑制劑、PI3K抑制劑、IDO抑制劑及NOD2刺激劑。
在另一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與HBV DNA聚合酶抑制劑及至少一種選自由以下組成之群的第二額外治療劑組合：HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、siRNA、miRNA基因治療劑、sshRNA、KDM5抑制劑及核蛋白調節劑(HBV核心或衣殼蛋白抑制劑)。
在一特定實施例中，本文所揭示之化合物或其醫藥學上可接受之鹽與化合物，諸如以下中所揭示之化合物以及其他用於治療HBV之藥物及其組合進行組合：美國公開案第2010/0143301 (Gilead Sciences)號、美國公開案第2011/0098248號(Gilead Sciences)、美國公開案第2009/0047249號(Gilead Sciences)、美國專利第8722054號(Gilead Sciences)、美國公開案第2014/0045849號(Janssen)、美國公開案第2014/0073642號(Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、美國公開案第2014/0350031號(Janssen)、WO2014/023813 (Janssen)、美國公開案第2008/0234251號(Array Biopharma)、美國公開案第2008/0306050號(Array Biopharma)、美國公開案第2010/0029585號(Ventirx Pharma)、美國公開案第2011/0092485號(Ventirx Pharma)、US2011/0118235 (Ventirx Pharma)、美國公開案第2012/0082658號(Ventirx Pharma)、美國公開案第2012/0219615號(Ventirx Pharma)、美國公開案第2014/0066432號(Ventirx Pharma)、美國公開案第2014/0088085號(Ventirx Pharma)、美國公開案第2014/0275167號(Novira Therapeutics)、美國公開案第2013/0251673號(Novira Therapeutics)、美國專利第8513184號(Gilead Sciences)、美國公開案第2014/0030221號(Gilead Sciences)、美國公開案第2013/0344030號(Gilead Sciences)、美國公開案第2013/0344029號(Gilead Sciences)、US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics)、美國公開案第2014/0343032號(Roche)、WO2014037480 (Roche)、美國公開案第2013/0267517號(Roche)、WO2014131847 (Janssen)、WO2014033176 (Janssen)、WO2014033170 (Janssen)、WO2014033167 (Janssen)、WO2015/059212 (Janssen)、WO2015118057(Janssen)、WO2015011281 (Janssen)、WO2014184365 (Janssen)、WO2014184350 (Janssen)、WO2014161888 (Janssen)、WO2013096744 (Novira)、US20150225355 (Novira)、US20140178337 (Novira)、US20150315159 (Novira)、US20150197533 (Novira)、US20150274652 (Novira)、US20150259324、(Novira)、US20150132258 (Novira)、US9181288 (Novira)、WO2014184350 (Janssen)、WO2013144129 (Roche)、US20100015178 (Incyte)、US2016137652 (Flexus Biosciences, Inc.)、WO2014073738 (Flexus Biosciences, Inc.)、WO2015188085 (Flexus Biosciences, Inc.)、美國公開案第2014/0330015號(Ono Pharmaceutical)、美國公開案第2013/0079327號(Ono Pharmaceutical)、美國公開案第2013/0217880號(Ono pharmaceutical)、WO2016057924 (Genentech/Constellation Pharmaceuticals)、US20140275092 (Genentech/Constellation Pharmaceuticals)、US20140371195 (Epitherapeutics)及US20140371214 (Epitherapeutics)、US20160102096 (Epitherapeutics)、US20140194469 (Quanticel)、US20140171432、US20140213591 (Quanticel)、US20160039808 (Quanticel)、US20140275084 (Quanticel)、WO2014164708 (Quanticel)、US9186337B2 (Oryzon Genomics)。癌症組合療法
在一個實施例中，本發明之化合物可與癌症治療之其他治療方法一起使用。較佳地，涵蓋與化學治療劑、激素、抗體、手術及/或輻射治療之組合療法。
在一些實施例中，其他抗癌療法為手術及/或放射線療法。
在一些實施例中，其他抗癌療法為至少一種額外癌症藥劑。
在一些實施例中，提供一種包含如本文所述之化合物或其醫藥學上可接受之鹽及至少一種其他癌症藥劑的組合。
在一些實施例中，提供一種包含如本文所述之化合物或其醫藥學上可接受之鹽及至少一種其他癌症藥劑的組合，其用於療法中。
在一些實施例中，提供包含如本文所述之化合物或其醫藥學上可接受之鹽及至少一種癌症藥劑的組合的用途，其用於製造供治療癌症用之藥劑。
其他癌症藥劑之實例包括嵌入物質，諸如蒽環黴素(anthracycline)、小紅莓(doxorubicin)、艾達黴素(idarubicin)、表柔比星(epirubicin)及道諾黴素(daunorubicin)；拓樸異構酶抑制劑，諸如伊立替康(irinotecan)、拓朴替康(topotecan)、喜樹鹼(camptothecin)、片螺素D (lamellarin D)、依託泊苷(etoposide)、替尼泊苷(teniposide)、米托蒽醌(mitoxantrone)、安吖啶(amsacrine)、玫瑰樹鹼(ellipticine)及金精三羧酸；亞硝基脲化合物，諸如卡莫司汀(carmustine) (BCNU)、洛莫司汀(lomustine) (CCNU)及鏈脲黴素(streptozocin)；氮芥類，諸如環磷醯胺、氮芥、烏拉莫司汀(uramustine)、苯達莫司汀(bendamustine)、美法侖(melphalan)、苯丁酸氮芥、馬磷醯胺(mafosfamide)、曲洛磷胺(trofosfamid)及異環磷醯胺；磺酸烷基酯，諸如白消安(busulfan)及曲奧舒凡(treosulfan)；烷基化劑，諸如丙卡巴嗪(procarbazin)、達卡巴嗪(dacarbazin)、替莫唑胺(temozolomid)及噻替派(thiotepa)；鉑類似物，諸如順鉑(cisplatin)、卡鉑(carboplatin)、奈達鉑(nedaplatin)、奧沙利鉑(oxaliplatin)、賽特鉑(satraplatin)及四硝酸三鉑(triplatin tetranitrate)；微管破壞性藥物，諸如長春花鹼(vinblastine)、秋水仙醯胺(colcemid)及諾考達唑(nocodazole)；抗葉酸劑，如甲胺喋呤(methotrexate)、胺基喋呤(aminopterin)、二氯甲胺喋呤(dichloromethotrexat)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)及普拉曲沙(pralatrexate)：嘌呤類似物，如硫唑嘌呤(azathioprine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、氟達拉濱(fludarabine)、磷酸氟達拉濱、噴司他汀(pentostatin)及克拉屈濱(cladribine)；嘧啶類似物，如5-氟尿嘧啶(5-fluorouracil)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-氮尿嘧啶(6-azauracil)、吉西他濱(gemcitabine)；類固醇，諸如吉西他津(gestagene)、安德羅津(androgene)、糖皮質激素、地塞米松(dexamethasone)、潑尼龍(prednisolone)及潑尼松(prednisone)；抗癌抗體，諸如單株抗體，例如阿侖單抗(alemtuzumab)、阿泊珠單抗(apolizumab)、西妥昔單抗(cetuximab)、依帕珠單抗(epratuzumab)、加利昔單抗(galiximab)、吉妥單抗(gemtuzumab)、伊匹單抗、拉貝珠單抗(labetuzumab)、帕尼單抗(panitumumab)、利妥昔單抗(rituximab)、曲妥珠單抗(trastuzumab)、尼妥珠單抗(nimotuzumab)、馬帕木單抗(mapatumumab)、馬妥珠單抗(matuzumab)、rhMab ICR62及帕妥珠單抗(pertuzumab)、放射性標記抗體及抗體-藥物結合物；抗癌肽，諸如放射性標記肽及肽-藥物結合物；以及紫杉烷及紫杉烷類似物，諸如紫杉醇(paclitaxel)及歐洲紫杉醇(docetaxel)。
在某些實施例中，提供一種用於治療或預防患有過度增生性病症或癌症或處於患過度增生性病症或癌症之風險下之人類或動物的過度增生性病症或癌症的方法，該方法包含向人類或動物投與治療有效量之如本文所揭示之本發明之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、一或兩種或一至三種)額外治療劑的組合。在一個實施例中，提供一種用於治療患有過度增生性病症或癌症或處於患過度增生性病症或癌症之風險下之人類或動物的過度增生性病症或癌症的方法，其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、一或兩種或一至三種)額外治療劑的組合。
在某些實施例中，本發明提供一種用於治療過度增生性病症或癌症之方法，其包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種適合於治療過度增生性病症或癌症之額外治療劑的組合。
本文所述之化合物可與以下中之一或多者一起使用或組合：化學治療劑、抗癌劑、抗血管生成劑、抗纖維化劑、免疫治療劑、治療性抗體、雙特異性抗體及「抗體樣」治療性蛋白質(諸如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗體-藥物結合物(ADC)、放射線治療劑、抗腫瘤劑、抗增生劑、溶瘤病毒、基因調節劑或編輯劑(諸如CRISPR/Cas9、鋅指核酸酶或合成核酸酶、TALEN)、嵌合抗原受體(chimeric antigen receptor；CAR) T細胞免疫治療劑、經工程改造之T細胞受體(TCR-T)或其任何組合。此等治療劑可呈化合物、抗體、多肽或聚核苷酸之形式。在一個實施例中，本文提供一種產品，其包含用於呈組合製劑形式同時、分開或依序用於療法的本文所述之化合物及額外治療劑。
一或多種治療劑包括(但不限於)基因、配位體、受體、蛋白質或因子之抑制劑、促效劑、拮抗劑、配位體、調節劑、刺激劑、阻斷劑、活化劑或抑制劑。額外治療劑之非限制性實例包括：埃布爾森鼠白血病病毒致癌基因同源物1基因(Abelson murine leukemia viral oncogene homolog 1 gene，ABL，諸如ABL1)、乙醯基-CoA羧化酶(諸如ACC1/2)、活化CDC激酶(ACK，諸如ACK1)、腺苷脫胺酶、腺苷受體(諸如A2B、A2a、A3)、腺苷酸環化酶、ADP核糖基環化酶-1、促腎上腺皮質激素受體(ACTH)、氣單胞菌溶素、AKT1基因、Alk-5蛋白激酶、鹼性磷酸酶、α1腎上腺素受體、α2腎上腺素受體、α-酮戊二酸去氫酶(KGDH)、胺基肽酶N、AMP活化蛋白激酶、退行性淋巴瘤激酶(ALK，諸如ALK1)、雄激素受體、血管生成素(諸如配位體-1、配位體-2)、血管收縮素原(AGT)基因、鼠類胸腺瘤病毒致癌基因同源物1(AKT)蛋白激酶(諸如AKT1、AKT2、AKT3)、載脂蛋白A-I (APOA1)基因、細胞凋亡誘發因子、細胞凋亡蛋白(諸如1、2)、細胞凋亡信號調節激酶(ASK，諸如ASK1)、精胺酸酶(I)、精胺酸脫亞胺酶、芳香酶、星狀同源物1 (ASTE1)基因、共濟失調毛細管擴張及Rad 3相關(ATR)絲胺酸/蘇胺酸蛋白激酶、極光蛋白激酶(諸如1、2)、Axl酪胺酸激酶受體、含桿狀病毒IAP重複序列蛋白5(BIRC5)基因、基礎免疫球蛋白(Basigin)、B細胞淋巴瘤2 (BCL2)基因、Bcl2結合組分3、Bcl2蛋白、BCL2L11基因、BCR(斷點簇集區)蛋白及基因、β腎上腺素受體、β-連環蛋白、B-淋巴細胞抗原CD19、B-淋巴細胞抗原CD20、B-淋巴細胞細胞黏附分子、B-淋巴細胞刺激因子配位體、骨成形性蛋白-10配位體、骨成形性蛋白-9配位體調節劑、短尾蛋白(Brachyury protein)、緩激肽受體(Bradykinin receptor)、B-Raf原癌基因(BRAF)、Brc-Abl酪胺酸激酶、布羅莫結構域及外部結構域(BET)含布羅莫結構域蛋白質(諸如BRD2、BRD3、BRD4)、布魯東氏酪胺酸激酶(BTK)、鈣調蛋白、鈣調蛋白依賴性蛋白激酶(CaMK，諸如CAMKII)、癌症睪丸抗原2、癌症睪丸抗原NY-ESO-1、癌症/睪丸抗原1B (CTAG1)基因、大麻受體(諸如CB1、CB2)、碳酸酐酶、酪蛋白激酶(CK，諸如CKI、CKII)、凋亡蛋白酶(諸如凋亡蛋白酶-3、凋亡蛋白酶-7、凋亡蛋白酶-9)、凋亡蛋白酶8細胞凋亡相關半胱胺酸肽酶CASP8-FADD樣調節劑、凋亡蛋白酶募集結構域蛋白質-15、組織蛋白酶G、CCR5基因、CDK活化激酶(CAK)、檢查點激酶(諸如CHK1、CHK2)、趨化因子(C-C基元)受體(諸如CCR2、CCR4、CCR5)、趨化因子(C-X-C基元)受體(諸如CXCR4、CXCR1及CXCR2)、趨化因子CC21配位體、膽囊收縮素CCK2受體、絨膜促性腺激素、c-Kit (酪胺酸蛋白激酶Kit或CD117)、緊密連接蛋白(Claudin)(諸如6、18)、分化簇(CD)(諸如CD4、CD27、CD29、CD30、CD33、CD37、CD40、CD40配位體受體、CD40配位體、CD40LG基因、CD44、CD45、CD47、CD49b、CD51、CD52、CD55、CD58、CD66e、CD70基因、CD74、CD79、CD79b、CD79B基因、CD80、CD95、CD99、CD117、CD122、CDw123、CD134、CDw137、CD158a、CD158b1、CD158b2、CD223、CD276抗原；群集素(clusterin，CLU)基因、群集素、c-Met(肝細胞生長因子受體(HGFR))、補體C3、結締組織生長因子、COP9信號體次單元5、CSF-1(群落刺激因子1受體)、CSF2基因、CTLA-4 (細胞毒性T淋巴細胞蛋白質4)受體、週期素D1、週期素G1、週期素依賴性激酶(CDK，諸如CDK1、CDK1B、CDK2-9)、環加氧酶(諸如1、2)、CYP2B1基因、半胱胺酸棕櫚醯基轉移酶豪豬同源物、細胞色素P450 11B2、細胞色素P450 17、細胞色素P450 17A1、細胞色素P450 2D6、細胞色素P450 3A4、細胞色素P450還原酶、細胞介素信號傳導-1、細胞介素信號傳導-3、細胞質異檸檬酸去氫酶、胞嘧啶脫胺酶、胞嘧啶DNA甲基轉移酶、細胞毒性T淋巴細胞蛋白質-4、DDR2基因、δ樣蛋白質配位體(諸如3、4)、去氧核糖核酸酶、Dickkopf-1配位體、二氫葉酸還原酶(DHFR)、二氫嘧啶去氫酶、二肽基肽酶IV、盤狀結構域受體(DDR，諸如DDR1)、DNA結合蛋白(諸如HU-β)、DNA依賴性蛋白激酶、DNA旋轉酶、DNA甲基轉移酶、DNA聚合酶(諸如α)、DNA引子酶、dUTP焦磷酸酶、L-多巴色素互變異構酶、棘皮動物微管樣蛋白質4、EGFR酪胺酸激酶受體、彈性蛋白酶、延伸因子1α2、延伸因子2、內皮因子、核酸內切酶、內質網素、內皮唾酸蛋白、內皮生長抑素、內皮素(諸如ET-A、ET-B)、zeste基因增強子同源物2(EZH2)、蝶素(EPH)酪胺酸激酶(諸如Epha3、Ephb4)、蝶素B2配位體、表皮生長因子、表皮生長因子受體(EGFR)、表皮生長因子受體(EGFR)基因、後生因子、上皮細胞黏附分子(EpCAM)、Erb-b2 (v-erb-b2禽類紅血球母細胞白血病病毒致癌基因同源物2)酪胺酸激酶受體、Erb-b3酪胺酸激酶受體、Erb-b4酪胺酸激酶受體、E-選擇素、雌二醇17β去氫酶、雌激素受體(諸如α、β)、雌激素相關受體、真核轉譯起始因子5A (EIF5A)基因、輸出蛋白1、胞外信號相關激酶(諸如1、2)、胞外信號調節激酶(ERK)、因子(諸如Xa、VIIa)、法尼酯X受體(FXR)、Fas配位體、脂肪酸合成酶(FASN)、鐵蛋白、FGF-2配位體、FGF-5配位體、纖維母細胞生長因子(FGF，諸如FGF1、FGF2、FGF4)、纖維結合蛋白、Fms相關酪胺酸激酶3 (Flt3)、局部黏著斑激酶(FAK，諸如FAK2)、葉酸水解酶前列腺特異性膜抗原1 (FOLH1)、葉酸受體(諸如α)、葉酸鹽、葉酸轉運體1、FYN酪胺酸激酶、成對基礎胺基酸裂解酶(FURIN)、β-葡糖苷酸酶、半乳糖苷基轉移酶、半乳糖凝集素-3、神經節苷脂GD2、糖皮質激素、糖皮質激素誘發之TNFR相關蛋白GITR受體、麩胺酸羧肽酶II、麩醯胺酸酶、麩胱甘肽S-轉移酶P、肝糖合成酶激酶(GSK，諸如3-β)、磷脂肌醇蛋白聚醣3 (GPC3)、促性腺激素釋放激素(GNRH)、顆粒球巨噬細胞群落刺激因子(GM-CSF)受體、顆粒球群落刺激因子(GCSF)配位體、生長因子受體結合蛋白2 (GRB2)、Grp78 (78 kDa葡萄糖調節蛋白)鈣結合蛋白、分子伴隨蛋白groEL2基因、熱休克蛋白(諸如27、70、90α、β)、熱休克蛋白基因、熱穩定腸毒素受體、刺蝟蛋白、肝素酶、肝細胞生長因子、HERV-H LTR相關蛋白2、己糖激酶、組織胺H2受體、組蛋白甲基轉移酶(DOT1L)、組蛋白去乙醯基酶(HDAC，諸如1、2、3、6、10、11)、組蛋白H1、組蛋白H3、HLAI類抗原(A-2α)、HLAII類抗原、同源盒蛋白質NANOG、HSPB1基因、人類白細胞抗原(HLA)、人類乳頭狀瘤病毒(諸如E6、E7)蛋白質、玻尿酸、玻尿酸酶、低氧誘導因子-1α (HIF1α)、母系印跡表現轉錄物(H19)基因、有絲分裂原活化蛋白激酶1 (MAP4K1)、酪胺酸蛋白激酶HCK、I-κ-B激酶(IKK，諸如IKKbe)、IL-1α、IL-1β、IL-12、IL-12基因、IL-15、IL-17、IL-2基因、IL-2受體α次單元、IL-2、IL-3受體、IL-4、IL-6、IL-7、IL-8、免疫球蛋白(諸如G、G1、G2、K、M)、免疫球蛋白Fc受體、免疫球蛋白γFc受體(諸如I、III、IIIA)、吲哚胺2,3-雙加氧酶(IDO，諸如IDO1)、吲哚胺吡咯2,3-雙加氧酶1抑制劑、胰島素受體、類胰島素生長因子(諸如1、2)、整合素α-4/β-1、整合素α-4/β-7、整合素α-5/β-1、整合素α-V/β-3、整合素α-V/β-5、整合素α-V/β-6、細胞間黏附分子1 (ICAM-1)、干擾素(諸如α、α2、β、γ)、黑色素瘤中缺乏的干擾素誘導蛋白2 (AIM2)、干擾素I型受體、介白素1配位體、介白素13受體α2、介白素2配位體、介白素-1受體相關激酶4 (IRAK4)、介白素-2、介白素-29配位體、異檸檬酸去氫酶(諸如IDH1、IDH2)、Janus激酶(JAK，諸如JAK1、JAK2)、Jun N端激酶、胰舒血管素相關肽酶3 (KLK3)基因、殺手細胞Ig樣受體、激酶插入結構域受體(KDR)、驅動蛋白樣蛋白KIF11、基爾斯滕大鼠肉瘤病毒致癌基因同源物(Kirsten rat sarcoma viral oncogene homolog，KRAS)基因、吻素(KiSS -1)受體、KIT基因、v-kit Hardy-Zuckerman 4貓科動物肉瘤病毒致癌基因同源物(KIT)酪胺酸激酶、乳鐵傳遞蛋白、羊毛甾醇-14去甲基酶、LDL受體相關蛋白-1、白三烯A4水解酶、李斯特菌溶胞素、L-選擇素、促黃體生成激素受體、裂解酶、淋巴細胞活化基因3蛋白(LAG-3)、淋巴細胞抗原75、淋巴細胞功能抗原-3受體、淋巴細胞特異性蛋白酪胺酸激酶(LCK)、淋巴細胞趨化因子、Lyn(Lck/Yes新穎)酪胺酸激酶、離胺酸去甲基酶(諸如KDM1、KDM2、KDM4、KDM5、KDM6、A/B/C/D)、溶血磷脂酸-1受體、溶酶體相關膜蛋白家族(LAMP)基因、離胺醯氧化酶同源物2、離胺醯氧化酶蛋白(LOX)、離胺醯氧化酶樣蛋白(LOXL，諸如LOXL2)、造血前驅細胞激酶1 (HPK1)、肝細胞生長因子受體(MET)基因、巨噬細胞群落刺激因子(MCSF)配位體、巨噬細胞遷移抑制因子、MAGEC1基因、MAGEC2基因、穹窿主體蛋白、MAPK活化蛋白激酶(諸如MK2)、Mas相關G蛋白偶合受體、基質金屬蛋白酶(MMP，諸如MMP2、MMP9)、Mcl-1分化蛋白、Mdm2 p53結合蛋白、Mdm4蛋白、Melan-A (MART -1)黑色素瘤抗原、黑色素細胞蛋白Pmel 17、黑色素細胞刺激激素配位體、黑色素瘤抗原家族A3 (MAGEA3)基因、黑色素瘤相關抗原(諸如1、2、3、6)、膜銅胺氧化酶、間皮素、MET酪胺酸激酶、代謝型麩胺酸受體1、金屬還原酶STEAP1 (前列腺六跨膜上皮抗原1)、轉移抑素、甲硫胺酸胺基肽酶-2、甲基轉移酶、粒線體3酮脂醯CoA硫解酶、有絲分裂原活化蛋白激酶(MAPK)、有絲分裂原活化蛋白激酶(MEK，諸如MEK1、MEK2)、mTOR (雷帕黴素機制目標(絲胺酸/蘇胺酸激酶)、mTOR複合物(諸如1、2)、黏蛋白(諸如1、5A、16)、mut T同源物(MTH，諸如MTH1)、Myc原癌基因蛋白、骨髓細胞白血病1 (MCL1)基因、肉豆蔻醯基化富含丙胺酸之蛋白激酶C受質(MARCKS)蛋白、NAD ADP核糖基轉移酶、利尿鈉肽受體C、神經細胞黏附分子1、神經激肽1 (NK1)受體、神經激肽受體、神經菌毛素2、NFκB活化蛋白、NIMA相關激酶9 (NEK9)、氧化氮合成酶、NK細胞受體、NK3受體、NKG2 A B活化NK受體、去甲腎上腺素轉運體、Notch (諸如Notch-2受體、Notch-3受體、Notch-4受體)、核紅細胞2相關因子2、核因子(NF) κB、核仁素、核仁磷酸蛋白、核仁磷酸蛋白-間變性淋巴瘤激酶(NPM-ALK)、2側氧基戊二酸去氫酶、2,5-寡聚腺苷酸合成酶、O-甲基鳥嘌呤DNA甲基轉移酶、類鴉片受體(諸如δ)、鳥胺酸去羧酶、乳清酸磷酸核糖轉移酶、孤兒核激素受體NR4A1、骨鈣化素、破骨細胞分化因子、骨橋蛋白、OX-40 (腫瘤壞死因子受體超家族成員4 TNFRSF4、或CD134)受體、P3蛋白質、p38激酶、p38MAP激酶、p53腫瘤抑制蛋白、副甲狀腺激素配位體、過氧化體增殖物活化受體(PPAR，諸如α、δ、γ)、P-醣蛋白(諸如1)、磷酸酶及張力蛋白同源物(PTEN)、磷脂醯肌醇3-激酶(PI3K)、磷酸肌醇-3激酶(PI3K，諸如α、δ、γ)、磷酸化酶激酶(PK)、PKN3基因、胎盤生長因子、血小板衍生生長因子(PDGF，諸如α、β)、血小板衍生生長因子(PDGF，諸如α、β)、多效性耐藥轉運蛋白、叢蛋白B1、PLK1基因、polo樣激酶(PLK)、Polo樣激酶1、聚ADP核糖聚合酶(PARP，諸如PARP1、2及3)、優先在黑素瘤中表現之抗原(PRAME)基因、異戊二烯基結合蛋白(PrPB)、可能的轉錄因子PML、孕酮受體、計劃性細胞死亡1(PD-1)、計劃性細胞死亡配位體1抑制劑(PD-L1)、鞘脂激活蛋白原(prosaposin，PSAP)基因、類前列腺素受體(EP4)、前列腺特異性抗原、前列腺酸性磷酸酶、蛋白酶體、蛋白質E7、蛋白質法呢基轉移酶、蛋白激酶(PK，諸如A、B、C)、蛋白質酪胺酸激酶、蛋白質酪胺酸磷酸酶β、原癌基因絲胺酸/蘇胺酸蛋白激酶(PIM，諸如PIM-1、PIM-2、PIM-3)、P-選擇素、嘌呤核苷磷酸化酶、嘌呤型受體P2X配位體閘控離子通道7( P2X7)、丙酮酸去氫酶(PDH)、丙酮酸去氫酶激酶、丙酮酸激酶(PYK)、5-α-還原酶、Raf蛋白激酶(諸如1、B)、RAF1基因、Ras基因、Ras GTP酶、RET基因、Ret酪胺酸激酶受體、視網膜母細胞瘤相關蛋白、視黃酸受體(諸如γ)、類視黃素X受體、Rheb (腦中富集的Ras同源物) GTP酶、ρ (Ras同源物)相關蛋白激酶2、核糖核酸酶、核糖核苷酸還原酶(諸如M2次單元)、核糖體蛋白S6激酶、RNA聚合酶(諸如I、II)、Ron (Recepteur d'Origine Nantais)酪胺酸激酶、ROS1 (ROS原癌基因1、受體酪胺酸激酶)基因、Ros1酪胺酸激酶、Runt相關轉錄因子3、γ-分泌酶、S100鈣結合蛋白A9、Sarco內質網鈣ATPase、第二粒線體衍生凋亡蛋白酶活化物(SMAC)蛋白、分泌型捲曲相關蛋白-2、信號蛋白-4D、絲胺酸蛋白酶、絲胺酸/蘇胺酸激酶(STK)、絲胺酸/蘇胺酸蛋白激酶(TBK，諸如TBK1)、信號轉導及轉錄(STAT，諸如STAT-1、STAT-3、STAT-5)、信號傳導淋巴細胞性活化分子(SLAM)家族成員7、前列腺六跨膜上皮抗原(STEAP)基因、SL細胞介素配位體、平滑(SMO)受體、碘化鈉共轉運蛋白、磷酸鈉共轉運蛋白2B、生長抑素受體(諸如1、2、3、4、5)、音蝟因子蛋白(Sonic hedgehog protein)、七激酶子(Son of sevenless，SOS)、特定蛋白1 (Sp1)轉錄因子、鞘磷脂合成酶、神經鞘胺醇激酶(諸如1、2)、神經鞘胺醇-1-磷酸鹽受體-1、脾酪胺酸激酶(SYK)、SRC基因、Src酪胺酸激酶、STAT3基因、類固醇硫酸酯酶、干擾素基因刺激劑(STING)受體、干擾素基因刺激劑蛋白、基質細胞衍生因子1配位體、SUMO (小泛素樣改質劑)、超氧化物歧化酶、存活素蛋白、突觸蛋白(Synapsin) 3、多配位體蛋白聚糖-1 (Syndecan-1)、共核蛋白α (Synuclein alpha)、T細胞表面醣蛋白CD28、tank結合激酶(TBK)、TATA盒結合蛋白相關因子RNA聚合酶I次單元B (TAF1B)基因、T細胞CD3醣蛋白ζ鏈、T細胞分化抗原CD6、T細胞免疫球蛋白及含黏蛋白結構域-3 (TIM-3)、T細胞表面醣蛋白CD8、Tec蛋白酪胺酸激酶、Tek酪胺酸激酶受體、端粒酶、端粒酶逆轉錄酶(TERT)基因、肌腱蛋白、TGFβ2配位體、血小板生成素受體、胸苷激酶、胸苷磷酸化酶、胸苷酸合成酶、胸腺素(諸如α1)、甲狀腺激素受體、促甲狀腺激素受體、組織因子、TNF相關細胞凋亡誘導配位體、TNFR1相關死亡結構域蛋白、TNF相關細胞凋亡誘導配位體(TRAIL)受體、TNFSF11基因、TNFSF9基因、類鐸受體(TLR，諸如1-13)、拓樸異構酶(諸如I、II、III)、轉錄因子、轉移酶、運鐵蛋白、轉型生長因子(TGF，諸如β)激酶、轉型生長因子TGF-β受體激酶、轉麩胺醯胺酶、易位相關蛋白、跨膜醣蛋白NMB、Trop-2鈣信號轉導蛋白、滋養層醣蛋白(TPBG)基因、滋養層醣蛋白、肌旋蛋白受體激酶(Trk)受體(諸如TrkA、TrkB、TrkC)、色胺酸5-羥化酶、微管蛋白、腫瘤壞死因子(TNF，諸如α、β)、腫瘤壞死因子13C受體、腫瘤進展基因座2 (TPL2)、腫瘤蛋白53 (TP53)基因、腫瘤抑制候選因子2 (TUSC2)基因、酪胺酸酶、酪胺酸羥化酶、酪胺酸激酶(TK)、酪胺酸激酶受體、具有免疫球蛋白樣及EGF樣結構域之酪胺酸激酶(TIE)受體、酪胺酸蛋白激酶ABL1抑制劑、泛素、泛素羧基水解酶同功酶L5、泛素硫酯酶-14、泛素結合酶E2I (UBE2I、UBC9)、尿素酶、尿激酶纖維蛋白溶酶原活化物、子宮球蛋白、香草素VR1、血管細胞黏附蛋白1、血管內皮生長因子受體(VEGFR)、T細胞活化之V域Ig抑制因子(VISTA)、VEGF-1受體、VEGF-2受體、VEGF-3受體、VEGF-A、VEGF-B、波形蛋白、維生素D3受體、原癌基因酪胺酸蛋白激酶Yes、Wee-1蛋白激酶、威爾姆斯氏腫瘤抗原1、威爾姆斯氏腫瘤蛋白、X連鎖細胞凋亡抑制蛋白、鋅指蛋白轉錄因子或其任何組合。
額外治療劑之非限制性實例可由其作用機制分類成例如以下各組：
- 抗代謝物/抗癌劑，諸如嘧啶類似物氟尿苷、卡培他濱(capecitabine)、阿糖胞苷、CPX-351 (脂質阿糖胞苷、道諾黴素)及TAS-118；
- 嘌呤類似物、葉酸拮抗劑(諸如普拉曲沙)及相關抑制劑；
- 抗增生/抗有絲分裂劑，包括天然產物，諸如長春花生物鹼(長春花鹼、長春新鹼(vincristine))及微管瓦解劑，諸如紫杉烷(紫杉醇、歐洲紫杉醇)、長春花鹼(vinblastin)、諾考達唑、埃博黴素(epothilone)、長春瑞賓(vinorelbine)(NAVELBINE®
)，及表鬼臼毒素(epipodophyllotoxin)(依託泊苷、替尼泊苷)；
- DNA損傷劑，諸如放射菌素、安吖啶、白消安、卡鉑、苯丁酸氮芥、順鉑、環磷醯胺(CYTOXAN®
)、放線菌素D、道諾黴素、小紅莓、表柔比星、異環磷醯胺、美法侖、二氯甲二乙胺、絲裂黴素C、米托蒽醌、亞硝基脲、丙卡巴嗪、紫杉醇(taxol)、克癌易(Taxotere)、替尼泊苷、依託泊苷及三伸乙基硫代磷醯胺；
- DNA低甲基化劑，諸如瓜達西汀(guadecitabine) (SGI-110)、ASTX727；
- 抗生素，諸如放線菌素D、道諾黴素、小紅莓、伊達比星、蒽環黴素、米托蒽醌、博萊黴素(bleomycin)、普卡黴素(plicamycin)(光神黴素(mithramycin))；
- 酶，諸如系統地代謝L-天冬醯胺且剝奪不能合成其自身天冬醯胺之細胞的L-天冬醯胺酶；
- 抗血小板劑；
- 靶向Bcl-2之DNAi寡核苷酸，諸如PNT2258；
- 活化或再活化潛在人類免疫缺陷病毒(HIV)之藥劑，諸如帕比諾他及羅米地辛；
- 天冬醯胺酶刺激劑，諸如克立他酶(crisantaspase)(Erwinase®)及GRASPA (ERY-001、ERY-ASP)、聚乙二醇化卡拉斯酶(calaspargase pegol)；
- 泛Trk、ROS1及ALK抑制劑，諸如恩曲替尼(entrectinib)、TPX-0005；
- 間變性淋巴瘤激酶(ALK)抑制劑，諸如艾樂替尼(alectinib)、色瑞替尼(ceritinib)；
- 抗增生/抗有絲分裂烷基化劑，諸如氮芥環磷醯胺及類似物(美法侖、氯芥苯丁酸、六甲蜜胺(hexamethylmelamine)及噻替派)、烷基亞硝基脲(卡莫司汀)及類似物、鏈脲黴素及三氮烯(達卡巴嗪(dacarbazine))；
- 抗增生/抗有絲分裂抗代謝物，諸如葉酸類似物(甲胺喋呤)；
- 鉑配位錯合物(順鉑、奧沙利鉑(oxiloplatinim)及卡鉑)、丙卡巴嗪、羥脲、米托坦(mitotane)及胺魯米特(aminoglutethimide)；
- 激素、激素類似物(雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡魯胺(bicalutamide)及尼魯胺(nilutamide))及芳香酶抑制劑(來曲唑(letrozole)及阿那曲唑(anastrozole))；
- 抗凝劑，諸如肝素、合成肝素鹽及其他凝血酶抑制劑；
- 纖維蛋白溶解劑，諸如組織纖維蛋白溶酶原活化因子、鏈球菌激酶、尿激酶、阿司匹林(aspirin)、雙嘧達莫(dipyridamole)、噻氯匹定(ticlopidine)及克羅匹多(clopidogrel)；
- 抗遷移劑；
- 抗分泌劑(布瑞汀(breveldin))；
- 免疫抑制劑，諸如他克莫司(tacrolimus)、西羅莫司(sirolimus)、硫唑嘌呤及黴酚酸酯(mycophenolate)；
- 生長因子抑制劑及血管內皮生長因子抑制劑；
- 纖維母細胞生長因子抑制劑，諸如FPA14；
- 抗VEGFR抗體，諸如IMC-3C5、GNR-011、塔尼比單抗(tanibirumab)；
- 抗VEGF/DDL4抗體，諸如ABT-165；
- 抗鈣黏素抗體，諸如HKT-288；
- 抗CD70抗體，諸如AMG-172；抗富含白胺酸重複序列15 (LRRC15)抗體，諸如ABBV-085.ARGX-110；
- 血管收縮素受體阻斷劑、氧化氮供體；
- 反義寡核苷酸，諸如AEG35156、IONIS-KRAS-2.5Rx、EZN-3042、RX-0201、IONIS-AR-2.5Rx、BP-100 (普瑞博森(prexigebersen))、IONIS-STAT3-2.5Rx；
- DNA干擾寡核苷酸，諸如PNT2258、AZD-9150；
- 抗ANG-2抗體，諸如MEDI3617及LY3127804；
- 抗ANG-1/ANG-2抗體，諸如AMG-780；
- 抗MET/EGFR抗體，諸如LY3164530；
- 抗EGFR抗體，諸如ABT-414、AMG-595、萊西單抗(necitumumab)、ABBV-221、馬佛多坦德帕土西珠單抗(depatuxizumab mafodotin)(ABT-414)、托木妥昔單抗(tomuzotuximab)、ABT-806、維必施(vectibix)、莫多西單抗(modotuximab)、RM-1929；
- 抗CSF1R抗體，諸如艾瑪圖單抗(emactuzumab)、LY3022855、AMG-820、FPA-008 (卡比拉單抗(cabiralizumab))；
- 抗CD40抗體，諸如RG7876、SEA-CD40、APX-005M、ABBV-428；
- 抗內皮因子抗體，諸如TRC105 (卡妥昔單抗(carotuximab))；
- 抗CD45抗體，諸如131I-BC8 (lomab-B)；
- 抗HER3抗體，諸如LJM716、GSK2849330；
- 抗HER2抗體，諸如馬妥昔單抗(margetuximab)、MEDI4276、BAT-8001；
- 抗HLA-DR抗體，諸如IMMU-114；
- 抗IL-3抗體，諸如JNJ-56022473；
- 抗OX40抗體，諸如MEDI6469、MEDI6383、MEDI0562 (塔沃西單抗(tavolixizumab))、MOXR0916、PF-04518600、RG-7888、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368；
- 抗EphA3抗體，諸如KB-004；
- 抗CD20抗體，諸如奧濱尤妥珠單抗(obinutuzumab)、IGN-002；
- 抗CD20/CD3抗體，諸如RG7828；
- 抗CD37抗體，諸如AGS67E、奧特勒土珠單抗(otlertuzumab；TRU-016)；
- 抗ENPP3抗體，諸如AGS-16C3F；
- 抗FGFR-3抗體，諸如LY3076226、B-701；
- 抗FGFR-2抗體，諸如GAL-F2；
- 抗C5抗體，諸如ALXN-1210；
- 抗CD27抗體，諸如瓦里木單抗(varlilumab) (CDX-1127)；
- 抗TROP-2抗體，諸如IMMU-132；
- 抗NKG2a抗體，諸如莫納珠單抗(monalizumab)；
- 抗VISTA抗體，諸如HMBD-002；
- 抗PVRIG抗體，諸如COM-701；
- 抗EpCAM抗體，諸如VB4-845；
- 抗BCMA抗體，諸如GSK-2857916；
- 抗CEA抗體，諸如RG-7813；
- 抗分化簇3 (CD3)抗體，諸如MGD015；
- 抗葉酸受體α抗體，諸如IMGN853；
- MCL-1抑制劑，諸如AMG-176、S-64315及AZD-5991、483-LM、A-1210477、UMI-77、JKY-5-037；
- epha2抑制劑，諸如MM-310；
- 抗LAG-3抗體，諸如瑞拉單抗(relatlimab；ONO-4482)、LAG-525、MK-4280、REGN-3767；
- raf激酶/VEGFR抑制劑，諸如RAF-265；
- 多蜂房蛋白(EED)抑制劑，諸如MAK683；
- 抗纖維母細胞活化蛋白(FAP)/IL-2R抗體，諸如RG7461；
- 抗纖維母細胞活化蛋白(FAP)/TRAIL-R2抗體，諸如RG7386；
- 抗岩藻糖基-GM1抗體，諸如BMS-986012；
- p38 MAP激酶抑制劑，諸如那力替尼(ralimetinib)；
- PRMT1抑制劑，諸如MS203；
- 神經鞘胺醇激酶2 (SK2)抑制劑，諸如奧帕尼布(opaganib)；
- FLT3-ITD抑制劑，諸如BCI-332；
- 核紅細胞2相關因子2刺激劑，諸如奧瑪韋隆(omaveloxolone；RTA-408)；
- 肌旋蛋白受體激酶(TRK)抑制劑，諸如LOXO-195、ONO-7579；
- 抗ICOS抗體，諸如JTX-2011、GSK3359609；
- 抗DR5 (TRAIL2)抗體，諸如DS-8273；
- 抗GD2抗體，諸如APN-301；
- 抗介白素-17 (IL-17)抗體，諸如CJM-112；
- 抗碳酸酐酶IX抗體，諸如TX-250；
- 抗CD38阿騰金(attenukine)，諸如TAK573；
- 抗黏蛋白1抗體，諸如加迪珠單抗(gatipotuzumab)；
- 黏蛋白1抑制劑，諸如GO-203-2C；
- MARCKS蛋白抑制劑，諸如BIO-11006；
- 葉酸拮抗劑，諸如阿弗地林(arfolitixorin)；
- 半乳糖凝集素-3抑制劑，諸如GR-MD-02；
- 磷酸化P68抑制劑，諸如RX-5902；
- CD95/TNF調節劑，諸如奧弗沃巴(ofranergene obadenovec)；
- PI3K/Akt/mTOR抑制劑，諸如ABTL-0812；
- 泛PIM激酶抑制劑，諸如INCB-053914；
- IL-12基因刺激劑，諸如EGEN-001、塔沃特德(tavokinogene telseplasmid)；
- 熱休克蛋白質HSP90抑制劑，諸如TAS-116、PEN-866；
- VEGF/HGF拮抗劑，諸如MP-0250；
- SYK酪胺酸激酶/FLT3酪胺酸激酶抑制劑，諸如TAK-659；
- SYK酪胺酸激酶/JAK酪胺酸激酶抑制劑，諸如ASN-002；
- FLT3酪胺酸激酶抑制劑，諸如FF-10101；
- FLT3酪胺酸激酶促效劑，諸如CDX-301；
- FLT3/MEK1抑制劑，諸如E-6201；
- IL-24拮抗劑，諸如AD-IL24；
- RIG-I促效劑，諸如RGT-100；
- 氣單胞菌溶素刺激劑，諸如托普欣(topsalysin)；
- P-醣蛋白1抑制劑，諸如HM-30181A；
- CSF-1拮抗劑，諸如ARRY-382、BLZ-945；
- 抗間皮素抗體，諸如SEL-403；
- 胸苷激酶刺激劑，諸如阿格維克(aglatimagene besadenovec)；
- Polo類激酶1抑制劑，諸如PCM-075；
- TLR-7促效劑，諸如TMX-101 (咪喹莫特)；
- NEDD8抑制劑，諸如佩沃塔特(pevonedistat，MLN-4924)、TAS-4464；
- 多效性路徑調節劑，諸如阿多米德(avadomide；CC-122)；
- FoxM1抑制劑，諸如硫鏈絲菌肽(thiostrepton)；
- 抗MUC1抗體，諸如Mab-AR-20.5；
- 抗CD38抗體，諸如伊薩土西單抗(isatuximab)、MOR-202；
- UBA1抑制劑，諸如TAK-243；
- Src酪胺酸激酶抑制劑，諸如VAL-201；
- VDAC/HK抑制劑，諸如VDA-1102；
- BRAF/PI3K抑制劑，諸如ASN-003；
- Elf4a抑制劑，諸如羅西替布(rohinitib)、eFT226；
- TP53基因刺激劑，諸如ad-p53；
- PD-L1/EGFR抑制劑，諸如GNS-1480；
- 視黃酸受體α (RARα)抑制劑，諸如SY-1425；
- SIRT3抑制劑，諸如YC8-02；
- 基質細胞衍生因子1配位體抑制劑，諸如聚乙二醇化奧拉希德(olaptesed pegol)(NOX-A12)；
- IL-4受體調節劑，諸如MDNA-55；
- 精胺酸酶-I刺激劑，諸如佩拉酶(pegzilarginase)；
- 拓樸異構酶I抑制劑/低氧誘導因子-1 α抑制劑，諸如PEG-SN38 (聚乙二醇化非特坎(firtecan pegol))；
- 低氧誘導因子-1α抑制劑，諸如PT-2977、PT-2385；
- CD122促效劑，諸如NKTR-214；
- p53腫瘤抑制蛋白刺激劑，諸如克維林(kevetrin)；
- Mdm4/Mdm2 p53結合蛋白抑制劑，諸如ALRN-6924；
- 驅動蛋白軸蛋白(KSP)抑制劑，諸如非那西布(filanesib)(ARRY-520)；
- CD80-fc融合蛋白抑制劑，諸如FPT-155；
- 多發性內分泌腺瘤蛋白(Menin)及混合系白血病(MLL)抑制劑，諸如KO-539；
- 肝x受體促效劑，諸如RGX-104；
- IL-10促效劑，諸如AM-0010；
- EGFR/ErbB-2抑制劑，諸如瓦尼替尼(varlitinib)；
- VEGFR/PDGFR抑制劑，諸如沃羅拉尼(vorolanib)；
- IRAK4抑制劑，諸如CA-4948；
- 抗TLR-2抗體，諸如OPN-305；
- 鈣調蛋白調節劑，諸如CBP-501；
- 糖皮質激素受體拮抗劑，諸如瑞拉蘭特(relacorilant) (CORT-125134)；
- 第二粒線體衍生凋亡蛋白酶活化物(SMAC)蛋白質抑制劑，諸如BI-891065；
- 乳鐵蛋白調節劑，諸如LTX-315；
- Kit酪胺酸激酶/PDGF受體α拮抗劑，諸如DCC-2618；
- KIT抑制劑，諸如PLX-9486；
- 核輸出蛋白1抑制劑，諸如艾塔尼西(eltanexor)；
- EGFR/ErbB2/Ephb4抑制劑，諸如特伐替尼(tesevatinib)；
- 抗CD33抗體，諸如IMGN-779；
- 抗KMA抗體，諸如MDX-1097；
- 抗TIM-3抗體，諸如TSR-022, LY-3321367, MBG-453；
- 抗CD55抗體，諸如PAT-SC1；
- 抗PSMA抗體，諸如ATL-101；
- 抗CD100抗體，諸如VX-15；
- 抗EPHA3抗體，諸如菲巴珠單抗(fibatuzumab)；
- 抗Erbb抗體，諸如CDX-3379、HLX-02、塞里班土單抗(seribantumab)；
- 抗APRIL抗體，諸如BION-1301；
- 抗Tigit抗體，諸如BMS-986207、RG-6058；
- CHST15基因抑制劑，諸如STNM-01；
- RAS抑制劑，諸如NEO-100;
- 生長抑素受體拮抗劑，諸如OPS-201；
- CEBPA基因刺激劑，諸如MTL-501；
- DKK3基因調節劑，諸如MTG-201；
- p70s6k抑制劑，諸如MSC2363318A；
- 甲硫胺酸胺基肽酶2 (MetAP2)抑制劑，諸如M8891、APL-1202；
- 精胺酸N-甲基轉移酶5抑制劑，諸如GSK-3326595；
- 抗計劃性細胞死亡蛋白1 (抗PD-1)抗體，諸如納武單抗(OPDIVO®、BMS-936558、MDX-1106)、派姆單抗(KEYTRUDA®、MK-3477、SCH-900475、拉立珠單抗(lambrolizumab)，CAS登記號1374853-91-4)、皮立珠單抗、PF-06801591、BGB-A317、GLS-010 (WBP-3055)、AK-103 (HX-008)、MGA-012、BI-754091、REGN-2810 (賽咪單抗(cemiplimab))、AGEN-2034、JS-001、JNJ-63723283、傑諾珠單抗(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、BAT-1306，以及抗計劃性死亡配位體1 (抗PD-L1)抗體，諸如BMS-936559、阿特珠單抗(MPDL3280A)、德瓦魯單抗(MEDI4736)、阿維魯單抗、CK-301 (MSB0010718C)、MEDI0680、CX-072、CBT-502、PDR-001 (斯帕塔利單抗(spartalizumab))、TSR-042 (多斯利單抗(dostarlimab))、JTX-4014、BGB-A333、SHR-1316、CS-1001 (WBP-3155、KN-035、IBI-308、FAZ-053及MDX1105-01)；
- PD-L1/VISTA拮抗劑，諸如CA-170；
- 抗PD-L1/TGFβ抗體，諸如M7824；
- 抗運鐵蛋白抗體，諸如CX-2029；
- 抗IL-8 (介白素-8)抗體，諸如HuMax-Inflam；
- ATM (共濟失調毛細管擴張)抑制劑，諸如AZD0156；
- CHK1抑制劑，諸如GDC-0575、LY2606368 (普瑞替布(prexasertib))、SRA737、RG7741 (CHK1/2)；
- CXCR4拮抗劑，諸如BL-8040、LY2510924、布利沙福(burixafor)(TG-0054)、X4P-002、X4P-001-IO；
- EXH2抑制劑，諸如GSK2816126；
- HER2抑制劑，諸如來那替尼、圖卡替尼(tucatinib) (ONT-380)；
- KDM1抑制劑，諸如ORY-1001、IMG-7289、INCB-59872、GSK-2879552；
- CXCR2拮抗劑，諸如AZD-5069；
- GM-CSF抗體，諸如朗齊魯單抗(lenzilumab)；
- DNA依賴性蛋白激酶抑制劑，諸如MSC2490484A (尼瑟替布(nedisertib))、VX-984、AsiDNA (DT-01)；
- 蛋白激酶C (PKC)抑制劑，諸如LXS-196、索塔妥林(sotrastaurin)；
- 選擇性雌激素受體下調劑(SERD)，諸如氟維司群(fulvestrant；Faslodex®)、RG6046、RG6047、艾拉司群(elacestrant；RAD-1901)及AZD9496；
- 選擇性雌激素受體共價拮抗劑(SERCA)，諸如H3B-6545；
- 選擇性雄激素受體調節劑(SARM)，諸如GTX-024、達諾米德(darolutamide)；
- 轉型生長因子-β (TGF-β)激酶拮抗劑，諸如高倫替布(galunisertib)；
- 抗轉型生長因子-β (TGF-β)抗體，諸如LY3022859、NIS793、XOMA 089；
- 雙特異性抗體，諸如MM-141 (IGF-1/ErbB3)、MM-111 (Erb2/Erb3)、JNJ-64052781 (CD19/CD3)、PRS-343 (CD-137/HER2)、AFM26 (BCMA/CD16A)、JNJ-61186372 (EGFR/cMET)、AMG-211 (CEA/CD3)、RG7802 (CEA/CD3)、ERY-974 (CD3/GPC3)、范茨珠單抗(vancizumab)(血管生成素/VEGF)、PF-06671008 (鈣黏素/CD3)、AFM-13 (CD16/CD30)、APVO436 (CD123/CD3)、弗圖珠單抗(flotetuzumab)(CD123/CD3)、REGN-1979 (CD20/CD3)、MCLA-117 (CD3/CLEC12A)、MCLA-128 (HER2/HER3)、JNJ-0819、JNJ-7564 (CD3/血紅素)、AMG-757 (DLL3-CD3)、MGD-013 (PD-1/LAG-3)、AK-104 (CTLA-4/PD-1)、AMG-330 (CD33/CD3)、AMG-420 (BCMA/CD3)、BI-836880 (VEFG/ANG2)、JNJ-63709178 (CD123/CD3)、MGD-007 (CD3/gpA33)、MGD-009 (CD3/B7H3)；
- 突變型選擇性EGFR抑制劑，諸如PF-06747775、EGF816 (納紮替尼(nazartinib))、ASP8273、ACEA-0010、BI-1482694；
- 抗GITR (糖皮質激素誘發之腫瘤壞死因子受體相關蛋白)抗體，諸如MEDI1873、FPA-154、INCAGN-1876、TRX-518、BMS-986156、MK-1248及GWN-323；
- 抗δ樣蛋白質配位體3 (DDL3)抗體，諸如特西諾瓦單抗(rovalpituzumab tesirine)；
- 抗聚集素抗體，諸如AB-16B5；
- 抗蝶素-A4 (EFNA4)抗體，諸如PF-06647263；
- 抗RANKL抗體，諸如地諾單抗(denosumab)；
- 抗間皮素抗體，諸如BMS-986148、抗MSLN-MMAE；
- 抗磷酸鈉共轉運蛋白2B (NaP2B)抗體，諸如立伐土珠單抗(lifastuzumab)；
- 抗c-Met抗體，諸如ABBV-399；
- 腺苷A2A受體拮抗劑，諸如CPI-444、AZD-4635、普雷迪南(preladenant)、PBF-509；
- α-酮戊二酸去氫酶(KGDH)抑制劑，諸如CPI-613；
- XPO1抑制劑，諸如西林俄(selinexor)(KPT-330)；
- 異檸檬酸去氫酶2 (IDH2)抑制劑，諸如艾那尼布(enasidenib)(AG-221)；
- IDH1抑制劑，諸如AG-120及AG-881 (IDH1及IDH2)、IDH-305及BAY-1436032；
- 介白素-3受體(IL-3R)調節劑，諸如SL-401；
- 精胺酸脫亞胺酶刺激劑，諸如聚乙二醇精胺酸酶(ADI-PEG-20)；
- 抗體-藥物結合物，諸如MLN0264 (抗GCC，抗鳥苷酸環化酶C)、T-DM1 (曲妥珠單抗恩他新(trastuzumab emtansine)、Kadcycla)、米拉珠單抗(milatuzumab)-小紅莓(hCD74-DOX)、貝倫妥單抗維多汀(brentuximab vedotin)、DCDT2980S、保納珠單抗維多汀(polatuzumab vedotin)、SGN-CD70A、SGN-CD19A、英妥珠單抗奧米欣(inotuzumab ozogamicin)、洛瓦土珠單抗美登素(lorvotuzumab mertansine)、SAR3419、尹薩珠單抗戈維特坎(isactuzumab govitecan)、因福土單抗維多汀(enfortumab vedotin；ASG-22ME)、ASG-15ME、DS-8201 (曲妥珠單抗德魯特坎(trastuzumab deruxtecan))、225Ac-林妥珠單抗(225Ac-lintuzumab)、U3-1402、177Lu-特特拉克斯坦-特圖瑪(177Lu-tetraxetan-tetuloma)、替索圖單抗維多汀(tisotumab vedotin)、阿內圖單抗拉夫坦辛(anetumab ravtansine)、CX-2009、SAR-566658、W-0101、保納珠單抗維多汀(polatuzumab vedotin)及ABBV-085；
- 緊密連接蛋白-18抑制劑，諸如克迪西單抗(claudiximab)；
- β-連環蛋白抑制劑，諸如CWP-291；
- 抗CD73抗體，諸如MEDI-9447 (奧勒魯單抗(oleclumab))、CPX-006、IPH-53、BMS-986179；
- CD73拮抗劑，諸如AB-680、PSB-12379、PSB-12441、PSB-12425；
- CD39/CD73拮抗劑，諸如PBF-1662；
- 趨化因子受體2 (CCR)抑制劑，諸如PF-04136309、CCX-872及BMS-813160 (CCR2/CCR5)；
- 胸苷酸合成酶抑制劑，諸如ONX-0801；
- ALK/ROS1抑制劑，諸如勞拉替尼(lorlatinib)；
- 端粒酶抑制劑，諸如G007-LK；
- Mdm2 p53結合蛋白抑制劑，諸如CMG-097、HDM-201；
- c-PIM抑制劑，諸如PIM447；
- BRAF抑制劑，諸如達拉非尼(dabrafenib)、維羅非尼(vemurafenib)、恩拉菲尼(encorafenib)(LGX818)、PLX8394；
- 神經鞘胺醇激酶-2 (SK2)抑制劑，諸如Yeliva® (ABC294640)；
- 細胞週期抑制劑，諸如司美替尼(selumetinib)(MEK1/2)及沙帕他濱(sapacitabine)；
- AKT抑制劑，諸如MK-2206、伊巴替布(ipatasertib)、阿弗替布(afuresertib)、AZD5363及ARQ-092、卡瓦替布(capivasertib)、曲西立濱(triciribine)；
- 抗CTLA-4 (細胞毒性T淋巴細胞蛋白質-4)抑制劑，諸如曲美木單抗(tremelimumab)、AGEN-1884、BMS-986218；
- c-MET抑制劑，諸如AMG-337、薩沃替尼(savolitinib)、提瓦替尼(tivantinib)(ARQ-197)、卡普尼布(capmatinib)及特潑替尼(tepotinib)、ABT-700、AG213、AMG-208、JNJ-38877618 (OMO-1)、默萊替尼(merestinib)、HQP-8361；
- c-Met/VEGFR抑制劑，諸如BMS-817378、TAS-115；
- c-Met/RON抑制劑，諸如BMS-777607；
- BRAF/EGFR抑制劑，諸如BGB-283；
- bcr/abl抑制劑，諸如瑞巴替尼(rebastinib)、阿西尼布(asciminib)；
- MNK1/MNK2抑制劑，諸如eFT-508；
- mTOR抑制劑/細胞色素P450 3A4刺激劑，諸如TYME-88；
- 離胺酸特異性去甲基酶-1 (LSD1)抑制劑，諸如CC-90011；
- Pan-RAF抑制劑，諸如LY3009120、LXH254、TAK-580；
- Raf/MEK抑制劑，諸如RG7304；
- CSF1R/KIT及FLT3抑制劑，諸如派西尼布(pexidartinib) (PLX3397)；
- 激酶抑制劑，諸如凡德他尼；
- E選擇素拮抗劑，諸如GMI-1271；
- 分化誘導劑，諸如維甲酸；
- 表皮生長因子受體(EGFR)抑制劑，諸如奧希替尼(osimertinib) (AZD-9291)；
- 拓樸異構酶抑制劑，諸如小紅莓、道諾黴素、放線菌素D、京尼平苷(eniposide)、表柔比星、依託泊苷、伊達比星、伊立替康、米托蒽醌、匹蒽醌(pixantrone)、索布佐生(sobuzoxane)、拓朴替康、伊立替康、MM-398 (伊立替康脂質體)、沃薩洛辛(vosaroxin)及GPX-150、阿多比星(aldoxorubicin)、AR-67、瑪韋替尼(mavelertinib)、AST-2818、阿維替尼(avitinib；ACEA-0010)及伊洛福芬(irofulven；MGI-114)；
- 皮質類固醇，諸如可的松(cortisone)、地塞米松、氫化可的松、甲基潑尼龍、潑尼松、潑尼龍；
- 生長因子信號轉導激酶抑制劑；
- 核苷類似物，諸如DFP-10917；
- Axl抑制劑，諸如BGB-324 (貝西替尼(bemcentinib))、SLC-0211；
- BET抑制劑，諸如INCB-054329、INCB057643、TEN-010、AZD-5153、ABT-767、BMS-986158、CC-90010、GSK525762 (莫尼西布(molibresib))、NHWD-870、ODM-207、GSK-2820151、GSK-1210151A、ZBC246、ZBC260、ZEN3694、FT-1101、RG-6146、CC-90010、米韋西布(mivebresib)、BI-894999、PLX-2853、PLX-51107、CPI-0610、GS-5829；
- PARP抑制劑，諸如奧拉帕尼(olaparib)、蘆卡帕尼(veliparib)、維利帕尼(veliparib)、他拉帕尼(talazoparib)、ABT-767、BGB-290；
- 蛋白酶體抑制劑，諸如依薩佐米(ixazomib)、卡非佐米(carfilzomib)(Kyprolis®)、馬瑞佐米(marizomib)；
- 麩醯胺酸酶抑制劑，諸如CB-839；
- 疫苗，諸如肽疫苗TG-01 (RAS)、GALE-301、GALE-302、萊尼哌嗎-s (nelipepimut-s)、SurVaxM、DSP-7888、TPIV-200、PVX-410、VXL-100、DPX-E7、ISA-101、6MHP、OSE-2101、加利哌嗎-S (galinpepimut-S)、SVN53-67/M57-KLH、IMU-131；細菌載體疫苗，諸如CRS-207/GVAX、阿利莫金非洛巴克(axalimogene filolisbac) (ADXS11-001)；腺病毒載體疫苗，諸如那多拉金非拉維克(nadofaragene firadenovec)；自體Gp96疫苗；樹突狀細胞疫苗，諸如CVactm、斯塔賽爾-T (stapuldencel-T)、艾他賽爾-T (eltrapuldencel-T)、SL-701、BSK01TM、洛卡賽爾-T (rocapuldencel-T) (AGS-003)、DCVAC、CVactm
、斯塔賽爾-T、艾他賽爾-T、SL-701、BSK01TM
、ADXS31-142；溶瘤疫苗，諸如塔里穆尼拉赫韋克(talimogene laherparepvec)、派替莫金德瓦維克(pexastimogene devacirepvec)、GL-ONC1、MG1-MA3、小病毒H-1、ProstAtak、恩那希瑞(enadenotucirev)、MG1MA3、ASN-002 (TG-1042)；治療性疫苗，諸如CVAC-301、CMP-001、PF-06753512、VBI-1901、TG-4010、ProscaVax™；腫瘤細胞疫苗，諸如Vigil® (IND-14205)、Oncoquest-L疫苗；減毒活的重組型血清型1脊髓灰白質炎病毒疫苗，諸如PVS-RIPO；阿達洛德西莫林(Adagloxad simolenin)；MEDI-0457；DPV-001，一種腫瘤衍生之自噬小體增濃型癌症疫苗；RNA疫苗，諸如CV-9209、LV-305；DNA疫苗，諸如MEDI-0457、MVI-816、INO-5401；表現p53之經修飾之痘瘡病毒安卡拉(vaccinia virus Ankara)疫苗，諸如MVA-p53；DPX-Survivac；BriaVax™；GI-6301；GI-6207；GI-4000；
- 抗DLL4 (δ樣配位體4)抗體，諸如登西珠單抗(demcizumab)；
- STAT-3抑制劑，諸如那帕布新(napabucasin) (BBI-608)；
- ATPase p97抑制劑，諸如CB-5083；
- 平滑(SMO)受體抑制劑，諸如Odomzo® (索尼德吉(sonidegib)，先前為LDE-225)、LEQ506、維莫德吉(vismodegib)(GDC-0449)、BMS-833923、格萊德吉(glasdegib)(PF-04449913)、LY2940680及伊曲康唑(itraconazole)；
- 干擾素α配位體調節劑，諸如干擾素α-2b、干擾素α-2a生物類似物(Biogenomics)、羅派干擾素(ropeginterferon) α-2b (AOP-2014、P-1101、PEG IFN α-2b)、Multiferon(Alfanative、Viragen)、干擾素α 1b、Roferon-A (Canferon、Ro-25-3036)、干擾素α-2a後續生物製劑(Biosidus)(Inmutag、Inter 2A)、干擾素α-2b後繼生物製劑(Biosidus-Bioferon、Citopheron、Ganapar，Beijing Kawin Technology-Kaferon)、Alfaferone、聚乙二醇化干擾素α-1b、聚乙二醇化干擾素α-2b後續生物製劑(Amega)、重組型人類干擾素α-1b、重組型人類干擾素α-2a、重組型人類干擾素α-2b、維托珠單抗(veltuzumab)-IFNα 2b結合物、Dynavax (SD-101)及干擾素α-n1 (Humoferon、SM-10500、Sumiferon)；
- 干擾素γ配位體調節劑，諸如干擾素γ (OH-6000、奧格瑪100 (Ogamma 100))；
- IL-6受體調節劑，諸如托西利單抗(tocilizumab)、思圖昔單抗(siltuximab)、AS-101 (CB-06-02、IVX-Q-101)；
- 端粒酶調節劑，諸如特托莫肽(tertomotide) (GV-1001、HR-2802、Riavax)及伊美司他(imetelstat) (GRN-163、JNJ-63935937)；
- DNA甲基轉移酶抑制劑，諸如替莫唑胺(temozolomide) (CCRG-81045)、地西他濱(decitabine)、瓜達西汀(S-110、SGI-110)、KRX-0402、RX-3117、RRx-001及阿紮胞苷(azacitidine)；
- DNA旋轉酶抑制劑，諸如匹蒽醌及索布佐生；
- Bcl-2家族蛋白質抑制劑，諸如ABT-263、維奈托克(venetoclax)(ABT-199)、ABT-737及AT-101；
- Notch抑制劑，諸如LY3039478 (克尼斯塔(crenigacestat))、他瑞妥單抗(tarextumab)(抗Notch2/3)、BMS-906024；
- 抗肌肉抑制素抑制劑，諸如蘭多單抗(landogrozumab)；
- 玻尿酸酶刺激劑，諸如PEGPH-20；
- Wnt路徑抑制劑，諸如SM-04755、PRI-724、WNT-974；
- γ-分泌酶抑制劑，諸如F-03084014、MK-0752、RO-4929097；
- Grb-2 (生長因子受體結合蛋白-2)抑制劑，諸如BP1001；
- TRAIL路徑誘導化合物，諸如ONC201、ABBV-621；
- 局部黏著斑激酶抑制劑，諸如VS-4718、迪法替尼(defactinib)、GSK2256098；
- 刺蝟抑制劑，諸如薩瑞德吉(saridegib)、索尼德吉(LDE225)、格拉德吉(glasdegib)及維莫德吉；
- 極光激酶抑制劑，諸如阿立塞替(alisertib) (MLN-8237)及AZD-2811、AMG-900、巴塞替尼(barasertib)、ENMD-2076；
- HSPB1調節劑(熱休克蛋白質27，HSP27)，諸如溴夫定(brivudine)、阿帕托森(apatorsen)；
-ATR抑制劑，諸如BAY-937、AZD6738、AZD6783、VX-803、VX-970 (貝佐替布(berzosertib))及VX-970；
- mTOR抑制劑，諸如賽泮替布(sapanisertib)及維塞替布(vistusertib) (AZD2014)、ME-344；
- mTOR/PI3K抑制劑，諸如吉達力絲(gedatolisib)、GSK2141795、奧米力絲(omipalisib)、RG6114；
- Hsp90抑制劑，諸如AUY922、奧那勒斯(onalespib) (AT13387)、SNX-2112、SNX5422；
- 鼠類雙重微小(mdm2)癌基因抑制劑，諸如DS-3032b、RG7775、AMG-232、HDM201及伊達努素(idasanutlin)(RG7388)；
- CD137促效劑，諸如烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab；PF-05082566)；
- STING促效劑，諸如ADU-S100 (MIW-815)、SB-11285、MK-1454、SR-8291、AdVCA0848、GSK-532、SYN-STING、MSA-1、SR-8291；
- FGFR抑制劑，諸如FGF-401、INCB-054828、BAY-1163877、AZD4547、JNJ-42756493、LY2874455、Debio-1347；
- 脂肪酸合成酶(FASN)抑制劑，諸如TVB-2640；
- 抗KIR單株抗體，諸如利瑞路單抗(lirilumab) (IPH-2102)、IPH-4102；
- 抗原CD19抑制劑，諸如MOR208、MEDI-551、AFM-11、因厄比利珠單抗(inebilizumab)；
- CD44結合劑，諸如A6；
- 蛋白磷酸酶2A (PP2A)抑制劑，諸如LB-100；
- CYP17抑制劑，諸如西維諾尼(seviteronel)(VT-464)、ASN-001、ODM-204、CFG920、乙酸阿比特龍(abiraterone acetate)；
- RXR促效劑，諸如IRX4204；
- 刺蝟/平滑(hh/Smo)拮抗劑，諸如塔拉德吉(taladegib)、帕替德吉(patidegib)；
- 補體C3調節劑，諸如因普拉姆PGG (Imprime PGG)；
- IL-15促效劑，諸如ALT-803、NKTR-255和hetIL-15；
- EZH2 (zeste基因增強子同源物2)抑制劑，諸如塔澤斯塔(tazemetostat)、CPI-1205、GSK-2816126；
- 溶瘤病毒，諸如派拉瑞普(pelareorep)、CG-0070、MV-NIS療法、HSV-1716、DS-1647、VCN-01、ONCOS-102、TBI-1401、塔沙圖瑞(tasadenoturev) (DNX-2401)、沃西金阿米維克(vocimagene amiretrorepvec)、RP-1、CVA21、Celyvir、LOAd-703、OBP-301；
- DOT1L (組蛋白甲基轉移酶)抑制劑，諸如皮諾斯塔(pinometostat) (EPZ-5676)；
- 毒素，諸如霍亂毒素(Cholera toxin)、蓖麻毒素、綠膿桿菌外毒素(Pseudomonas exotoxin)、百日咳博德氏菌(Bordetella pertussis)腺苷酸環化酶毒素、白喉毒素及凋亡蛋白酶活化劑；
- DNA質體，諸如BC-819；
- PLK 1、2及3之PLK抑制劑，諸如沃納塞替(volasertib)(PLK1)；
- WEE1抑制劑，諸如AZD1775 (阿達替布(adavosertib))；
- ρ激酶(ROCK)抑制劑，諸如AT13148、KD025；
- ERK抑制劑，諸如GDC-0994、LY3214996、MK-8353；
- IAP抑制劑，諸如ASTX660、debio-1143、比林納潘特、APG-1387、LCL-161；
- RNA聚合酶抑制劑，諸如魯尼特丁(lurbinectedin)(PM-1183)、CX-5461；
- 微管蛋白抑制劑，諸如PM-184、BAL-101553 (利沙布林(lisavanbulin))及OXI-4503、弗拉帕欣(fluorapacin)(AC-0001)、普拉布林(plinabulin)；
- 類鐸受體4 (TL4)促效劑，諸如G100、GSK1795091及PEPA-10；
- 延伸因子1α2抑制劑，諸如普替德新(plitidepsin)；
- CD95抑制劑，諸如APG-101、APO-010、阿蘇賽普(asunercept)；
- WT1抑制劑，諸如DSP-7888；
- 剪接因子3B亞單元1 (SF3B1)抑制劑，諸如H3B-8800；
- PDGFR α/KIT突變體特異性抑制劑，諸如BLU-285；
- SHP-2抑制劑，諸如TNO155 (SHP-099)、RMC-4550；以及
- 類視黃素Z受體γ (RORγ)促效劑，諸如LYC-55716。
在一些實施例中，本文中提供治療或預防患有過度增生性病症或癌症或處於患過度增生性病症或癌症之風險下之人類或動物的過度增生性病症或癌症的方法，其包含向人類或動物投與治療有效量之如本文中所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如一種、兩種、三種、一或兩種或一至三種)選自由以下組成之群之額外治療劑的組合：細胞凋亡信號調節激酶(ASK)抑制劑；布魯東氏酪胺酸激酶(BTK)抑制劑；分化簇47 (CD47)抑制劑；週期素依賴型激酶(CDK)抑制劑；盤狀結構域受體(DDR)抑制劑；組蛋白去乙醯基酶(HDAC)抑制劑；吲哚胺-吡咯-2,3-雙加氧酶(IDO1)抑制劑；Janus激酶(JAK)抑制劑；離胺醯氧化酶樣蛋白質(LOXL)抑制劑；基質金屬蛋白酶(MMP)抑制劑；有絲分裂原活化蛋白激酶(MEK)抑制劑；磷脂醯肌醇3-激酶(PI3K)抑制劑；脾酪胺酸激酶(SYK)抑制劑；類鐸受體8 (TLR8)抑制劑；類鐸受體9 (TLR9)抑制劑；酪胺酸激酶抑制劑(TKI)及其任何組合或其醫藥學上可接受之鹽。非限制性實例包含：
-細胞凋亡信號調節激酶 (ASK) 抑制劑
：ASK抑制劑包括ASK1抑制劑。ASK1抑制劑之實例包括(但不限於)WO 2011/008709 (Gilead Sciences)及WO 2013/112741 (Gilead Sciences)中描述之抑制劑；
-布魯 東 氏酪胺酸激酶 (BTK) 抑制劑
：BTK抑制劑之實例包括(但不限於) (S)-6-胺基-9-(1-(丁-2-炔醯基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡替尼(ACP-196)、BGB-3111、CB988、HM71224、依魯替尼、M-2951 (伊沃替尼(evobrutinib))、M7583、替拉替尼(tirabrutinib)(ONO-4059)、PRN-1008、司培替尼(CC-292)、TAK-020、維卡替尼(vecabrutinib)、ARQ-531、SHR-1459、DTRMWXHS-12、TAS-5315；
-分化簇 47 (CD47) 抑制劑 ：
CD47抑制劑之實例包括(但不限於)抗CD47 mAb (Vx-1004)、抗人類CD47 mAb (CNTO-7108)、CC-90002、CC-90002-ST-001、人類化抗CD47抗體(Hu5F9-G4)、NI-1701、NI-1801、RCT-1938及TTI-621；
-週期素依賴型激酶 (CDK) 抑制劑 ：
CDK抑制劑包括CDK 1、2、3、4、6、7及9之抑制劑，諸如阿貝力布(abemaciclib)、阿昔迪布(alvocidib)(HMR-1275、夫拉平度(flavopiridol))、AT-7519、戴那西里(dinaciclib)、艾博蘭斯(ibrance)、FLX-925、LEE001、帕泊昔布(palbociclib)、瑞博西尼(ribociclib)、瑞戈替布(rigosertib)、西林俄(selinexor)、UCN-01、SY1365、CT-7001、SY-1365、G1T38、米西西尼(milciclib)、曲拉西尼(trilaciclib)及TG-02；
-盤狀結構域受體 (DDR) 抑制劑：
DDR抑制劑包括DDR1及/或DDR2之抑制劑。DDR抑制劑之實例包括(但不限於) WO 2014/047624 (Gilead Sciences)、US 2009-0142345 (Takeda Pharmaceutical)、US 2011-0287011 (Oncomed Pharmaceuticals)、WO 2013/027802 (Chugai Pharmaceutical)及WO 2013/034933 (Imperial Innovations)中所揭示之抑制劑；
-組蛋白去乙醯基酶 (HDAC) 抑制劑：
HDAC抑制劑之實例包括(但不限於)阿貝司他(abexinostat)、ACY-241、AR-42、BEBT-908、貝林諾他(belinostat)、CKD-581、CS-055 (HBI-8000)、CUDC-907 (非米斯他(fimepinostat))、恩替諾特(entinostat)、吉韋諾他(givinostat)、莫塞諾他(mocetinostat)、帕比諾他(panobinostat)、普拉諾他(pracinostat)、奎西諾他(quisinostat)(JNJ-26481585)、雷米諾他、瑞科諾他(ricolinostat)、SHP-141、丙戊酸(VAL-001)、伏立諾他、替諾斯汀(tinostamustine)、雷米斯特(remetinostat)、恩替諾特；
-吲哚胺 - 吡咯 -2,3- 雙加氧酶 (IDO1) 抑制劑：
IDO1抑制劑之實例包括但不限於BLV-0801、艾帕斯塔、F-001287、GBV-1012、GBV-1028、GDC-0919、因多莫得、NKTR-218、基於NLG-919之疫苗、PF-06840003、哌喃並萘醌衍生物(SN-35837)、雷米諾他、SBLK-200802、BMS-986205及shIDO-ST、EOS-200271、KHK-2455、LY-3381916；
-Janus 激酶 (JAK) 抑制劑：
JAK抑制劑抑制JAK1、JAK2及/或JAK3。JAK抑制劑之實例包括(但不限於) AT9283、AZD1480、巴瑞替尼(baricitinib)、BMS-911543、非達替尼(fedratinib)、非戈替尼(filgotinib)(GLPG0634)、甘多替尼(gandotinib)(LY2784544)、INCB039110 (itacitinib)、來他替尼(lestaurtinib)、莫羅替尼(momelotinib)(CYT0387)、NS-018、帕瑞替尼(pacritinib)(SB1518)、皮非替尼(peficitinib)(ASP015K)、盧佐替尼(ruxolitinib)、托法替尼(tofacitinib)(先前為塔索替尼(tasocitinib))、INCB052793及XL019；
-離胺醯氧化酶樣蛋白質 (LOXL) 抑制劑 ：
LOXL抑制劑包括LOXL1、LOXL2、LOXL3、LOXL4及/或LOXL5之抑制劑。LOXL抑制劑之實例包括(但不限於) WO 2009/017833 (Arresto Biosciences)中所述之抗體。LOXL2 抑制劑之實例包括但不限於 WO 2009/017833 (Arresto Biosciences) 、 WO 2009/035791 (Arresto Biosciences) 及 WO 2011/097513 (Gilead Biologics) 中所述之抗體。
-基質金屬蛋白酶 (MMP) 抑制劑：
MMP抑制劑包括MMP1至10之抑制劑。MMP9抑制劑之實例包括(但不限於)馬立馬司他(marimastat)(BB-2516)、西馬司他(cipemastat)(Ro 32-3555)、GS-5745 (安德西單抗(andecaliximab))及WO 2012/027721 (Gilead Biologics)中描述之抑制劑；
-有絲分裂原活化蛋白激酶 (MEK) 抑制劑：
MEK抑制劑包括安奎諾爾(antroquinonol)、畢尼替尼(binimetinib)、考比替尼(cobimetinib) (GDC-0973、XL-518)、MT-144、司美替尼(AZD6244)、索拉非尼(sorafenib)、曲美替尼(trametinib) (GSK1120212)、阿瑟替布(uprosertib) +曲美替尼、PD-0325901、皮馬瑟替(pimasertib)、LTT462、AS703988、CC-90003、瑞法美替尼(refametinib)；
-磷脂醯肌醇 3- 激酶 (PI3K) 抑制劑：
PI3K抑制劑包括PI3Kγ、PI3Kδ、PI3Kβ、PI3Kα及/或泛PI3K之抑制劑。PI3K抑制劑之實例包括(但不限於) ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕昔布(BKM120)、BYL719 (阿培昔布)、CH5132799、考班昔布(BAY 80-6946)、杜維昔布、GDC-0032、GDC-0077、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾德昔布(Zydelig®
)、INCB50465、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞戈替布、RP5090、RP6530、SRX3177、泰尼昔布、TG100115、TGR-1202 (溫布昔布(umbralisib))、TGX221、WX-037、X-339、X-414、XL147 (SAR245408)、XL499、XL756、渥曼青黴素(wortmannin)、ZSTK474以及WO 2005/113556 (ICOS)、WO 2013/052699 (Gilead Calistoga)、WO 2013/116562 (Gilead Calistoga)、WO 2014/100765 (Gilead Calistoga)、WO 2014/100767 (Gilead Calistoga)及WO 2014/201409 (Gilead Sciences)中描述之化合物；
-脾酪胺酸激酶 (SYK) 抑制劑 ：
SYK抑制劑之實例包括(但不限於) 6-(1H-吲唑-6-基)-N-(4-(N-嗎啉基)苯基)咪唑并[1,2-a]吡嗪-8-胺、BAY-61-3606、賽度替尼(cerdulatinib) (PRT-062607)、恩妥替尼(entospletinib)、福他替尼(fostamatinib)(R788)、HMPL-523、NVP-QAB 205 AA、R112、R343、塔馬替尼(tamatinib)(R406)以及US 8450321 (Gilead Connecticut)中所描述之抑制劑及U.S. 2015/0175616中所描述之抑制劑；
-類鐸 受體 8 (TLR8) 抑制劑：
TLR8抑制劑之實例包括(但不限於) E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫特、雷西莫特、VTX-1463及VTX-763；
-類鐸 受體 9 (TLR9) 抑制劑：
TLR9抑制劑之實例包括(但不限於) AST-008、IMO-2055、IMO-2125、利福莫特(lefitolimod)、利騰莫特、MGN-1601及PUL-042；及
-酪胺酸 - 激酶抑制劑 (TKI) ：
TKI可靶向表皮生長因子受體(EGFR)以及纖維母細胞生長因子(FGF)、血小板衍生生長因子(PDGF)及血管內皮生長因子(VEGF)之受體。TKI之實例包括(但不限於)阿法替尼(afatinib)、ARQ-087 (德贊替尼(derazantinib))、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、布加替尼(brigatinib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克諾拉尼(crenolanib)、達可替尼(dacomitinib)、達沙替尼(dasatinib)、多韋替尼(dovitinib)、E-6201、厄達替尼(erdafitinib)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、吉列替尼(gilteritinib)(ASP-2215)、FP-1039、HM61713、埃克替尼(icotinib)、伊馬替尼(imatinib)、KX2-391 (Src)、拉帕替尼(lapatinib)、來他替尼(lestaurtinib)、樂伐替尼(lenvatinib)、米哚妥林(midostaurin)、尼達尼布(nintedanib)、ODM-203、奧希替尼(osimertinib)(AZD-9291)、普納替尼(ponatinib)、波齊奧替尼(poziotinib)、喹雜替尼(quizartinib)、拉多替尼(radotinib)、羅西替尼(rociletinib)、索凡替尼(sulfatinib)(HMPL-012)、舒尼替尼(sunitinib)、替沃尼布(tivoanib)及TH-4000、MEDI-575 (抗PDGFR抗體)。
如本文所使用之術語「化學治療劑(chemotherapeutic agent/chemotherapeutic)」(或在用化學治療劑治療之情況下之「化學療法」)意在涵蓋適用於治療癌症之任何非蛋白質(亦即非肽)化合物。化學治療劑之實例包括(但不限於)：烷基化劑，諸如噻替派及環磷醯胺(CYTOXAN®
)；磺酸烷基酯，諸如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan)；氮丙啶，諸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)及烏瑞替派(uredepa)；乙烯亞胺及甲基三聚氰胺，包括六甲蜜胺、三伸乙基三聚氰胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三米蜜胺(trimemylolomelamine)；乙醯精寧(acetogenin)，尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone)；喜樹鹼，包括合成類似物拓朴替康；苔蘚蟲素、卡利他汀(callystatin)；CC-1065，包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物；念珠藻素，尤其念珠藻素1及念珠藻素8；海兔毒素(dolastatin)；倍癌黴素(duocarmycin)，包括合成類似物KW-2189及CBI-TMI；艾榴塞洛素(eleutherobin)；5-氮胞苷；水鬼蕉鹼(pancratistatin)；沙考地汀(sarcodictyin)；海綿抑素；氮芥類，諸如苯丁酸氮芥、萘氮芥、環磷醯胺、葡磷醯胺、伊沃醯胺(evofosfamide)、苯達莫司汀(bendamustine)、雌莫司汀(estramustine)、異環磷醯胺、氮芥、氧化氮芥鹽酸鹽、美法侖、新恩比興(novembichin)、芬司特瑞(phenesterine)、潑尼莫司汀(prednimustine)、曲洛磷胺(trofosfamide)及尿嘧啶氮芥；亞硝基脲，諸如卡莫司汀、氯脲黴素、福莫司汀(foremustine)、洛莫司汀、尼莫司汀(nimustine)及雷莫司汀(ranimustine)；抗生素，諸如烯二炔抗生素(例如卡奇黴素(calicheamicin)，尤其卡奇黴素γII及卡奇黴素φI1)、達內黴素(dynemicin) (包括達內黴素A)、雙膦酸鹽(諸如氯屈膦酸鹽)、埃斯培拉黴素(esperamicin)、新抑癌蛋白發色團及相關色蛋白烯二炔抗生素色素體、阿克拉黴素(aclacinomycin)、放線菌素、安麯黴素(authramycin)、偶氮絲胺酸、博萊黴素、放線菌素C、卡拉比辛(carabicin)、卡尼米辛(carrninomycin)、嗜癌素、色黴素、放線菌素D、道諾黴素、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、小紅莓(包括N-嗎啉基-小紅莓、氰基-N-嗎啉基-小紅莓、2-吡咯啉基-小紅莓及去氧小紅莓)、表柔比星、依索比星(esorubicin)、艾達黴素、麻西羅黴素(marcellomycin)、絲裂黴素(諸如絲裂黴素C)、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非羅黴素(porfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲黴素、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)及佐柔比星(zorubicin)；抗代謝物，諸如甲胺喋呤及5-氟尿嘧啶(5-FU)；葉酸類似物，諸如迪莫林(demopterin)、甲胺喋呤、蝶羅呤(pteropterin)及曲美沙特(trimetrexate)；嘌呤類似物，諸如氟達拉濱、6-巰基嘌呤、硫咪嘌呤及硫鳥嘌呤；嘧啶類似物，諸如安西他濱(ancitabine)、阿紮胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、雙去氧尿苷、去氧氟尿苷、依諾他濱(enocitabine)及氟尿苷；雄激素，諸如卡魯睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇、美雄烷及睾內酯；抗腎上腺，諸如胺魯米特、米托坦及曲洛司坦(trilostane)；葉酸補充劑，諸如亞葉酸；放射性治療劑，諸如鐳-223；新月毒素(trichothecenes)，尤其T-2毒素、弗納庫林A (verracurin A)、桿孢菌素A及蛇形菌素；類紫杉醇，諸如紫杉醇(TAXOL®
)、阿布拉生(abraxane)、歐洲紫杉醇(TAXOTERE®
)、卡巴他賽(cabazitaxel)、BIND-014、替司他賽(tesetaxel)；鉑類似物，諸如順鉑及卡鉑、NC-6004奈鉑；乙醯葡醛酯；醛磷醯胺糖苷；胺基乙醯丙酸；恩尿嘧啶(eniluracil)；安吖啶；赫布西爾(hestrabucil)；比生群(bisantrene)；艾達曲克(edatraxate)；得弗伐胺(defofamine)；秋水仙鹼(demecolcine)；地吖醌(diaziquone)；艾弗欣(elformthine)；依利醋銨(elliptinium acetate)；埃坡黴素(epothilone)；依託格魯(etoglucid)；硝酸鎵；羥基脲；磨菇多糖；甲醯四氫葉酸；氯尼達明(lonidamine)；類美登素，諸如美登素及安絲菌素(ansamitocins)；丙脒腙(mitoguazone)；米托蒽醌；莫哌達醇(mopidamol)；二胺硝吖啶；噴司他汀；苯來美特(phenamet)；吡柔比星(pirarubicin)；洛索蒽醌(losoxantrone)；氟嘧啶；亞葉酸；鬼臼酸；2-乙基醯肼；丙卡巴肼；多醣-K (PSK)；雷佐生(razoxane)；根瘤菌素；西佐糖(sizofiran)；螺旋鍺；細交鏈孢菌酮酸；曲貝替定(trabectedin)、三亞胺醌；2,2',2''-特洛米安(2,2',2''-tricUorotriemylamine)；胺基甲酸酯；長春地辛(vindesine)；達卡巴嗪；甘露醇氮芥；二溴甘露醇；二溴衛矛醇；哌泊溴烷(pipobroman)；加西托星(gacytosine)；阿拉伯糖苷(「Ara-C」)；環磷醯胺；賽派塔(thiopeta)；苯丁酸氮芥；吉西他濱(GEMZAR®
)；6-硫代鳥嘌呤；巰基嘌呤；甲胺喋呤；長春花鹼；鉑；依託泊苷(VP-16)；異環磷醯胺；米托蒽醌；長春新鹼；長春瑞濱(vinorelbine) (NAVELBINE®
)；諾凡特龍(novantrone)；替尼泊苷；依達曲沙；道諾黴素；胺基喋呤；希羅達(xeoloda)；伊班膦酸鹽(ibandronate)；CPT-11；拓樸異構酶抑制劑RFS 2000；二氟甲基鳥胺酸(DFMO)；類視黃素，諸如視黃酸；卡培他濱；NUC-1031；FOLFIRI (氟尿嘧啶、甲醯四氫葉酸及伊立替康)；以及以上物質中之任一者之醫藥學上可接受之鹽、酸或衍生物。
「化學治療劑」之定義亦包括抗激素劑，諸如用以調節或抑制對腫瘤之激素作用之抗雌激素及選擇性雌激素受體調節劑(SERM)、芳香酶抑制劑、抗雄激素及以上物質中之任一者之醫藥學上可接受之鹽、酸或衍生物。抗激素劑
抗雌激素及SERM之實例包括例如他莫昔芬(包括NOLVADEXTM
)、雷諾昔芬、曲洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(FARESTON®
)。
芳香酶抑制劑調節腎上腺中之雌激素產生。實例包括4(5)-咪唑、胺魯米特、乙酸甲地孕酮(MEGACE®
)、依西美坦(exemestane)、福美司坦(formestane)、法屈唑(fadrozole)、伏羅唑(vorozole；RIVISOR®
)、來曲唑(FEMARA®
)及阿那曲唑(ARIMIDEX®
)。
抗雄激素之實例包括阿帕魯胺(apalutamide)、阿比特龍、恩雜魯胺(enzalutamide)、氟他胺(flutamide)、加利特隆(galeterone)、尼魯胺、比卡魯胺、亮丙立德(leuprolide)、戈舍瑞林、ODM-201、APC-100、ODM-204。
孕酮受體拮抗劑之實例包括奧那司酮。抗血管生成劑
抗血管生成劑包括(但不限於)類視黃素酸及其衍生物、2-甲氧雌二醇、ANGIOSTATIN®
、ENDOSTATIN®
、瑞戈非尼(regorafenib)、尼庫拉布(necuparanib)、蘇拉明(suramin)、角鯊胺(squalamine)、金屬蛋白酶-1之組織抑制劑、金屬蛋白酶-2之組織抑制劑、纖維蛋白溶酶原活化物抑制劑-1、纖維蛋白溶酶原活化物抑制劑-2、軟骨衍生之抑制劑、紫杉醇(白蛋白結合型紫杉醇)、血小板因子4、硫酸魚精蛋白(鯡精蛋白)、硫酸鹽化幾丁質衍生物(由雪蟹殼製備)、硫酸鹽化多醣肽聚醣複合物(sp-pg)、星形孢菌素、基質代謝調節劑(包括脯胺酸類似物，諸如l-氮雜環丁烷-2-甲酸(LACA)、順羥基脯胺酸、d,I-3,4-去氫脯胺酸、硫脯胺酸)、α,α'-二吡啶基、β-胺基丙腈反丁烯二酸鹽、4-丙基-5-(4-吡啶基)-2(3h)-噁唑酮、甲胺喋呤、米托蒽醌、肝素、干擾素、2巨球蛋白-血清、金屬蛋白酶-3之雞抑制劑(ChIMP-3)、胰凝乳蛋白酶抑制劑(chymostatin)、十四硫酸β-環糊精、依匹黴素(eponemycin)、菸黴素(fumagillin)、硫代蘋果酸金鈉、d-青黴胺、β-1-抗膠原酶-血清、α-2-抗纖維蛋白溶酶、比生群、氯苯紮利二鈉(lobenzarit disodium)、n-2-羧基苯基-4-氯胺基苯甲酸二鈉或「CCA」、沙力度胺(thalidomide)、血管生成抑制性類固醇、羧基胺基咪唑、金屬蛋白酶抑制劑(諸如BB-94)、S100A9之抑制劑(諸如他喹莫德(tasquinimod))。其他抗血管生成劑包括抗體，較佳地針對以下此等血管生成生長因子之單株抗體：β-FGF、α-FGF、FGF-5、VEGF同功異型物、VEGF-C、HGF/SF及Ang-1/Ang-2。抗纖維化劑
抗纖維化劑包括但不限於諸如β-胺基丙腈(BAPN)之類化合物，以及關於離胺醯氧化酶抑制劑及其在治療與膠原蛋白異常沈積相關之疾病及病狀中之用途的US 4965288及關於抑制LOX以治療各種病理性纖維化病況之化合物的US 4997854中所揭示之化合物，該等文獻以引用之方式併入本文中。其他例示性抑制劑描述於關於諸如2-異丁基-3-氟-烯丙胺、2-異丁基-3-氯-烯丙胺或2-異丁基-3-溴-烯丙胺之化合物之US 4943593；關於2-(1-萘基氧基甲基)-3-氟烯丙胺之US 5021456、US 5059714、US 5120764、US 5182297、US 5252608；及US 2004-0248871中，皆以引用之方式併入本文中。
例示性抗纖維化劑亦包括與離胺醯氧化酶之活性位點之羰基反應的一級胺，且更尤其在結合羰基之後生成共振穩定化產物的一級胺，諸如以下一級胺：乙二胺(emylenemamine)、肼、苯肼及其衍生物；胺脲及脲衍生物；胺基腈，諸如BAPN或2-硝基乙胺；不飽和或飽和鹵胺，諸如2-溴基-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺及對鹵基苄胺；及硒基高半胱胺酸內酯。
其他抗纖維化劑為滲透或不滲透細胞之銅螯合劑。例示性化合物包括阻斷由離胺醯氧化酶使離胺醯殘基及羥離胺醯殘基氧化脫胺而產生醛衍生物的間接抑制劑。實例包括硫醇胺(尤其D-青黴胺)及其類似物，諸如2-胺基-5-巰基-5-甲基己酸、D-2-胺基-3-甲基-3-((2-乙醯胺基乙基)二硫基)丁酸、對2-胺基-3-甲基-3-((2-胺基乙基)二硫基)丁酸、硫化鈉-4-((對1-二甲基-2-胺基-2-羧基乙基)二硫基)丁烷、2-乙醯胺基乙基-2-乙醯胺基乙硫醇磺酸鹽及三水合鈉-4-巰基丁烷亞磺酸鹽。免疫治療劑
免疫治療劑包括且不限於適用於治療個體之治療性抗體。治療性抗體之一些實例包括阿巴伏單抗(abagovomab)、ABP-980、阿達木單抗(adecatumumab)、阿夫妥珠單抗(afutuzumab)、阿侖單抗、阿妥莫單抗(altumomab)、阿瑪西單抗(amatuximab)、麻安莫單抗(anatumomab)、阿西莫單抗(arcitumomab)、巴維昔單抗、貝妥莫單抗(bectumomab)、貝伐單抗(bevacizumab)、比伐珠單抗(bivatuzumab)、布林莫單抗(blinatumomab)、貝倫妥單抗、坎妥珠單抗(cantuzumab)、卡托莫西單抗(catumaxomab)、CC49、西妥昔單抗、西他土珠單抗(citatuzumab)、西妥木單抗(cixutumumab)、昔瓦土單抗(clivatuzumab)、康納木單抗(conatumumab)、達西珠單抗(dacetuzumab)、達洛圖單抗(dalotuzumab)、達雷木單抗(daratumumab)、地莫單抗(detumomab)、迪奴圖單抗(dinutuximab)、德珠單抗(drozitumab)、杜里土單抗(duligotumab)、杜西吉土單抗(dusigitumab)、依美昔單抗(ecromeximab)、埃羅妥珠單抗(elotuzumab)、艾米貝珠單抗(emibetuzumab)、恩斯土昔單抗(ensituximab)、鄂托默單抗(ertumaxomab)、埃達珠單抗(etaracizumab)、伐吐珠單抗(farletuzumab)、費拉妥珠單抗(ficlatuzumab)、非吉單抗(figitumumab)、法蘭土單抗(flanvotumab)、弗妥昔單抗(futuximab)、加尼圖單抗(ganitumab)、吉妥珠單抗、吉瑞昔單抗(girentuximab)、格雷巴土木單抗(glembatumumab)、布突默單抗(ibritumomab)、伊戈伏單抗(igovomab)、伊姆加土珠單抗(imgatuzumab)、因達西單抗(indatuximab)、英妥珠單抗(inotuzumab)、英妥木單抗(intetumumab)、伊派利單抗(YERVOY®、MDX-010、BMS-734016及MDX-101)、伊妥木單抗(iratumumab)、拉貝珠單抗、來沙木單抗(lexatumumab)、林妥珠單抗、洛瓦土珠單抗、魯卡木單抗(lucatumumab)、馬帕木單抗、馬妥珠單抗、米拉珠單抗、明瑞莫單抗(minretumomab)、米妥莫單抗(mitumomab)、莫格利珠單抗(mogamulizumab)、莫昔土莫單抗(moxetumomab)、那莫單抗(naptumomab)、納納土單抗(narnatumab)、萊西單抗、尼妥珠單抗、諾非單抗(nofetumomab)、OBI-833、奧比珠單抗、奧卡拉珠單抗(ocaratuzumab)、奧伐木單抗(ofatumumab)、奧拉單抗(olaratumab)、奧那組單抗(onartuzumab)、奧普珠單抗(oportuzumab)、奧戈伏單抗(oregovomab)、帕尼單抗、帕薩珠單抗(parsatuzumab)、帕蘇多托克斯(pasudotox)、帕特里土單抗(patritumab)、潘妥莫單抗(pemtumomab)、帕妥珠單抗、平妥單抗(pintumomab)、普托木單抗(pritumumab)、拉克莫單抗(racotumomab)、拉德瑞單抗(radretumab)、雷莫蘆單抗(ramucirumab) (Cyramza®)、里樂木單抗(rilotumumab)、利妥昔單抗、羅妥木單抗(robatumumab)、薩馬里珠單抗(samalizumab)、沙妥莫單抗(satumomab)、西羅珠單抗(sibrotuzumab)、司妥昔單抗、索利托單抗(solitomab)、辛圖珠單抗(simtuzumab)、他卡珠單抗(tacatuzumab)、他普莫單抗(taplitumomab)、泰納莫單抗(tenatumomab)、泰普洛單抗(teprotumumab)、替加珠單抗(tigatuzumab)、托西莫單抗(tositumomab)、曲妥珠單抗、土庫珠單抗(tucotuzumab)、烏妥昔單抗(ublituximab)、維托珠單抗、沃爾希珠單抗(vorsetuzumab)、伏妥莫單抗(votumumab)、紮魯姆單抗(zalutumumab)及3F8。利妥昔單抗可用於治療和緩性B細胞癌症，其包括邊緣區淋巴瘤、WM、CLL及小淋巴細胞性淋巴瘤。利妥昔單抗與化學治療劑之組合尤其有效。
例示性治療性抗體可進一步用放射性同位素粒子，諸如銦-111、釔-90 (90Y-昔瓦土單抗)或碘-131標記或與其組合。癌症基因療法及細胞療法
癌症基因療法及細胞療法包括：將正常基因插入癌細胞中以替換突變或改變之基因；用於使突變基因沉默之基因修飾；用於直接殺死癌細胞之基因方法；包括輸注經設計以替換個體大部分自身免疫系統以增強針對癌細胞之免疫反應，或活化個體之自身免疫系統(T細胞或自然殺手細胞)以殺死癌細胞，或發現且殺死癌細胞的免疫細胞；用於改變細胞活性以進一步改變針對癌症之內源性免疫反應性的基因方法。基因編輯器
基因組編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統。CAR-T 細胞療法 及 TCR-T 細胞 療法
CAR-T細胞療法包括經工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞群體，其中CAR包含腫瘤抗原結合域。免疫效應細胞為T細胞或NK細胞。TCR-T細胞療法包括經工程改造以靶向腫瘤細胞表面上之腫瘤衍生肽之TCR-T細胞。細胞可為自體或同種異體的。
在一些實施例中，CAR包含抗原結合域、跨膜結構域及細胞內信號傳導結構域。
在一些實施例中，細胞內結構域包含初級信號傳導結構域、共刺激結構域或初級信號傳導結構域與共刺激結構域兩者。
在一些實施例中，初級信號傳導結構域包含選自由以下組成之群之一或多種蛋白質的功能信號傳導域：CD3 ζ、CD3 γ、CD3 δ、CD3 ε、共同FcR γ (FCERIG)、FcR β (Fc ε Rlb)、CD79a、CD79b、FcγRIIa、DAP10及DAP12。
在一些實施例中，共刺激結構域包含選自由以下組成之群之一或多種蛋白質的功能結構域：CD27、CD28、4-1BB (CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴細胞功能相關抗原-1 (LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、與CD83特異性結合之配位體、CDS、ICAM-1、GITR、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRF1)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1 ld、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 1c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46及NKG2D。
在一些實施例中，跨膜結構域包含選自由以下組成之群之蛋白質的跨膜結構域：T細胞受體之α、β或ζ鏈、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、LFA-1 (CD1 la、CD18)、ICOS (CD278)、4-1BB (CD137)、GITR、CD40、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRF1)、CD160、CD19、IL2Rβ、IL2Rγ、IL7R u、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1 ld、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D及NKG2C。
在一些實施例中，抗原結合域結合腫瘤抗原。
在一些實施例中，腫瘤抗原係選自由以下組成之群：CD19；CD123；CD22；CD30；CD171；CS-1 (亦稱為CD2子集1、CRACC、SLAMF7、CD319及19A24)；C型凝集素樣-1 (CLL-1或CLECLI)；CD33；表皮生長因子受體變異體III (EGFRvlll)；神經節苷脂G2 (GD2)；神經節苷脂GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer)；TNF受體家族成員B細胞成熟(BCMA)；Tn抗原((Tn Ag)或(GaINAcu-Ser/Thr))；前列腺特異性膜抗原(PSMA)；受體酪胺酸激酶樣孤兒受體1 (RORI)；Fms樣酪胺酸激酶3 (FLT3)；腫瘤相關醣蛋白72 (TAG72)；CD38；CD44v6；癌胚抗原(CEA)；上皮細胞黏附分子(EPCAM)；B7H3 (CD276)；KIT (CD117)；介白素-13受體次單元α-2 (IL-13Ra2或CD213A2)；間皮素；介白素11受體α (IL-11Ra)；前列腺幹細胞抗原(PSCA)；蛋白酶絲胺酸21(睾蛋白或PRSS21)；血管內皮生長因子受體2 (VEGFR2)；路易斯(Y)抗原；CD24；血小板衍生生長因子受體β (PDGFR-β)；階段特異性胚抗原-4 (SSEA-4)；CD20；δ樣3 (DLL3)；葉酸受體α；受體酪胺酸蛋白激酶，ERBB2 (Her2/neu)；黏蛋白1，細胞表面相關(MUC1)；表皮生長因子受體(EGFR)；神經細胞黏附分子(NCAM)；前列腺酶；前列腺酸性磷酸酶(PAP)；延伸因子2突變(ELF2M)；蝶素B2；纖維母細胞活化蛋白(FAP)；類胰島素生長因子1受體(IGF-I受體)、碳酸酐酶IX (CAIX)；蛋白酶體(前驅體、巨蛋白因子)次單元，β型，9 (LMP2)；醣蛋白100 (gp100)；致癌基因融合蛋白，由斷點簇區域(BCR)及阿貝爾森鼠類白血病病毒致癌基因同源物1 (Abl)組成(bcr-abl)；酪胺酸酶；蝶素A型受體2(EphA2)；岩藻糖基GM1；唾液酸基路易斯黏附分子(sLe)；神經節苷脂GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer)；轉麩胺醯胺酶5 (TGS5)；高分子量黑色素瘤相關抗原(HMWMAA)；鄰乙醯基-GD2神經節苷脂(OAcGD2)；葉酸受體β；腫瘤內皮標記物1 (TEM1/CD248)；腫瘤內皮標記物7相關(TEM7R)；前列腺六跨膜上皮抗原I (STEAP1)；緊密連接蛋白6 (CLDN6)；促甲狀腺激素受體(TSHR)；G蛋白偶合受體C類第5組成員D (GPRCSD)；X染色體開放閱讀框架61 (CXORF61)；CD97；CD179a；退行性淋巴瘤激酶(ALK)；聚唾液酸；胎盤特異性1 (PLAC1)；globoH糖基神經醯胺之六醣部分(GloboH)；乳腺分化抗原(NY-BR-1)；尿溶蛋白2 (UPK2)；A型肝炎病毒細胞受體1 (HAVCR1)；腎上腺素受體β 3 (ADRB3)；泛連接蛋白3 (PANX3)；G蛋白偶合受體20 (GPR20)；淋巴細胞抗原6複合物，基因座K 9 (LY6K)；嗅覺受體51E2 (ORS IE2)；TCRγ交替閱讀框架蛋白質(TARP)；威爾姆斯腫瘤蛋白(WT1)；癌症/睪丸抗原1 (NY-ESO-1)；癌症/睪丸抗原2 (LAGE-la)；黑色素瘤相關抗原1 (MAGE-A1)；ETS易位變異基因6，位於染色體12p上(ETV6-AML)；精子蛋白17 (SPA17)；X抗原家族，成員1A (XAGE1)；血管生成素結合細胞表面受體2 (Tie 2)；黑色素瘤癌症睪丸抗原-1 (MADCT-1)；黑色素瘤癌症睪丸抗原-2 (MAD-CT-2)；Fos相關抗原1；腫瘤蛋白p53 (p53)；p53突變體；前列腺蛋白；存活素；端粒酶；前列腺癌腫瘤抗原-1 (PCTA-1或半乳糖凝集素8)、由T細胞識別的黑色素瘤抗原1 (MelanA或MARTI)；大鼠肉瘤(Ras)突變體；人類端粒酶逆轉錄酶(hTERT)；肉瘤易位斷點；黑色素瘤細胞凋亡抑制劑(ML-IAP)；ERG (跨膜蛋白酶，絲胺酸2 (TMPRSS2) ETS融合基因)；N-乙醯基葡糖胺基-轉移酶V (NA17)；成對盒蛋白Pax-3 (PAX3)；雄激素受體；週期素B1；v-myc禽類髓細胞瘤病病毒致癌基因神經母細胞瘤衍生同源物(MYCN)；Ras同源物家族成員C (RhoC)；酪胺酸酶相關蛋白2 (TRP-2)；細胞色素P450 1B1(CYP IBI)；CCCTC結合因子(鋅指蛋白)樣(BORIS或印記位點調節物兄弟因子)，由T細胞識別之鱗狀細胞癌抗原3 (SART3)；成對盒蛋白Pax-5 (PAX5)；前頂體素結合蛋白sp32 (OY-TES I)；淋巴細胞特異性蛋白酪胺酸激酶(LCK)；A激酶錨定蛋白4 (AKAP-4)；滑膜肉瘤，X斷點2 (SSX2)；晚期糖基化最終產物受體(RAGE-I)；腎普遍存在1 (RUI)；腎普遍存在2 (RU2)；豆莢蛋白；人類乳頭狀瘤病毒E6 (HPV E6)；人類乳頭狀瘤病毒E7 (HPV E7)；腸羧酯酶；熱休克蛋白70-2突變(mut hsp70-2)；CD79a；CD79b；CD72；白細胞相關免疫球蛋白樣受體1 (LAIRI)；IgA受體之Fc片段(FCAR或CD89)；白細胞免疫球蛋白樣受體子族A成員2 (LILRA2)；CD300分子樣家族成員f (CD300LF)；C型凝集素結構域家族12成員A (CLEC12A)；骨髓基質細胞抗原2 (BST2)；EGF樣模組，含有黏蛋白樣激素受體樣2 (EMR2)；淋巴細胞抗原75 (LY75)；磷脂肌醇蛋白聚醣-3 (GPC3)；Fc受體樣5 (FCRL5)；以及免疫球蛋白λ樣多肽1 (IGLL1)。
在一些實施例中，腫瘤抗原係選自CD150、5T4、ActRIIA、B7、BMCA、CA-125、CCNA1、CD123、CD126、CD138、CD14、CD148、CD15、CD19、CD20、CD200、CD21、CD22、CD23、CD24、CD25、CD26、CD261、CD262、CD30、CD33、CD362、CD37、CD38、CD4、CD40、CD40L、CD44、CD46、CD5、CD52、CD53、CD54、CD56、CD66a-d、CD74、CD8、CD80、CD92、CE7、CS-1、CSPG4、ED-B纖維結合蛋白、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、GD2、GD3、HER1-HER2組合、HER2-HER3組合、HERV-K、HIV-1包膜醣蛋白gp120、HIV-1包膜醣蛋白gp41、HLA-DR、HM1.24、HMW-MAA、Her2、Her2/neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1-細胞黏附分子、路易Y、Ll-CAM、MAGE A3、MAGE-A1、MART-1、MUC1、NKG2C配位體、NKG2D配位體、NYESO-1、OEPHa2、PIGF、PSCA、PSMA、ROR1、T101、TAC、TAG72、TIM-3、TRAIL-R1、TRAIL-Rl (DR4)、路徑-R2 (DR5)、VEGF、VEGFR2、WT-I、G蛋白偶合受體、α胎蛋白(AFP)、血管生成因子、外源性同源結合分子(ExoCBM)、癌基因產物、抗葉酸受體、c-Met、癌胚抗原(CEA)、細胞週期蛋白(D 1)、蝶素B2、上皮腫瘤抗原、雌激素受體、胎兒乙醯膽鹼受體、葉酸結合蛋白、gp100、B型肝炎表面抗原、κ鏈、κ輕鏈、kdr、λ鏈、活素(livin)、黑素瘤相關抗原、間皮素、小鼠雙微基因2同源物(MDM2)、黏蛋白16(MUC16)、突變型p53、突變型ras、壞死抗原、癌胚抗原、ROR2、孕酮受體、前列腺特異性抗原、tEGFR、肌腱蛋白、P2-微球蛋白及Fc受體樣5 (FcRL5)。
細胞療法之非限制性實例包括艾普塞爾-L (Algenpantucel-L)、西普塞爾-T (Sipuleucel-T)、(BPX-501)瑞沃賽爾(rivogenlecleucel) US9089520、WO2016100236、AU-105、ACTR-087、經活化之同種異體自然殺手細胞CNDO-109-AANK、MG-4101、AU-101、BPX-601、FATE-NK100、LFU-835造血幹細胞、伊米塞爾-T (Imilecleucel-T)、巴塔賽爾-T (baltaleucel-T)、PNK-007、UCARTCS1、ET-1504、ET-1501、ET-1502、ET-190、CD19-ARTEMIS、ProHema、經FT-1050治療之骨髓幹細胞療法、CD4CARNK-92細胞、CryoStim、AlloStim、慢病毒轉導之huCART-內消旋細胞、CART-22細胞、EGFRt/19-28z/4-1BBL CAR T細胞、自體4H11-28z/fIL-12/EFGRt T細胞、CCR5-SBC-728-HSPC、CAR4-1BBZ、CH-296、dnTGFbRII-NY-ESOc259T、Ad-RTS-IL-12、IMA-101、IMA-201、CARMA-0508、TT-18、CMD-501、CMD-503、CMD-504、CMD-502、CMD-601、CMD-602、CSG-005。
在一些實施例中，腫瘤靶向抗原包括：α-胎蛋白，諸如ET-1402及AFP-TCR；炭疽毒素受體1，諸如抗TEM8 CAR T細胞療法；B細胞成熟抗原(BCMA)，諸如bb-2121、UCART-BCMA、ET-140、KITE-585、MCM-998、LCAR-B38M、CART-BCMA、SEA-BCMA、BB212、UCART-BCMA、ET-140、P-BCMA-101、AUTO-2 (APRIL-CAR)；抗CLL-1抗體，諸如KITE-796；B7同源物6，諸如CAR-NKp30及CAR-B7H6；B淋巴細胞抗原CD19，諸如TBI-1501、CTL-119 huCART-19 T細胞、JCAR-015 US7446190、JCAR-014、JCAR-017 (WO2016196388、WO2016033570、WO2015157386)、西卡思羅(axicabtagene ciloleucel) (KTE-C19)、US7741465、US6319494、UCART-19、EBV-CTL、T替沙津魯-T (T tisagenlecleucel-T) (CTL019)、WO2012079000、WO2017049166、表現CD19CAR-CD28-CD3ζ-EGFRt之T細胞、CD19/4-1BBL鎧裝CAR T細胞療法、C-CAR-011、CIK-CAR.CD19、CD19CAR-28-ζ T細胞、PCAR-019、MatchCART、DSCAR-01、IM19 CAR-T；B淋巴細胞抗原CD20，諸如ATTCK-20；B淋巴細胞細胞黏著物，諸如UCART-22、JCAR-018 WO2016090190；NY-ESO-1，諸如GSK-3377794、TBI-1301；碳酸酐酶，諸如DC-Ad-GMCAIX；凋亡蛋白酶9自殺基因，諸如CaspaCIDe DLI、BPX-501；CCR5，諸如SB-728；CDw123，諸如MB-102、UCART-123；CD20m，諸如CBM-C20.1；CD4，諸如ICG-122；CD30，諸如CART30 (CBM-C30.1)；CD33，諸如CIK-CAR.CD33；CD38，諸如T-007、UCART-38；CD40配位體，諸如BPX-201；CEACAM蛋白4調節劑，諸如MG7-CART；緊密連接蛋白6，諸如CSG-002；靶向EBV，諸如CMD-003；EGFR，諸如自體4H11-28z/fIL-12/EFGRt T細胞；核酸內切酶，諸如PGN-514、PGN-201；埃-巴二氏病毒(Epstein-Barr virus)特異性T淋巴細胞，諸如TT-10；Erbb2，諸如CST-102、CIDeCAR；神經節苷脂(GD2)，諸如4SCAR-GD2；麩胺酸羧肽酶II，諸如CIK-CAR.PSMA、CART-PSMA-TGFβRDN、P-PSMA-101；磷脂醯肌醇蛋白聚糖-3 (GPC3)，諸如TT-16、GLYCAR；血紅素，諸如PGN-236；肝細胞生長因子受體，諸如抗cMet RNA CAR T；人類乳頭狀瘤病毒E7蛋白，諸如KITE-439；免疫球蛋白γ Fc受體III，諸如ACTR087；IL-12，諸如DC-RTS-IL-12；IL-12促效劑/黏蛋白16，諸如JCAR-020；IL-13 α 2，諸如MB-101；IL-2，諸如CST-101；K-Ras GTP酶，諸如抗KRAS G12V mTCR細胞療法；神經細胞黏附分子L1 L1CAM (CD171)，諸如JCAR-023；潛伏性膜蛋白1/潛伏性膜蛋白2，諸如Ad5f35-LMPd1-2轉導之自體樹突狀細胞；黑色素瘤相關抗原10，諸如MAGE-A10C796T MAGE-A10 TCR；黑色素瘤相關抗原3/黑色素瘤相關抗原6 (MAGE A3/A6)，諸如KITE-718；間皮素，諸如CSG-MESO、TC-210；NKG2D，諸如NKR-2；Ntrkr1酪胺酸激酶受體，諸如JCAR-024；T細胞受體，諸如BPX-701、IMCgp100；T淋巴細胞，諸如TT-12；腫瘤浸潤性淋巴細胞，諸如LN-144、LN-145；及威爾姆斯腫瘤蛋白，諸如JTCR-016、WT1-CTL。淋巴瘤或白血病組合療法
在一些實施例中，額外治療劑適用於治療淋巴瘤或白血病。此等藥劑包括阿地介白素、阿昔迪布、三水合阿米福汀(amifostine trihydrate)、胺基喜樹鹼(aminocamptothecin)、抗瘤酮A10 (antineoplaston A10)、抗瘤酮AS2-1、抗胸腺細胞球蛋白、三氧化二砷、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛(beta alethine)、BMS-345541、硼替佐米(bortezomib)(VELCADE®
)、硼替佐米(VELCADE®
，PS-341)、苔蘚蟲素1、布舒凡(bulsulfan)、坎帕斯-1H (campath-1H)、卡鉑、卡非佐米(carfilzomib)(Kyprolis®
)、卡莫司汀、乙酸卡泊芬淨(caspofungin acetate)、CC-5103、苯丁酸氮芥、CHOP (環磷醯胺、小紅莓、長春新鹼及潑尼松)、順鉑、克拉屈濱、氯法拉濱、薑黃素、CVP (環磷醯胺、長春新鹼及潑尼松)、環磷醯胺、環孢靈(cyclosporine)、阿糖胞苷、地尼介白素(denileukin diftitox)、地塞米松、歐洲紫杉醇、海兔毒素10、小紅莓、鹽酸小紅莓、DT-PACE (地塞米松、沙力度胺、順鉑、小紅莓、環磷醯胺及依託泊苷)、恩紮妥林(enzastaurin)、阿法依泊汀(epoetin alfa)、依託泊苷、依維莫司(everolimus)(RAD001)、FCM (氟達拉濱、環磷醯胺及米托蒽醌)、FCR (氟達拉濱、環磷醯胺及利妥昔單抗)、非瑞替尼(fenretinide)、非格司亭(filgrastim)、夫拉平度(flavopiridol)、氟達拉濱、FR (氟達拉濱及利妥昔單抗)、格爾德黴素(geldanamycin)(17-AAG)、hyperCVAD (超分割環磷醯胺、長春新鹼、小紅莓、地塞米松、甲胺喋呤及阿糖胞苷)、ICE (異環磷醯胺、卡鉑及依託泊苷)、異環磷醯胺、鹽酸伊立替康、干擾素α-2b、伊沙匹隆、來那度胺(REVLIMID®
，CC-5013)、淋巴激素活化之殺手細胞、MCP (米托蒽醌、苯丁酸氮芥及潑尼龍)、美法侖、美司鈉(mesna)、甲胺喋呤、鹽酸米托蒽醌、莫特沙芬釓(motexafin gadolinium)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、奈拉濱(nelarabine)、奧巴克拉(obatoclax)(GX15-070)、奧利默森(oblimersen)、乙酸奧曲肽(octreotide acetate)、Ω-3脂肪酸、Omr-IgG-am (WNIG，Omrix)、奧沙利鉑、紫杉醇、帕泊昔布(PD0332991)、派非格司亭(pegfilgrastim)、聚乙二醇化脂質鹽酸小紅莓、派瑞弗辛(perifosin)、潑尼龍、潑尼松、重組型flt3配位體、重組型人類血小板生成素、重組型干擾素α、重組型介白素-11、重組型介白素-12、利妥昔單抗、R-CHOP (利妥昔單抗及CHOP)、R-CVP (利妥昔單抗及CVP)、R-FCM (利妥昔單抗及FCM)、R-ICE (利妥昔單抗及ICE)及R-MCP (利妥昔單抗及MCP)、R-羅斯維汀(R-roscovitine)(塞利希布(seliciclib)、CYC202)、沙格司亭(sargramostim)、檸檬酸西地那非(sildenafil citrate)、辛伐他汀(simvastatin)、西羅莫司、苯乙烯基碸、他克莫司、坦螺旋黴素(tanespimycin)、坦羅莫司(temsirolimus)(CCl-779)、沙力度胺、治療性同種異體淋巴細胞、噻替派、替吡法尼(tipifarnib)、長春新鹼、硫酸長春新鹼、酒石酸氫長春瑞賓、SAHA (辛二醯苯胺異羥肟酸，或辛二醯基、苯胺及氧肟酸)、維羅非尼(Zelboraf®
)、維奈托克(ABT-199)。
一種改良方法為放射免疫療法，其中單株抗體與放射性同位素粒子，諸如銦-111、釔-90及碘-131組合。組合療法之實例包括(但不限於)碘-131托西莫單抗(BEXXAR®
)、釔-90替伊莫單抗(ibritumomab tiuxetan)(ZEVALIN®
)及BEXXAR®
與CHOP。
上述療法可補充有幹細胞移植或治療或與其組合。治療性程序包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、幹細胞輸注、在幹細胞支持下之骨髓消融、經活體外處理之周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博萊黴素、習知手術、輻射療法及非清髓性同種異體造血幹細胞移植。非霍奇金氏淋巴瘤 (Non-Hodgkin ' s Lymphomas) 組合療法
在一些實施例中，額外治療劑適用於治療非霍奇金氏淋巴瘤(NHL)，尤其B細胞起源之非霍奇金氏淋巴瘤，該等額外治療劑包括單株抗體、標準化學療法方法(例如CHOP、CVP、FCM、MCP及其類似方法)、放射免疫療法及其組合，尤其抗體療法與化學療法結合。
用於治療NHL/B細胞癌症的未結合單株抗體之實例包括利妥昔單抗、阿侖單抗、人類或人類化抗CD20抗體、盧米西單抗(lumiliximab)、抗TNF相關細胞凋亡誘發配位體(抗TRAIL)、貝伐珠單抗、加利昔單抗、依帕珠單抗、SGN-40及抗CD74。
用於治療NHL/B細胞癌症之實驗抗體藥劑之實例包括：奧伐木單抗、ha20、PRO131921、阿侖單抗、加利昔單抗、SGN-40、CHIR-12.12、依帕珠單抗、盧米西單抗、阿泊珠單抗、米拉珠單抗及貝伐單抗。
用於NHL/B細胞癌症之化學療法的標準方案之實例包括：CHOP、FCM、CVP、MCP、R-CHOP、R-FCM、R-CVP及R-MCP。
用於NHL/B細胞癌症之放射免疫療法之實例包括釔-90替伊莫單抗(ZEVALIN®
)及碘-131托西莫單抗(BEXXAR®
)。套細胞淋巴瘤組合療法
在一些實施例中，額外治療劑適用於治療套細胞淋巴瘤(MCL)，其包括組合化學療法，諸如CHOP、hyperCVAD及FCM。此等方案亦可補充有單株抗體利妥昔單抗以形成組合療法R-CHOP、hyperCVAD-R及R-FCM。上文所提及之療法中之任一者可與幹細胞移植或ICE組合以治療MCL。
適用於治療MCL之治療劑之其他實例包括：
‐ 免疫療法，諸如單株抗體(如利妥昔單抗)及癌症疫苗，諸如GTOP-99，其係基於個別個體之腫瘤之基因組成；
‐ 放射免疫療法，其中單株抗體與放射性同位素粒子組合，諸如碘-131托西莫單抗(BEXXAR®
)、釔-90替伊莫單抗(ZEVALIN®
)及BEXXAR®
依序與CHOP一起用於治療；
‐ 自體幹細胞移植與高劑量化學療法聯合，投與蛋白酶體抑制劑，諸如硼替佐米(VELCADE®
或PS-341)，或投與抗血管生成劑，諸如沙力度胺，尤其與利妥昔單抗組合；
‐ 引起Bcl-2蛋白質分解且提高對化學療法之癌細胞敏感性之藥物，諸如奧利默森，與其他化學治療劑組合；
‐ mTOR抑制劑，其可引起細胞生長之抑制及甚至細胞死亡。非限制性實例為西羅莫司、坦羅莫司(TORISEL®
，CCI-779)、CC-115、CC-223、SF-1126、PQR-309 (必米昔布(bimiralisib))、沃塔昔布(voxtalisib)、GSK-2126458以及坦羅莫司與RITUXAN®
、VELCADE®
或其他化學治療劑之組合；
‐ 其他藥劑，諸如夫拉平度、帕泊昔布(PD0332991)、R-羅斯維汀(塞利(selicicilib)，CYC202)、苯乙烯碸、奧巴克拉(GX15-070)、TRAIL、抗TRAIL死亡受體DR4及DR5抗體、坦羅莫司(TORISEL®
，CCl-779)、依維莫司(RAD001)、BMS-345541、薑黃素、SAHA、沙立度胺、來那度胺(REVLIMID®
，CC-5013)及格爾德黴素(17-AAG)。瓦爾登斯特倫氏巨球蛋白血症 (Waldenstrom ' s Macroglobulinemia) 組合療法
在一些實施例中，額外治療劑適用於治療瓦爾登斯特倫氏巨球蛋白血症(WM)，其包括阿地介白素、阿侖單抗、阿昔迪布、三水合阿米福汀、胺基喜樹鹼、抗瘤酮A10、抗瘤酮AS2-1、抗胸腺細胞球蛋白、三氧化二砷、自體人類腫瘤衍生之HSPPC-96、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛、硼替佐米(VELCADE®
)、苔蘚蟲素1、白消安、坎帕斯-1H、卡鉑、卡莫司汀、乙酸卡泊芬淨、CC-5103、順鉑、氯法拉濱、環磷醯胺、環孢靈、阿糖胞苷、地尼介白素、地塞米松、歐洲紫杉醇、海兔毒素10、鹽酸小紅莓、DT-PACE、恩紮妥林、阿法依泊汀、依帕珠單抗(hLL2-抗CD22人類化抗體)、依託泊苷、依維莫司、非瑞替尼、非格司亭、氟達拉濱、異環磷醯胺、銦-111單株抗體MN-14、碘-131托西莫單抗、鹽酸伊立替康、伊沙匹隆、淋巴激素活化之殺手細胞、美法侖、美司鈉、甲胺喋呤、鹽酸米托蒽醌、單株抗體CD19 (諸如替沙津魯-T、CART-19、CTL-019)、單株抗體CD20、莫特沙芬釓、黴酚酸嗎啉乙酯、奈拉濱、奧利默森、乙酸奧曲肽、ω-3脂肪酸、奧沙利鉑、紫杉醇、派非格司亭、聚乙二醇化脂質體鹽酸小紅莓、噴司他汀、哌立福新、潑尼松、重組型flt3配位體、重組型人類血小板生成素、重組型干擾素α、重組型介白素-11、重組型介白素-12、利妥昔單抗、沙格司亭、檸檬酸西地那非(VIAGRA®
)、辛伐他汀、西羅莫司、他克莫司、坦螺旋黴素、沙立度胺、治療性同種異體淋巴細胞、噻替派、替吡法尼、托西莫單抗、維托珠單抗、硫酸長春新鹼、酒石酸氫長春瑞賓、伏立諾他、WT1 126-134肽疫苗、WT-1類似物肽疫苗、釔-90替伊莫單抗、釔-90人類化依帕珠單抗及其任何組合。
用於治療WM之治療性程序之其他實例包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、幹細胞輸注、在幹細胞支持下之骨髓消融、經活體外處理之周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博萊黴素、習知手術、輻射療法及非清髓性同種異體造血幹細胞移植。彌漫性大 B 細胞淋巴瘤組合療法
在一些實施例中，其他治療劑適用於治療彌漫性大B細胞淋巴瘤(DLBCL)，其包括環磷醯胺、小紅莓、長春新鹼、潑尼松、抗CD20單株抗體、依託泊苷、博萊黴素、關於WM所列出之許多藥劑及其任何組合，諸如ICE及R-ICE。慢性淋巴細胞性白血病組合療法
在一些實施例中，額外治療劑適用於治療慢性淋巴細胞性白血病(CLL)，其包括苯丁酸氮芥、環磷醯胺、氟達拉濱、噴司他汀、克拉屈濱、小紅莓、長春新鹼、潑尼松、潑尼龍、阿侖單抗、關於WM所列出之許多藥劑以及組合化學療法及化學免疫療法，包括以下常用組合方案：CVP、R-CVP、ICE、R-ICE、FCR及FR。骨髓纖維化組合療法
在一些實施例中，額外治療劑適合於治療骨髓纖維化，其包括刺蝟抑制劑、組蛋白去乙醯基酶(HDAC)抑制劑及酪胺酸激酶抑制劑。刺蝟抑制劑之非限制性實例係薩瑞德吉及維莫德吉。
HDAC抑制劑之實例包括但不限於普拉諾他及帕比諾他。
酪胺酸激酶抑制劑之非限制性實例為來他替尼、伯舒替尼、伊馬替尼、吉爾替尼、拉多替尼及卡博替尼。過度增生性疾病組合療法
在一些實施例中，額外治療劑適用於治療過度增生性疾病，其包括吉西他濱、白蛋白結合型紫杉醇及吉西他濱/白蛋白結合型紫杉醇與JAK抑制劑及/或PI3Kδ抑制劑。膀胱癌組合療法
在一些實施例中，額外治療劑適用於治療膀胱癌，其包括阿特珠單抗、卡鉑、順鉑、歐洲紫杉醇、小紅莓、氟尿嘧啶(5-FU)、吉西他濱、伊多米德(idosfamide)、干擾素α-2b、甲胺喋呤、絲裂黴素、白蛋白結合型紫杉醇、紫杉醇、培美曲塞、噻替派、長春鹼及其任何組合。乳癌組合療法
在一些實施例中，額外治療劑適合於治療乳癌，其包括白蛋白結合型紫杉醇、阿那曲唑、卡培他濱、卡鉑、順鉑、環磷醯胺、歐洲紫杉醇、小紅莓、表柔比星、依維莫司、依西美坦、氟尿嘧啶、氟維司群、吉西他濱、伊沙匹隆、拉帕替尼、來曲唑、甲胺喋呤、米托蒽醌、紫杉醇、聚乙二醇化脂質體小紅莓、帕妥珠單抗、他莫昔芬、托瑞米芬、曲妥珠單抗、長春瑞賓及其任何組合。三陰性乳癌組合療法
在一些實施例中，額外治療劑適用於治療三陰性乳癌，其包括環磷醯胺、歐洲紫杉醇、小紅莓、表柔比星、氟尿嘧啶、紫杉醇及其組合。結腸直腸癌組合療法
在一些實施例中，額外治療劑適用於治療結腸直腸癌，其包括貝伐珠單抗、卡培他濱、西妥昔單抗、氟尿嘧啶、伊立替康、甲醯四氫葉酸、奧沙利鉑、帕尼單抗、阿柏西普(ziv-aflibercept)及其任何組合。去勢抵抗性前列腺癌組合療法
在一些實施例中，額外治療劑適合於治療去勢抵抗性前列腺癌，其包括阿比特龍、卡巴他賽、歐洲紫杉醇、恩雜魯胺、潑尼松、西普塞爾-T及其任何組合。食道及食道胃接合處癌症組合療法
在一些實施例中，額外治療劑適用於治療食道及食道胃接合處癌症，其包括卡培他濱、卡鉑、順鉑、歐洲紫杉醇、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲醯四氫葉酸、奧沙利鉑、紫杉醇、雷莫蘆單抗、曲妥珠單抗及其任何組合。胃癌組合療法
在一些實施例中，額外治療劑適用於治療胃癌，其包括卡培他濱、卡鉑、順鉑、歐洲紫杉醇、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲醯四氫葉酸、絲裂黴素、奧沙利鉑、紫杉醇、雷莫蘆單抗、曲妥珠單抗及其任何組合。頭頸癌組合療法
在一些實施例中，額外治療劑適合於治療頭頸癌，其包括阿法替尼、博萊黴素、卡培他濱、卡鉑、西妥昔單抗、順鉑、歐洲紫杉醇、氟尿嘧啶、吉西他濱、羥基脲、甲胺喋呤、納武單抗、紫杉醇、派姆單抗、長春瑞賓及其任何組合。肝膽癌症組合療法
在一些實施例中，額外治療劑適用於治療肝膽癌，其包括卡培他濱、順鉑、氟嘧啶、5-氟尿嘧啶、吉西他濱、奧沙利鉑、索拉非尼及其任何組合。肝細胞癌組合療法
在一些實施例中，額外治療劑適合於治療肝細胞癌，其包括卡培他濱、小紅莓、吉西他濱、索拉非尼及其任何組合。非小細胞肺癌組合療法
在一些實施例中，額外治療劑適用於治療非小細胞肺癌(NSCLC)，其包括阿法替尼、白蛋白結合之紫杉醇、艾樂替尼、貝伐珠單抗、貝伐珠單抗、卡博替尼、卡鉑、順鉑、克卓替尼、達拉非尼、歐洲紫杉醇、埃羅替尼、依託泊苷、吉西他濱、納武單抗、紫杉醇、派姆單抗、培美曲塞、雷莫蘆單抗、曲美替尼、曲妥珠單抗、凡德他尼、維羅非尼、長春鹼、長春瑞賓及其任何組合。小細胞肺癌組合療法
在一些實施例中，額外治療劑適合於治療小細胞肺癌(SCLC)，其包括苯達莫司汀、卡鉑、順鉑、環磷醯胺、歐洲紫杉醇、小紅莓、依託泊苷、吉西他濱、伊派利單抗、伊立替康、納武單抗、紫杉醇、替莫唑胺、拓朴替康、長春新鹼、長春瑞賓及其任何組合。黑色素瘤組合療法
在一些實施例中，額外治療劑適合於治療黑色素瘤，其包括白蛋白結合型紫杉醇、卡鉑、順鉑、考比替尼(cobimetinib)、達拉非尼、達拉巴嗪(dacarbazine)、IL-2、伊馬替尼、干擾素α-2b、伊派利單抗、亞硝基脲、納武單抗、紫杉醇、派姆單抗、伊派利單抗、替莫唑胺、曲美替尼、維羅非尼、長春鹼及其任何組合。卵巢癌組合療法
在一些實施例中，額外治療劑適用於治療卵巢癌，其包括5-氟尿嘧啶、白蛋白結合型紫杉醇、六甲蜜胺、阿那曲唑、貝伐珠單抗、卡培他濱、卡鉑、順鉑、環磷醯胺、歐洲紫杉醇、小紅莓、依託泊苷、依西美坦、吉西他濱、異環磷醯胺、伊立替康、來曲唑、乙酸亮丙立德、脂質體小紅莓、乙酸甲地孕酮、美法侖、奧拉帕尼、奧沙利鉑、紫杉醇、帕佐泮尼(Pazopanib)、培美曲塞、他莫昔芬、拓朴替康、長春瑞賓及其任何組合。胰臟癌組合療法
在一些實施例中，額外治療劑適用於治療胰臟癌，其包括5-氟尿嘧啶、白蛋白結合型紫杉醇、卡培他濱、順鉑、歐洲紫杉醇、埃羅替尼、氟嘧啶、吉西他濱、伊立替康、甲醯四氫葉酸、奧沙利鉑、紫杉醇及其任何組合。腎細胞癌組合療法
在一些實施例中，額外治療劑適合於治療腎細胞癌，其包括阿西替尼、貝伐單抗、卡博替尼、埃羅替尼、依維莫司、樂伐替尼、納武單抗、帕佐泮尼、索拉非尼、舒尼替尼、坦羅莫司及其任何組合。VIII. 套組
本發明提供一種套組，其包含本發明之化合物或其醫藥學上可接受之鹽。該套組可進一步包含例如用於治療病毒感染之使用說明書。使用說明書一般為書面說明書，但含有說明書之電子儲存媒體(例如磁碟或光碟)亦為可接受的。
本發明亦提供一種醫藥套組，其包含有包含本發明之化合物或其醫藥學上可接受之鹽的一或多個容器。與該(等)容器視情況相關聯的可為呈由管理藥品製造、使用或銷售之政府機構所規定之形式之通告，該通告反映機構對製造、使用或銷售用於人類投與的認可。各組分(若存在超過一種組分)可封裝於單獨容器中，或在交叉反應性及儲存期限准許的情況下，可將一些組分合併於一個容器中。套組可呈單位劑型、散裝包裝(例如多劑量包裝)或次單位劑量。套組亦可包括多個單位劑量之化合物及使用說明書，且以足以供藥房(例如醫院藥房及混配藥房)儲存及使用之量封裝。
亦提供製品，其包含單位劑量之本發明之化合物或其醫藥學上可接受之鹽，呈適合包裝用於本文所述之方法中。適合包裝為此項技術中已知，且包括例如小瓶、容器、安瓿、瓶子、罐、軟包裝及其類似物。製品可進一步經滅菌及/或密封。 IX. 實例
如本文中所使用之縮寫具有如下各別含義：
| Ac | 乙酸酯 |
| ACN | 乙腈 |
| BippyPhos | 5-(二第三丁基膦基)-1',3',5'-三苯基-1'H-[1,4']聯吡唑 |
| Bn | 苯甲基 |
| br. s | 寬單峰 |
| Bu | 丁基 |
| dba | 二亞苄基丙酮 |
| DCM | 二氯甲烷 |
| dd | 雙二重峰 |
| ddd | 兩個雙二重峰 |
| DIPE | 二異丙醚 |
| DMF | 二甲基甲醯胺 |
| DMSO | 二甲亞碸 |
| dr | 非對映異構體比率 |
| DSC | 差示掃描熱量測定 |
| DVS | 動態蒸汽吸附 |
| ee | 對映異構體過量 |
| equiv | 當量 |
| Et | 乙基 |
| EtOAc | 乙酸乙酯 |
| EtOH | 乙醇 |
| ft | 英尺(長度) |
| g | 公克 |
| GC | 氣相層析 |
| h | 小時 |
| HBV | B型肝炎病毒 |
| HCV | C型肝炎病毒 |
| HFIPA | 六氟異丙醇 |
| HIV | 人類免疫缺陷病毒 |
| HPLC | 高壓液相層析 |
| IPA | 異丙醇 |
| IPAc | 乙酸異丙酯 |
| iPr | 異丙基 |
| iPrOAc或IPAc | 乙酸異丙酯 |
| kg | 公斤 |
| L | 公升 |
| m | 多重峰 |
| M | 莫耳濃度 |
| Me | 甲基 |
| MEK | 甲基乙基酮 |
| MeOH | 甲醇 |
| Me-THF | 2甲基四氫呋喃 |
| mg | 毫克 |
| MHz | 兆赫茲 |
| MIBK | 甲基異丁基酮 |
| min | 分鐘 |
| mL | 毫升 |
| mmol | 毫莫耳 |
| mol | 莫耳 |
| MTBE | 甲基-第三丁基醚 |
| N | 當量濃度 |
| NLT | 不少於 |
| NMR | 核磁共振 |
| Ph | 苯基 |
| RH | 相對濕度 |
| s | 單重峰 |
| t-Bu | 第三丁基 |
| td | 三雙重峰 |
| Tf | 三氟甲磺酸酯 |
| TFE | 三氟乙醇 |
| TGA | 熱解重量分析 |
| THF | 四氫呋喃 |
| TMS | 三甲基矽烷基 |
| vol | 體積 |
| wt | 重量 |
| XRPD | X射線粉末繞射 |
| δ | 化學位移 |
| μL | 微升 |
化合物I之固體形式(多晶形物、溶劑合物及水合物)藉由多種以下方法表徵。
藉由PANalytical X'Pert PRO MPD繞射儀，使用由使用長細焦光源及鎳濾光器產生之Cu Kα輻射之入射光束收集XRPD圖案。繞射儀使用對稱布拉格-布倫塔諾幾何學(Bragg-Brentano geometry)組態。分析之前，對矽樣本(NIST SRM 640e)進行分析以檢驗Si 111峰之所觀測位置與NIST認證的位置一致。樣品之樣本製備成薄的圓形層，置於零背景矽基板上之中央。使用抗散射狹縫(SS)以使空氣所產生之背景降至最低。使用針對入射光束及繞射光束之索勒狹縫(Soller slit)以使軸向發散變寬降至最低。使用距離樣品240 mm之掃描位置敏感偵測器(X'Celerator)及資料收集器軟體2.2b版收集繞射圖案。
使用TA Instruments 2920及Q2000差示掃描量熱計收集差示掃描熱量測定(DSC)資料。使用NIST可追蹤之銦金屬進行溫度校準。將樣品置放於覆蓋有蓋子且捲曲之T zero鋁DSC盤中。接著準確記錄重量。將組態為樣品盤之稱量鋁盤放置於池之參考側面上。將樣品以10℃/分鐘自-30℃加熱至250℃。
使用TA Instruments Discovery熱重量分析儀收集熱解重量分析(TGA)資料。使用鎳及AlumeI™進行溫度校準。將每一樣品置放在鋁盤中並插入TG爐內。在氮氣吹掃下加熱鍋爐。將樣品以10℃/分鐘自周圍溫度加熱至350℃。
在VTI SGA-100蒸汽吸附分析器上收集水分吸附/解吸附資料。使用NaCl及PVP作為校準標準物。在分析之前不乾燥樣品。在氮氣淨化下以10% RH增量，收集5%至95% RH範圍內之吸附及解吸附資料。用於分析之平衡準則為5分鐘內重量變化小於0.0100%，最大平衡時間為3小時。在資料部分中所報導之重量%係相對於如在儀器上量測的在5% RH下平衡之前引入的總樣品質量。實例 1. 製備化合物 I 
向經氮氣沖洗之50 L夾套反應器中饋入化合物A (2.69 kg，6.07莫耳，1.0當量)。接著添加二氯甲烷(10.13 L，13.44 kg)。攪動設定成175 RPM且攪動內含物直至觀測到溶液。以使內部溫度不超過35℃的速率饋入三氟乙酸(4.53 L，6.75 kg)(大約30分鐘)。在添加三氟乙酸之後，護套設定成46℃(維持平緩回流)。在此溫度下攪動內含物3小時，且接著護套設定成15℃。一旦內部溫度達到20℃，就饋入乙醇(從正庚烷變性)(8.56 L，6.75 kg)且使內含物在20℃下攪拌14小時。在此時間量之後，不均勻內含物經由台式多過濾器過濾至經氮氣沖洗之100 L夾套反應器中。
將二氯甲烷(5.21 L，6.91 kg)饋入50 L反應器中且溶液經過濾器沖洗至100 L反應器中。接著向100 L反應器饋入水(15.5 L，15.5 kg)及乙酸乙酯(19.0 L，17.0 kg)。攪動設定成175 RPM且夾套設定成87℃。使內含物加熱至回流，保持30分鐘。在此時間量之後，夾套設定成20℃。將水層排出。向反應器中饋入水(18.4 L，18.4 kg)，且攪動設定成200 RPM。饋入30% w/w NaOH (8.61 kg)且將內含物在30℃下攪動30分鐘(夾套設定成40℃)。接著饋入乙酸乙酯(45.0 L，40.4 kg)且夾套設定成55℃。一旦內部溫度達到45℃，就在200 RPM下攪動內含物30分鐘。在此時間量之後，停止攪動且使各相分離且排出水層。饋入4.5% w/w碳酸氫鈉水溶液(由605 g碳酸氫鈉及12.8 kg水製備)且在45℃之內部溫度下在200 RPM下攪動內含物30分鐘。在此時間量之後，停止攪動且使各層分離。將水層排出且夾套設定成20℃。將內含物在此溫度下在氮氣下老化14小時。接著夾套設定成55℃。一旦內部溫度達到45℃，就饋入4.5% w/w碳酸氫鈉水溶液(由605 g碳酸氫鈉及12.8 kg水製備)且在45℃下攪動內含物(200 RPM) 30分鐘。接著停止攪動，使各相分離，且排出水層。饋入4.5% w/w碳酸氫鈉水溶液(由605 g碳酸氫鈉及12.8 kg水製備)。在45℃下攪動內含物(200 RPM)30分鐘。接著停止攪動，使各相分離且排出水層。添加水(13.6 L，13.6 kg)並在45℃下攪動內含物(150 RPM) 30分鐘。在此時間量之後，停止攪動且使各相分離且排出水層。實例 2. 形式 I
反應器經組態用於真空蒸餾，且夾套設定成70℃且攪動設定成150 RPM。經由真空蒸餾移除溶劑至大約30 L。夾套設定成35℃且用氮氣回填反應器。饋入乙酸乙酯(45 L，40.4 kg)且將反應器加熱至70℃，攪動設定成150 RPM且降低壓力。經由真空蒸餾移除溶劑至大約30 L。夾套設定成35℃且用氮氣回填反應器。如所述重複乙酸乙酯蒸餾次序5次。在饋入45 L乙酸乙酯用於各次序之後，五次蒸餾的最終體積為大約30 L。針對水含量，將內含物取樣(目標＜0.5% H2
O)。在通過水含量標準之後，將夾套加熱至70℃，攪動設定成150 RPM且降低壓力且繼續蒸餾至大約22 L。夾套設定成35℃且用氮氣回填反應器。饋入乙酸乙酯(15 L，13.5 kg)且經1.0 μm過濾器精緻過濾內含物至結晶器中。結晶器上之夾套設定成70℃且攪動設定成150 RPM。降低容器壓力，且繼續蒸餾至大約18 L。一旦達到此目標體積，就用氮氣回填結晶器且夾套設定成87℃。饋入乙酸乙酯(9.5 L，8.5 kg)且攪動內含物，直至觀測到均質溶液。在所有固體溶解之後，開始從85℃勻速冷卻至20℃，歷經8小時。
濾出固體且用乙酸乙酯(6.1 L，5.5 kg)洗滌濕濾餅。過濾器上之夾套設定成46℃且在氮氣排放下內含物在減壓下乾燥24小時。化合物I (形式I)以優良純度分離(99.6%分析，99.7% AN)。
視情況，將化合物I (1.2 kg，4.0 mol)饋入50 L夾套反應器中，接著饋入乙酸乙酯(25 L，22 kg)。結晶器上之夾套設定成87℃且攪動設定成150 RPM。攪動內含物，直至觀測到溶液。在所有固體溶解之後，開始從85℃勻速冷卻至20℃，歷經8小時。濾出固體且用乙酸乙酯(6.1 L，5.5 kg)洗滌濕濾餅。過濾器上之夾套設定成46℃且在氮氣排放下內含物在減壓下乾燥24小時。分離化合物I形式I。
形式I為未溶劑化相。其XRPD圖案展示於圖1中。表 1 ： 化合物 I 形式 I 之晶體資料及資料收集參數
表 2. 形式 I 之峰表
實例 3. 龍膽酸
| 實驗式 | C14 H20 FN5 O | |
| 分子量 | 293.35 | |
| 溫度 | 100(2) K | |
| 波長 | 1.54178 Å | |
| 晶系 | 四方 | |
| 空間群 | P41 | |
| 單位晶胞尺寸 | a= 8.0344(2) Å | α= 90°. |
| b= 8.0344(2) Å | β= 90°. | |
| c= 23.7871(7) Å | γ= 90°. | |
| 體積 | 1535.49(9) Å3 | |
| Z | 4 | |
| 密度(計算值) | 1.269Mg/m3 | |
| 吸光係數 | 0.766 mm-1 | |
| F(000) | 624 | |
| 晶體尺寸 | 0.450×0.320×0.290 mm3 | |
| 資料收集之θ範圍 | 5.506至71.991° | |
| 指數範圍 | -9＜=h＜=9，-9＜=k＜=9，-27＜=l＜=28 | |
| 所收集之反射 | 36463 | |
| 獨立反射 | 2954 [R(int) = 0.0397] | |
| 相對於θ之完整性 = 67.679° | 99.4 % | |
| 精修方法 | F2 之全矩陣最小平方 | |
| 資料/限制/參數 | 2954 /1 / 203 | |
| F2 之擬合優度 | 1.219 | |
| 最終R指數[I＞2σ(I)] | R1 = 0.0339，wR2 = 0.0824 | |
| R指數(所有資料) | R1 =0.0341，wR2 = 0.0827 | |
| 絕對結構參數 | 弗拉克(Flack)參數：0.12(4) 霍夫特(Hooft)參數：0.10(4) | |
| 消光係數 | 0.0098(8) | |
| 最大差異峰及穀 | 0.146及-0.147 e. Å -3 | |
| 位置[°2θ] | 相對強度[%] |
| 10.9 | 42.72 |
| 11.5 | 17.57 |
| 13.2 | 47.27 |
| 14.7 | 38.18 |
| 15.5 | 53.84 |
| 15.6 | 39.90 |
| 18.4 | 2.21 |
| 19.0 | 8.77 |
| 21.4 | 66.66 |
| 21.9 | 100.00 |
| 22.3 | 5.33 |
| 23.2 | 30.44 |
| 24.2 | 4.77 |
| 24.6 | 6.37 |
| 24.9 | 26.03 |
| 25.7 | 8.09 |
| 26.5 | 4.13 |
| 27.0 | 11.23 |
| 28.8 | 2.99 |
| 29.7 | 3.56 |
| 30.4 | 3.53 |
| 30.9 | 1.12 |
| 31.8 | 3.44 |
| 33.2 | 4.08 |
| 34.0 | 4.63 |
| 34.7 | 4.13 |
| 35.4 | 3.16 |
| 36.1 | 4.79 |
| 38.2 | 3.29 |
| 39.1 | 3.36 |
在Avantium Crystal16®多反應器系統中將化合物I形式I (37.01 mg)、約一莫耳當量龍膽酸(18.1 mg)及乙腈(300 µl)加熱至50℃。在約15分鐘之後，關閉反應器系統以快速冷卻至周圍溫度。在達到周圍溫度之後，將樣品再加熱至約50℃，保持約4小時，且接著以0.1℃/min冷卻至約10℃。藉由真空過濾收集固體，添加至二氯甲烷(0.5 ml)中且在周圍溫度下攪拌。在約5小時之後，藉由真空過濾收集固體且分析。
化合物I龍膽酸XRPD圖案展示於圖2中。表 3. 龍膽酸之峰表
| 位置[°2θ] | 相對強度[%] |
| 4.4 | 100.00 |
| 8.7 | 72.12 |
| 12.3 | 1.88 |
| 12.9 | 10.71 |
| 13.9 | 2.00 |
| 14.4 | 1.57 |
| 14.9 | 15.64 |
| 16.3 | 4.01 |
| 17.3 | 4.71 |
| 18.9 | 3.58 |
| 19.5 | 6.04 |
| 20.5 | 3.38 |
| 21.7 | 1.94 |
| 22.2 | 0.99 |
| 23.0 | 2.82 |
| 24.8 | 14.51 |
| 25.7 | 7.28 |
| 26.3 | 5.81 |
| 27.1 | 3.43 |
| 27.7 | 1.53 |
| 33.1 | 0.10 |
| 39.4 | 0.87 |
DSC曲線展示於圖3中且呈現在約178℃下之一個吸熱轉變。TGA曲線展示於圖4中且指示相未溶劑化。動態蒸汽吸附曲線展示於圖5中且資料指示在25℃下在高達95% RH下該形式吸附約1.1 %水。發現材料在實驗後未改變形式。實例 4. 馬尿酸
在Avantium Crystal16®多反應器系統中將化合物I形式I (40.09 mg)、約一莫耳當量馬尿酸(24.5 mg)及丙酮(300 µl)加熱至約50℃。在約15分鐘之後，關閉反應器系統以快速冷卻至周圍溫度。在達到周圍溫度之後，將樣品再加熱至約50℃，保持約4小時，且接著以0.1℃/min冷卻至約10℃。藉由真空過濾收集固體且分析。
化合物I馬尿酸XRPD圖案展示於圖6中。表 4. 馬尿酸之峰表
| 位置[°2θ] | 相對強度[%] |
| 2.9 | 9.03 |
| 5.0 | 100.00 |
| 7.6 | 8.23 |
| 10.4 | 3.52 |
| 12.6 | 11.30 |
| 14.6 | 1.07 |
| 17.6 | 3.41 |
| 18.1 | 1.74 |
| 19.0 | 6.51 |
| 20.3 | 3.61 |
| 25.2 | 28.94 |
| 25.6 | 5.54 |
| 26.3 | 3.35 |
| 26.7 | 2.49 |
| 27.2 | 2.27 |
| 27.9 | 1.49 |
| 28.5 | 4.96 |
| 29.2 | 1.51 |
DSC曲線展示於圖7中且呈現在約127℃下之一個吸熱轉變。TGA曲線展示於圖8中且指示相未溶劑化。動態蒸汽吸附曲線展示於圖9中且資料指示在25℃下在高達95% RH下該形式吸附約0.68%水。發現材料在實驗後未改變形式。實例 5. 磷酸形式 I
化合物I磷酸鹽形式I藉由使化合物I形式I (39.14 mg)及2莫耳當量磷酸(18 µl，85%水溶液)溶解於丙酮(300 µl)中來分離。反應產生凝膠且用多種溶劑濕磨，該等溶劑包括乙酸乙酯、二乙醚及最終乙腈與異丙醇之混合物(67/33 v/v，300 µl)。在乙腈/異丙醇混合物中在周圍溫度下攪拌約5天後產生固體。藉由真空過濾收集固體且將濕餅用異丙醇(100 µl)洗滌。
化合物I磷酸形式I XRPD圖案展示於圖10中。表 5. 磷酸形式 I 之峰表
| 位置[°2θ] | 相對強度[%] |
| 3.7 | 100.00 |
| 6.1 | 86.20 |
| 7.1 | 45.11 |
| 12.1 | 13.70 |
| 14.2 | 16.17 |
| 18.8 | 8.77 |
| 21.6 | 16.10 |
| 24.0 | 9.08 |
| 27.4 | 32.26 |
| 28.2 | 16.79 |
DSC曲線展示於圖11中且呈現在約43℃、118℃及202℃下之若干個吸熱轉變。TGA曲線展示於圖12中且指示相溶劑化。未進一步表徵此形式。實例 6. 磷酸形式 II
化合物I磷酸鹽材料II藉由使化合物I形式I (53.00 mg)及1莫耳當量磷酸(13 µl，85%水溶液)在異丙醇(500 µl)中冷卻來分離。注意在磷酸添加至化合物I與異丙醇之混合物後即觀察到紫色變色，但在混合時變透明。反應產生凝膠且用多種溶劑濕磨，該等溶劑包括乙腈、二乙醚及乙腈/異丙醇(67/33 v/v)。藉由使凝膠在二乙醚中形成漿液且添加化合物I磷酸鹽形式I之晶種來使固體結晶。在攪拌約3天後藉由真空過濾分離固體。
化合物I磷酸形式II XRPD圖案展示於圖13中。表 6. 磷酸形式 II 之峰表
| 位置[°2θ] | 相對強度[%] |
| 5.4 | 86.78 |
| 6.3 | 100.00 |
| 10.4 | 7.13 |
| 11.5 | 4.54 |
| 13.6 | 6.08 |
| 15.4 | 6.17 |
| 15.8 | 14.48 |
| 16.3 | 7.56 |
| 18.1 | 18.65 |
| 18.5 | 6.00 |
| 18.9 | 21.75 |
| 20.6 | 12.08 |
| 21.4 | 6.04 |
| 22.4 | 3.94 |
| 23.6 | 6.50 |
| 23.8 | 8.09 |
| 24.1 | 10.39 |
| 26.0 | 1.56 |
| 26.7 | 22.49 |
| 27.4 | 11.38 |
| 28.7 | 3.62 |
| 29.2 | 2.37 |
| 31.5 | 2.31 |
| 32.4 | 2.96 |
DSC曲線展示於圖14中且呈現在約42℃及95℃下之兩個吸熱轉變。TGA曲線展示於圖15中且指示相溶劑化。未進一步表徵此形式。實例 7. 丁二酸
在Mettler-Toledo EasyMax Synthesis Workstation中在約60℃下使化合物I形式I (35.7 mg)及約半莫耳當量丁二酸(7.54 mg)溶解於異丙醇(0.5 ml)中。使溶液經約9小時冷卻至約5℃。藉由真空過濾收集固體，空氣乾燥約10分鐘，且分析。
化合物I丁二酸XRPD圖案展示於圖16中。表 7. 丁二酸之峰表
| 位置[°2θ] | 相對強度[%] |
| 4.6 | 19.38 |
| 6.8 | 100.00 |
| 9.3 | 36.09 |
| 12.7 | 3.55 |
| 13.2 | 8.09 |
| 13.6 | 4.77 |
| 14.1 | 5.61 |
| 14.9 | 5.69 |
| 15.8 | 6.68 |
| 17.5 | 10.00 |
| 18.2 | 4.60 |
| 18.7 | 16.13 |
| 19.0 | 14.47 |
| 19.3 | 6.42 |
| 19.7 | 4.79 |
| 20.7 | 7.51 |
| 21.3 | 5.50 |
| 22.0 | 4.99 |
| 22.5 | 5.25 |
| 23.0 | 8.23 |
| 25.7 | 19.51 |
| 27.0 | 7.81 |
| 27.4 | 2.60 |
| 28.3 | 2.18 |
| 28.7 | 2.77 |
| 30.1 | 1.75 |
| 36.4 | 2.43 |
DSC曲線展示於圖17中且呈現在約96℃及115℃下之兩個吸熱轉變。TGA曲線展示於圖18中且指示相未溶劑化。動態蒸汽吸附曲線展示於圖19中且資料指示在25℃下在高達95% RH下該形式吸附約1.2 %水。發現材料在實驗後未改變形式。實例 8. 乙二磺酸形式 I
自丙酮中之冷卻實驗中分離乙二磺酸形式I。在一個實驗中，在Avantium Crystal16®多反應器系統中將化合物I形式I (34.19 mg)、約一莫耳當量1,2-乙二磺酸水合物(27.3 mg)及丙酮(300 µl)加熱至約50℃。在約15分鐘之後，關閉反應器系統以快速冷卻至周圍溫度。在達到周圍溫度之後，將樣品再加熱至約50℃，保持約4小時，且接著以0.1℃/min冷卻至約10℃。藉由真空過濾收集固體且分析。
化合物I乙二磺酸形式I XRPD圖案展示於圖20中。表 8. 乙二磺酸形式 I 之峰表
實例 9. 乙二磺酸形式 II
| 位置[°2θ] | 相對強度[%] |
| 4.4 | 35.07 |
| 7.9 | 18.17 |
| 8.7 | 34.95 |
| 9.5 | 13.63 |
| 11.0 | 4.33 |
| 12.5 | 13.87 |
| 13.0 | 27.50 |
| 13.3 | 18.20 |
| 16.2 | 12.07 |
| 16.6 | 15.51 |
| 18.0 | 7.15 |
| 18.3 | 14.71 |
| 19.4 | 5.11 |
| 20.0 | 18.66 |
| 20.6 | 18.20 |
| 21.1 | 23.42 |
| 21.4 | 5.31 |
| 22.1 | 100.00 |
| 22.3 | 36.92 |
| 23.4 | 13.75 |
| 23.7 | 8.93 |
| 24.1 | 6.11 |
| 24.9 | 4.91 |
| 26.0 | 13.56 |
| 26.9 | 4.30 |
| 28.4 | 3.97 |
| 29.9 | 12.63 |
| 30.6 | 8.80 |
| 38.4 | 2.24 |
藉由在二氯甲烷中形成漿液來分離化合物I乙二磺酸形式II。亦自丙酮中之冷卻實驗中分離化合物I乙二磺酸鹽形式II。程序包括在Mettler-Toledo EasyMax反應器中在約60℃下使化合物I形式I (32.10 mg)溶解於丙酮(800 µl)中。將1,2-乙磺酸水合物(1.1莫耳當量，26.05 mg)添加至溶液中，且得到深紫色溶液。使溶液經約6.5小時冷卻至約20℃。
化合物I乙二磺酸形式II XRPD圖案展示於圖21中。表 9. 乙二磺酸形式 II 之峰表
| 位置[°2θ] | 相對強度[%] |
| 4.5 | 100.00 |
| 5.6 | 5.00 |
| 8.4 | 25.24 |
| 9.2 | 19.22 |
| 11.7 | 2.28 |
| 12.9 | 15.31 |
| 13.4 | 9.50 |
| 14.9 | 1.79 |
| 16.6 | 24.61 |
| 17.3 | 4.83 |
| 17.9 | 11.71 |
| 18.3 | 13.46 |
| 19.4 | 3.82 |
| 21.0 | 3.01 |
| 22.2 | 31.30 |
| 24.2 | 14.40 |
| 26.0 | 5.90 |
| 27.2 | 7.37 |
儘管出於清楚理解之目的已藉助於說明及實例相當詳細地描述前述揭示內容，但熟習此項技術者應瞭解，可在隨附申請專利範圍之範疇內實踐某些改變及修改。另外，在不與本說明書相矛盾的程度上，各參考文獻，包括本說明書中所提及之所有美國專利、美國專利申請公開案、美國專利申請案、外國專利、外國專利申請案及非專利公開案均以全文引用之方式併入本文中。當本申請案與本文所提供之參考文獻之間存在衝突時，應以本申請案為準。
圖1展示化合物I形式I之XRPD圖案。
圖2展示化合物I龍膽酸之XRPD圖案。
圖3展示化合物I龍膽酸之DSC熱圖像。
圖4展示化合物I龍膽酸之TGA曲線。
圖5展示化合物I龍膽酸之DVS曲線。
圖6展示化合物I馬尿酸之XRPD圖案。
圖7展示化合物I馬尿酸之DSC熱圖像。
圖8展示化合物I馬尿酸之TGA曲線。
圖9展示化合物I馬尿酸之DVS曲線。
圖10展示化合物I磷酸形式I之XRPD圖案。
圖11展示化合物I磷酸形式I之DSC熱圖像。
圖12展示化合物I磷酸形式I之TGA曲線。
圖13展示化合物磷酸形式II之XRPD圖案。
圖14展示化合物I磷酸形式II之DSC熱圖像。
圖15展示化合物I磷酸形式II之TGA曲線。
圖16展示化合物I丁二酸之XRPD圖案。
圖17展示化合物I丁二酸之DSC熱圖像。
圖18展示化合物I丁二酸之TGA曲線。
圖19展示化合物I丁二酸之DVS曲線。
圖20展示化合物I乙二磺酸形式I之XRPD圖案。
圖21展示化合物I乙二磺酸形式II之XRPD圖案。
Claims (27)
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇龍膽酸之結晶形式：
- 如請求項1之結晶形式，其中XRPD圖案在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ(±0.2° 2θ)處包含四個或更多個峰。
- 如請求項1之結晶形式，其中該XRPD圖案在4.4°、8.7°及14.9° 2θ(±0.2° 2θ)處包含峰。
- 如請求項3之結晶形式，其中該XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ(±0.2° 2θ)處包含一或多個額外峰。
- 如請求項3之結晶形式，其中該XRPD圖案進一步在12.9°、17.3°、19.5°、24.8°、25.7°或26.3° 2θ(±0.2° 2θ)處包含兩個或更多個額外峰。
- 如請求項1之結晶形式，其中該XRPD圖案在12.9°、24.8°及25.7° 2θ(±0.2° 2θ)處包含峰。
- 如請求項6之結晶形式，其中該XRPD圖案進一步在4.4°、8.7°、14.9°、17.3°、19.5°或26.3° 2θ(±0.2° 2θ)處包含一或多個額外峰。
- 如請求項6之結晶形式，其中該XRPD圖案進一步在4.4°、8.7°、14.9°、24.8°或26.3° 2θ(±0.2° 2θ)處包含兩個或更多個額外峰。
- 如請求項1至8中任一項之結晶形式，其中該XRPD圖案在4.4°、8.7°、12.9°、14.9°、17.3°、19.5°、24.8°、25.7°及26.3° 2θ(±0.2° 2θ)處包含峰。
- 如請求項1至8中任一項之結晶形式，其中該XRPD圖案實質上如圖2中所示。
- 如請求項1至8中任一項之結晶形式，其中差示掃描熱量測定(DSC)熱分析圖在約178℃下開始吸熱。
- 如請求項1至8中任一項之結晶形式，其中DSC熱分析圖實質上如圖3中所示。
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1- 醇馬尿酸之結晶形式：
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇磷酸之結晶形式：
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇丁二酸之結晶形式：
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
- 一種(R)-2-((2-胺基-7-氟吡啶并[3,2-d]嘧啶-4-基)胺基)-2-甲基己-1-醇乙二磺酸之結晶形式：
- 一種醫藥組合物，其包含如請求項1至18中任一項之結晶形式及一或多種醫藥學上可接受之賦形劑。
- 如請求項19之醫藥組合物，其中該結晶形式為該龍膽酸鹽。
- 一種如請求項1至18中任一項之結晶形式的用途，其用於製造供治療或預防HBV感染用之藥劑。
- 如請求項21之用途，其中該藥劑進一步包含一或多種額外治療劑或與一或多種額外治療劑併用。
- 如請求項22之用途，其中該一或多種額外治療劑與該結晶形式同時投與。
- 如請求項22至23中任一項之用途，其中該一或多種額外治療劑係選自由以下組成之群：HBV組合藥物、HBV疫苗、HBV DNA聚合酶抑制劑、免疫調節劑、類鐸受體(TLR)調節劑、干擾素α受體配位體、玻尿酸 酶抑制劑、B型肝炎表面抗原(HBsAg)抑制劑、細胞毒性T淋巴細胞相關蛋白4(ipi4)抑制劑、親環素抑制劑、HBV病毒進入抑制劑、靶向病毒mRNA之反義寡核苷酸、短干擾RNA(siRNA)及ddRNAi核酸內切酶調節劑、核糖核苷酸還原酶抑制劑、HBVE抗原抑制劑、共價閉合環狀DNA(cccDNA)抑制劑、法尼酯(farnesoid)X受體促效劑、HBV抗體、CCR2趨化因子拮抗劑、胸腺素促效劑、細胞介素、核蛋白調節劑、視黃酸誘導性基因1刺激劑、NOD2刺激劑、磷脂醯肌醇3-激酶(PI3K)抑制劑、吲哚胺-2,3-雙加氧酶(IDO)路徑抑制劑、PD-1抑制劑、PD-L1抑制劑、重組胸腺素α-1促效劑、布魯東氏酪胺酸激酶(Bruton's tyrosine kinase，BTK)抑制劑、KDM抑制劑、HBV複製抑制劑、精胺酸酶抑制劑及其他HBV藥物。
- 如請求項22至23中任一項之用途，其中該一或多種額外治療劑係選自由以下組成之群：阿德福韋(adefovir)(Hepsera®)、反丁烯二酸替諾福韋二吡呋酯(tenofovir disoproxil fumarate)+恩曲他濱(emtricitabine)(Truvada®)、反丁烯二酸替諾福韋二吡呋酯(Viread®)、恩替卡韋(entecavir)(Baraclude®)、拉米夫定(lamivudine)(Epivir-HBV®)、替諾福韋艾拉酚胺(tenofovir alafenamide)、替諾福韋、替諾福韋二吡呋酯(tenofovir disoproxil)、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替比夫定(telbivudine)(Tyzeka®)、Clevudine®、恩曲他濱(Emtriva®)、聚乙二醇化干擾素α-2b(PEG-Intron®)、Multiferon®、干擾素α 1b(Hapgen®)、干擾素α-2b(Intron A®)、聚乙二醇化干擾素α-2a(Pegasys®)、干擾素α-n1(Humoferon®)、利巴韋林(ribavirin)、干擾素β-1a(Avonex®)、Bioferon、Ingaron、Inmutag (Inferon)、Algeron、Roferon-A、Oligotide、Zutectra、Shaferon、干擾素α-2b(Axxo)、Alfaferone、干擾素α-2b、Feron、干擾素-α 2(CJ)、Bevac、Laferonum、Vipeg、Blauferon-B、Blauferon-A、Intermax α、Realdiron、Lanstion、Pegaferon、PDferon-B、α干擾素2b、Kalferon、Pegnano、Feronsure、PegiHep、Optipeg A、Realfa 2B、Reliferon、聚乙二醇化干擾素α-2b、Reaferon-EC、Proquiferon、Uniferon、Urifron、干擾素α-2b、Anterferon、Shanferon、MOR-22、介白素-2(IL-2)、重組人類介白素-2(Shenzhen Neptunus)、Layfferon、卡舒寧(Ka Shu Ning)、上生雷泰(Shang Sheng Lei Tai)、Intefen、Sinogen、Fukangtai、Alloferon及西莫介白素(celmoleukin)。
- 如請求項22至23中任一項之用途，其中該一或多種額外治療劑係選自由以下組成之群：恩替卡韋、阿德福韋、反丁烯二酸替諾福韋二吡呋酯、替諾福韋艾拉酚胺、替諾福韋、替諾福韋二吡呋酯、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替比夫定及拉米夫定。
- 如請求項22至23中任一項之用途，其中該一或多種額外治療劑係選自由替諾福韋艾拉酚胺、反丁烯二酸替諾福韋艾拉酚胺及半反丁烯二酸替諾福韋艾拉酚胺組成之群。
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| TW202212339A (zh) | 2019-04-17 | 2022-04-01 | 美商基利科學股份有限公司 | 類鐸受體調節劑之固體形式 |
| TW202115056A (zh) | 2019-06-28 | 2021-04-16 | 美商基利科學股份有限公司 | 類鐸受體調節劑化合物的製備方法 |
| TW202310852A (zh) | 2021-05-13 | 2023-03-16 | 美商基利科學股份有限公司 | ＴＬＲ８調節化合物及抗ＨＢＶ ｓｉＲＮＡ療法之組合 |
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| TW202104219A (zh) | 2021-02-01 |
| KR20210151942A (ko) | 2021-12-14 |
| CN113906023A (zh) | 2022-01-07 |
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