TW201831489A - 布魯頓氏酪胺酸激酶之抑制劑 - Google Patents
布魯頓氏酪胺酸激酶之抑制劑 Download PDFInfo
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
本文提供6-胺基-9-[(3R)-1-(2-丁炔醯基)-3-吡咯啶基]-7-(4-苯氧基苯基)-7,9-二氫-8H-嘌呤-8-酮之形式、其組合物、其製備方法及其使用方法。
Description
本申請案概言之係關於用於治療疾病之治療劑及組合物，且更具體而言係關於布魯頓氏酪胺酸激酶(Bruton's Tyrosine Kinase，BTK)抑制劑。
BTK係激酶之Tec家族成員且參與B細胞中之信號轉導及肥胖細胞之活化。已將若干化合物鑑別為BTK抑制劑。實例揭示於以下中：美國專利第7,514,444號、第8,501,724號、第8,557,803號、第8,940,725號、第8,940,893號、第9,199,997及第9,371,325號；美國公開專利申請案第2014/0142099號；PCT公開案第WO 2008/121742號、第WO 2013/010380號、第WO 2013/010868號、第WO 2013/010869號、第WO 2015/002894及第WO 2015/048689號。將一些BTK抑制劑評估為(例如)自體免疫疾病及癌症之潛在治療劑。
需要研發抑制BTK以治療由BTK介導之疾病、病症或病況之治療劑。
在一態樣中，本文提供具有以下結構之化合物(I)之鹽及共晶體形式：
在一些態樣中，本文提供化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二 磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽。在某些態樣中，本文提供呈鹽或共晶體形式之化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽。
在另一態樣中，提供包含化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽及一或多種醫藥學上可接受之載劑或賦形劑的醫藥組合物。亦提供包含化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之製品及單位劑型。亦提供包含本文所述化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽及使用說明書(例如，於BTK介導之病症、例如自體免疫疾病或癌症中之使用說明書)的套組。
在一種變化形式中，提供治療有需要之人類之BTK介導之病症之方法，其包含向人類投與化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽或其組合物(包括醫藥組合物)。在一些實施例中，BTK介導之病症係自體免疫疾病或癌症。
亦提供化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽或其組合物(包括醫藥組合物)之用途，其用於製造用於治療對BTK活性之抑制有反應之疾病(例如自體免疫疾病或癌症)的藥劑。
另外提供製造化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之方法的此外，提供產生包含化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之組合物的方法。
製造化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之方法包含組合適宜酸及化合物(I)與適宜 溶劑或適宜溶劑混合物。適宜酸可包括但不限於硫酸、草酸、乙烷-1,2-二磺酸、萘-1,5-二磺酸、富馬酸及琥珀酸。適宜溶劑可包括但不限於甲醇、乙醇、水、乙酸異丙酯、乙酸乙酯、甲基第三丁基醚、正庚烷、乙腈、丙酮、2-甲基四氫呋喃、四氫呋喃、甲基異丁基酮、甲基乙基酮、二氯甲烷、2-丙醇、1-丙醇、1-丁醇及其任何混合物。亦提供藉由本文詳述之方法(例如製造方法)獲得之化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽。
可藉由參照以下說明結合附圖最佳地理解本揭示案。
圖1A-1D分別顯示化合物(I)半硫酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖2A-2D分別顯示化合物(I)草酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖3A-3D分別顯示化合物(I)半乙二磺酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖4A-4D分別顯示化合物(I)乙二磺酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖5A-5D分別顯示化合物(I)半萘二磺酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖6A-6D分別顯示化合物(I)富馬酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
圖7A-7D分別顯示化合物(I)琥珀酸鹽之X射線粉末繞射圖案(XRPD)圖案、差示掃描量熱法(DSC)溫度記錄圖、熱重分析(TGA)溫度記錄圖及動態氣相吸附(DVS)圖。
提供以下說明以使得熟習此項技術者能夠製得及使用各個實施例。具體化合物、方法、技術及應用之說明僅作為實例提供。彼等熟習此項技術者將容易地明瞭對本文所述實例之各種修改，且可在不背離各個實施例之精神及範疇的情況下將本文所述一般原理應用於其他實例及應用。因此，各個實施例並不意欲限於本文所述及顯示實例，而是被給與和申請專利範圍一致之範疇。
如本申請案中所使用，除非在使用其之上下文中另外指明，否則以下詞語及片語通常意欲具有如下文所述之含義。術語「約」包括且闡述值或參數本身。舉例而言，「約x」包括且闡述「x」本身。在某一實施例中，術語「約」在與量測結合使用或用於修飾值、單位、常數或值範圍時係指+/- 1-10%之變化。在一些實施例中，術語「約」在與量測結合使用或用於修飾值、單位、常數或值範圍時係指+/- 5%之變化。在一些實施例中，術語「約」在與量測結合使用或用於修飾值、單位、常數或值範圍時係指+/- 10%之變化。術語「之間」包括且闡述值或參數本身。舉例而言，「介於x與y之間」包括且闡述「x」及「y」本身。術語「及/或」包括替代之標的物以及組合之標的物。例如，「x及/或y」包括「x或y」以及「x及y」。
給定式之化合物意欲涵蓋本揭示案之化合物及該等化合物之鹽、酯、異構物、互變異構物、溶劑合物、同位素、水合物、形式(包括多形體、擬態多 晶型、晶體或共晶體形式)及前藥。另外，本揭示案之化合物可具有一或多個不對稱中心，且可以外消旋混合物、非外消旋混合物、非鏡像異構物之混合物或以個別鏡像異構物或非鏡像異構物形式產生。存在於給定式之任何給定化合物中之立體異構物的數量取決於所存在不對稱中心之數量(存在2n種可能的立體異構物，其中n係不對稱中心之數量)。個別立體異構物(包括個別鏡像異構物及非鏡像異構物)以及立體異構物之外消旋及非外消旋混合物涵蓋於本發明之範疇內，除非另外明確指示，否則其皆意欲由本說明書之結構來繪示。本揭示案之化合物包括可分離之旋轉異構物或阻轉異構物。
「異構物」係具有相同分子式之不同化合物。異構物包括立體異構物、鏡像異構物及非鏡像異構物。「立體異構物」係僅原子在空間中之排列方式不同之異構物。「鏡像異構物」係一對彼此為非重疊鏡像之立體異構物。鏡像異構物對之1：1混合物為「外消旋」混合物。若適當，術語「(±)」用於指示外消旋混合物。「非鏡像異構物」係具有至少兩個不對稱原子、但彼此不為鏡像之立體異構物。
根據Cahn Ingold Prelog R S系統來指定絕對立體化學。當化合物係純鏡像異構物時，每一手性碳之立體化學可指定為R或S。絕對構形未知之拆分化合物端視其在鈉D線波長下旋轉偏振光之平面之方向(右旋或左旋)指定為(+)或(-)。
「互變異構物」係由同一有機分子內之原子或官能基之遷移產生且導致其一或多個結構骨架、電子密度分佈及化學性質之變化的結構異構物。應理解，本文揭示之化合物包括互變異構形式，但未必明確顯示。在一個實例中，嘌呤可由以下互變異構物中之任一者表示：
因此，在提及嘌呤互變異構物種之任一者時包括其他互變異構形式。
若所繪示結構與給與該結構之名稱之間存在差異，則以所繪示結構為準。此外，若結構或結構之一部分的立體化學未以(例如)粗體、楔形線或虛線表示出來，則應將該結構或該結構之一部分理解為涵蓋其所有立體異構物。
術語「溶劑合物」係指藉由組合如本文揭示之任何式之化合物與溶劑所形成的複合物。術語「水合物」係指藉由組合本文揭示之任何式之化合物與水所形成的複合物。
本文給出之任一式或結構亦意欲表示化合物之未標記形式以及經同位素標記形式。經同位素標記之化合物具有由本文所給出式繪示之結構，只是一或多個原子由具有所選原子質量或質量數的原子置換。可納入本揭示案之化合物中之同位素的實例包括氫、碳、氮、氧、磷、氟及氯之同位素，例如但不限於2H(氘，D)、3H(氚)、11C、13C、14C、15N、18F、31P、32P、35S、36Cl及125I。本揭示案之各種經同位素標記之化合物，例如其中納入諸如例如3H、13C及14C等放射性同位素之彼等。此等經同位素標記之化合物可用於代謝研究、反應動力學研究、檢測或成像技術(例如正電子發射斷層攝影(PET)或單光子發射電腦斷層攝影(SPECT)，包括藥物或受質組織分佈分析)或患者之放射性治療。
本揭示案亦包括本文揭示之任一式之化合物，其中附接至碳原子之1至「n」個氫由氘置換，其中n係分子中氫之數量。該等化合物在投與哺乳動物時展現增加之代謝抗性且因此可用於延長式(I)-(III)化合物之半衰期。參見(例如)Foster,「Deuterium Isotope Effects in Studies of Drug Metabolism」,Trends Pharmacal.Sci.5(12)：524-527(1984)。該等化合物係藉由業內熟知之方式(例如藉由採用一或多個氫原子經氘置換之起始材料)來合成。
本揭示案之經氘標記或取代之治療化合物具有改良之與分佈、代謝及排泄(ADME)相關之DMPK(藥物代謝及藥物動力學)性質。用較重同位素(例 如氘)進行取代因更強代謝穩定性可提供某些治療優點，例如延長之活體內半衰期或降低之劑量需求。18F標記之化合物可用於PET或SPECT研究。經同位素標記之本揭示案之化合物及其前藥通常可藉由實施在反應圖中或在下文所述實例及製備中所揭示之程序藉由用易於獲得之經同位素標記之試劑取代未經同位素標記之試劑來製備。此外，用較重同位素、尤其氘(亦即，2H或D)進行取代因更強代謝穩定性可提供某些治療優點，例如延長之活體內半衰期或劑量需求降低或治療指數改良。應瞭解，在此上下文中氘被視為本文揭示之任一式之化合物之取代基。
該較重同位素(具體而言氘)之濃度可由同位素富集因子定義。在本揭示案之化合物中，未明確命名為同位素之任何原子意指代表該原子之任何穩定同位素。除非另外陳述，否則在位置明確命名為「H」或「氫」時，該位置應理解為在其天然豐度同位素組合物處具有氫。因此，在本揭示案之化合物中，明確命名為氘(D)之任何原子意欲代表氘。
在許多情形下，本揭示案之化合物藉助胺基及/或羧基或與其類似之基團之存在能夠形成酸及/或鹼式鹽。鹼或酸加成鹽可自無機及有機鹼來製備。
在一些實施例中，鹽係「醫藥學上可接受之鹽」。給定化合物之醫藥學上可接受之鹽係指保留給定化合物之生物有效性及性質且在生物或其他方面合意之鹽。參見：P.Heinrich Stahl及Camille G.Wermuth(編輯)Pharmaceutical Salts：Properties,Selection,and Use(International Union of Pure and Applied Chemistry),Wiley-VCH；第2修訂版(2011年5月16日)。
本文所述化合物可以化學結構或名稱形式提供。舉例而言，化合物(I)可使用ChemBioDraw Ultra 10.0命名且應理解為可使用其他名稱來鑑別相同結構之化合物。其他化合物或基團可利用共用名稱或系統性或非系統性名稱來命名。該等化合物亦可使用化學領域中公認之其他命名系統及符號(包括例如化 學文摘服務社(Chemical Abstract Service，CAS)及國際純化學及應用化學聯合會(International Union of Pure and Applied Chemistry，IUPAC))來命名。
本申請案提供抑制BTK活性、適用作BTK抑制劑之化合物。在一態樣中，BTK抑制劑係具有以下結構之化合物(I)之鹽或形式：
化合物(I)亦可表示為6-胺基-9-[(3R)-1-(2-丁炔醯基)-3-吡咯啶基]-7-(4-苯氧基苯基)-7,9-二氫-8H-嘌呤-8-酮。
在另一態樣中，BTK抑制劑係化合物(I)之鹽或共晶體形式。在某一實施例中，BTK抑制劑係化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽。化合物(I)之半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽及琥珀酸鹽可以任何形式、包括鹽或共晶體形式提出。該等鹽或共晶體形式可由各種固態分析數據(包括例如X射線粉末繞射圖案(XRPD)、差示掃描量熱法(DSC)、熱重分析(TGA)及單晶X射線結晶學)表徵。熟習此項技術者應識別可用於生成該等表徵數據之各種技術或方法。除非另外陳述，否則本文提供之XRPD圖案係於室溫下藉由粉末X射線繞射儀生成。
化合物(I)之結晶鹽或共晶體形式可提供生物利用度及穩定性之優點，其適用作醫藥組合物中之活性成分。美國專利第8,557,803中揭示之6-胺基-9-[(3R)-1-(2-丁炔醯基)-3-吡咯啶基]-7-(4-苯氧基苯基)-7,9-二氫-8H-嘌呤-8-酮係BTK抑制劑之實例。BTK抑制劑之鹽揭示於(例如)美國專利第9,199,997號及第 9,371,325號中。該等參照文獻中之每一者之全文以引用方式併入本文中。與第9,199,997號及第9,371,325號中揭示之鹽之溶解度相比，化合物(I)半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之鹽或共晶體形式可具有類似或增強之溶解度。在一些實施例中，化合物(I)之鹽或共晶體形式、本申請案之化合物、本文所述化合物、本申請案之BTK抑制劑、此處所述BTK抑制劑或其變化形式之術語係指呈鹽或共晶體形式之化合物(I)半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽。醫藥原料藥或活性成分之晶體結構之變化可影響醫藥產品或活性成分之溶解速率(其可影響生物利用度)、可製造性(例如，易於操作、能夠一致地製備已知強度之劑量)及穩定性(例如，熱穩定性、儲放壽命)。該等變化可影響呈不同劑量或遞送形式(例如固體經口劑型，包括錠劑及膠囊)之醫藥組合物之製備或調配。與其他形式(例如非結晶或非晶型)相比，結晶型可提供期望或適宜吸濕性、粒徑控制、溶解速率、溶解度、純度、物理及化學穩定性、可製造性、產率及/或過程控制。因此，化合物(I)之結晶鹽或共晶體形式可提供如下優點：改良活性劑之製造過程或化合物或活性成分之藥物產品形式之穩定性或可儲存性，或具有作為活性劑之適宜生物利用度及/或穩定性。
已發現使用某些酸可產生不同固體形式之化合物(I)，包括半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽及琥珀酸鹽形式，其可展現本文所述之一或多種有利之特徵，包括但不限於生物利用度及穩定性。本文所述形式之製備及表徵之過程。術語「實質上如……中所示」在提及(例如)XRPD圖案、DSC溫度記錄圖、TGA溫度記錄圖或DVS圖時包括不必與本文繪示之彼等相同、但在由熟習此項技術者考慮時在實驗誤差或偏差之限制內的圖案、溫度記錄圖或圖。
在一態樣中，提供化合物(I)半硫酸鹽，其中結晶型展現實質上如圖1A中所示之XRPD圖案。化合物(I)半硫酸鹽展現實質上如圖1B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)半硫酸鹽展現實質上如圖1C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)半硫酸鹽展現實質上如圖1D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)半硫酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖1A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)半硫酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)半硫酸鹽具有包含6.6、18.6及23.7之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)半硫酸鹽具有包含6.6、7.1、13.7、18.6及23.7之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)半硫酸鹽具有包含自約25℃至約150℃約0.6%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)半硫酸鹽具有包含約192℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)半硫酸鹽具有包含於約25℃下自約10%至約90% RH約1.2%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)半硫酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖1A中所示之XRPD圖案；(b)實質上如圖1B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)草酸鹽，其中結晶型展現實質上如圖2A中所示之XRPD圖案。化合物(I)草酸鹽展現實質上如圖2B中所示之差示掃描量 熱法(DSC)溫度記錄圖。化合物(I)草酸鹽展現實質上如圖2C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)草酸鹽展現實質上如圖2D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)草酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖2A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)草酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)草酸鹽具有包含7.2、18.2及23.3之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)草酸鹽具有包含7.2、13.8、18.2、20.2及23.3之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)草酸鹽具有包含自約25℃至約100℃約0.6%之重量損失之熱重分析溫度記錄圖。在一個實施例中，化合物(I)草酸鹽之溫度記錄圖進一步包含自約100℃至約200℃約11%之重量損失。在某些實施例中，化合物(I)草酸鹽具有包含約171℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)草酸鹽具有包含於約25℃下自約10%至約90% RH約0.5%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)草酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖2A中所示之XRPD圖案；(b)實質上如圖2B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)半乙二磺酸鹽，其中結晶型展現實質上如圖3A中所示之XRPD圖案。化合物(I)半乙二磺酸鹽展現實質上如圖3B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)半乙二磺酸鹽展現實質上如圖 3C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)半乙二磺酸鹽展現實質上如圖3D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)半乙二磺酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖3A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)半乙二磺酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)半乙二磺酸鹽具有包含5.9、11.8及17.6之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)半乙二磺酸鹽具有包含5.9、11.8、17.6、21.2及23.6之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)半乙二磺酸鹽具有包含自約25℃至約100℃約3.3%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)半乙二磺酸鹽具有包含約165℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)半乙二磺酸鹽具有包含於約25℃下自約10%至約90% RH約3%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)半乙二磺酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖3A中所示之XRPD圖案；(b)實質上如圖3B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)乙二磺酸鹽，其中結晶型展現實質上如圖4A中所示之XRPD圖案。化合物(I)乙二磺酸鹽展現實質上如圖4B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)乙二磺酸鹽展現實質上如圖4C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)乙二磺酸鹽展現實質上如圖4D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)乙二磺酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖4A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)乙二磺酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)乙二磺酸鹽具有包含5.7、16.6及24.2之°2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)乙二磺酸鹽具有包含5.7、11.1、16.6、22.2及24.2之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)乙二磺酸鹽具有包含自約25℃至約100℃約4.0%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)乙二磺酸鹽具有包含約154℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)乙二磺酸鹽具有包含於約25℃下自約10%至約90% RH約22%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)乙二磺酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖4A中所示之XRPD圖案；(b)實質上如圖4B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)半萘二磺酸鹽，其中結晶型展現實質上如圖5A中所示之XRPD圖案。化合物(I)半萘二磺酸鹽展現實質上如圖5B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)半萘二磺酸鹽展現實質上如圖5C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)半萘二磺酸鹽展現實質上如圖5D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)半萘二磺酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質 上如圖5A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)半萘二磺酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)半萘二磺酸鹽具有包含15.5、16.5及23.8之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)半萘二磺酸鹽具有包含5.6、15.5、16.5、20.3及23.8之° 2θ反射(+/-0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)半萘二磺酸鹽具有包含自約25℃至約125℃約1.5%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)半萘二磺酸鹽具有包含約180℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)半萘二磺酸鹽具有包含於約25℃下自約10%至約90% RH約6.5%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)半萘二磺酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖5A中所示之XRPD圖案；(b)實質上如圖5B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)富馬酸鹽，其中結晶型展現實質上如圖6A中所示之XRPD圖案。化合物(I)富馬酸鹽展現實質上如圖6B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)富馬酸鹽展現實質上如圖6C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)富馬酸鹽展現實質上如圖6D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)富馬酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖6A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包 括針對化合物(I)富馬酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)富馬酸鹽具有包含13.0、16.6及19.9之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)富馬酸鹽具有包含8.3、13.0、16.6、19.0及19.9之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)富馬酸鹽具有包含自約25℃至約100℃約0.04%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)富馬酸鹽具有包含約158℃下之吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)富馬酸鹽具有包含於約25℃下自約10%至約90% RH約0.1%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)富馬酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖6A中所示之XRPD圖案；(b)實質上如圖6B中所示之DSC溫度記錄圖。
在一態樣中，提供化合物(I)琥珀酸鹽，其中結晶型展現實質上如圖7A中所示之XRPD圖案。化合物(I)琥珀酸鹽展現實質上如圖7B中所示之差示掃描量熱法(DSC)溫度記錄圖。化合物(I)琥珀酸鹽展現實質上如圖7C中所示之熱重分析(TGA)溫度記錄圖。化合物(I)琥珀酸鹽展現實質上如圖7D中所示之動態氣相吸附(DVS)圖。
在一些實施例中，化合物(I)琥珀酸鹽具有展示具有最大強度之至少兩個、至少三個、至少四個或至少五個° 2θ反射的XRPD圖案，作為實質上如圖7A中所示之XRPD圖案。應理解，相對強度可根據多個因素(包括樣品製備、安裝及用於獲得譜之儀器及分析程序及設置)變化。因此，本文列舉之峰歸屬(包括針對化合物(I)琥珀酸鹽)意欲涵蓋+/- 0.2° 2θ之變化。
在某些實施例中，化合物(I)琥珀酸鹽具有包含13.2、16.5及18.0之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。在一個實施例中，化合物(I)琥珀酸鹽具有包含8.2、13.2、16.5、18.0及18.6之° 2θ反射(+/- 0.2° 2θ)之XRPD圖案。
在某些實施例中，化合物(I)琥珀酸鹽具有包含自約25℃至約125℃約0.2%之重量損失之熱重分析溫度記錄圖。在某些實施例中，化合物(I)琥珀酸鹽具有包含約142℃及約160℃下之兩個吸熱之差示掃描量熱曲線。在某些實施例中，化合物(I)琥珀酸鹽具有包含於約25℃下自約10%至約90% RH約0.2%之水攝取的動態氣相吸附等溫線。在一些實施例中，化合物(I)琥珀酸鹽具有以下性質中之至少一者或二者：(a)實質上如圖7A中所示之XRPD圖案；(b)實質上如圖7B中所示之DSC溫度記錄圖。
本發明化合物具有BTK抑制活性且因此可用作用於預防及/或治療BTK有關之疾病(亦即，B細胞及/或肥胖細胞參與之疾病，例如過敏性病、自體免疫疾病、發炎性疾病、血栓栓塞性疾病、癌症及移植抗宿主疾病)之試劑。本發明化合物亦實踐對B細胞活化之選擇性抑制作用且因此有效用作B細胞活化之抑制劑。
合成化合物(I)之一種方法已先前闡述於美國專利第8,557,803號中。此參考文獻之全文且具體而言關於化合物(I)之合成以引用方式併入本文中。本文所述化合物(I)之鹽或共晶體形式可自化合物(I)製備。舉例而言，在一態樣中，提供產生包含本文所述化合物(I)之鹽或共晶體形式之組合物的方法，其中該方法包含組合化合物(I)與適宜酸及適宜溶劑或適宜溶劑之混合物以產生包含本文所述化合物(I)之鹽或共晶體形式之組合物。
適於鹽或共晶體形成之酸可包括但不限於(例如)硫酸、草酸、乙烷-1,2-二磺酸、萘-1,5-二磺酸、富馬酸及琥珀酸。適於鹽或共晶體形成之溶劑可包 括但不限於(例如)甲醇、乙醇、水、乙酸異丙酯、乙酸乙酯、甲基第三丁基醚、正庚烷、乙腈、丙酮、2-甲基四氫呋喃、四氫呋喃、甲基異丁基酮、甲基乙基酮、二氯甲烷、2-丙醇、1-丙醇、1-丁醇及其任何混合物。在另一態樣中，亦提供根據本文所述方法中之任一者產生之本文所述化合物(I)的鹽或共晶體形式。
在一個實施例中，提供產生包含化合物(I)半硫酸鹽之組合物之方法，其中該方法包含(i)組合化合物(I)與硫酸及適宜溶劑以獲得混合物；(ii)將步驟(i)中獲得之混合物加熱至約70℃；(iii)將步驟(ii)中獲得之混合物冷卻至約0℃；及(iv)收集步驟(iii)中獲得之固體材料以獲得化合物(I)半硫酸鹽。
在另一實施例中，提供產生包含化合物(I)草酸鹽之組合物之方法，其中該方法包含(i)於約21℃下組合化合物(I)與草酸及適宜溶劑以獲得混合物；(ii)收集步驟(i)中獲得之固體材料以獲得化合物(I)草酸鹽。
在另一實施例中，提供產生包含化合物(I)半乙二磺酸鹽之組合物之方法，其中該方法包含(i)於約21℃下組合化合物(I)與乙烷-1,2-二磺酸二水合物及適宜溶劑以獲得混合物；(ii)收集步驟(i)中獲得之固體材料以獲得化合物(I)半乙二磺酸鹽。
在另一實施例中，提供產生包含化合物(I)乙二磺酸鹽之組合物之方法，其中該方法包含(i)於約21℃下組合化合物(I)與乙烷-1,2-二磺酸二水合物及適宜溶劑以獲得混合物；(ii)收集步驟(i)中獲得之固體材料以獲得化合物(I)乙二磺酸鹽。
在另一實施例中，提供產生包含化合物(I)半萘二磺酸鹽之組合物之方法，其中該方法包含(i)組合化合物(I)與萘-1,5-二磺酸及適宜溶劑以獲得混合物；(ii)將步驟(i)中獲得之混合物加熱至約50℃；(iii)將步驟ii)中獲得之混合物冷卻至約20℃；及(iv)收集步驟(iii)中獲得之固體材料以獲得化合物(I)半萘二磺酸鹽。
在另一實施例中，提供產生包含化合物(I)富馬酸鹽之組合物之方法，其中該方法包含(i)組合化合物(I)與富馬酸及適宜溶劑；(ii)將步驟(i)中獲得之混合物加熱至約50℃；(iii)將步驟(ii)中獲得之混合物冷卻至約20℃；及(iv)收集步驟(iii)中獲得之固體材料以獲得化合物(I)富馬酸鹽。
在另一實施例中，提供產生包含化合物(I)琥珀酸鹽之組合物之方法，其中該方法包含(i)組合化合物(I)與琥珀酸及適宜溶劑；(ii)將步驟(i)中獲得之混合物加熱至約50℃；(iii)將步驟(ii)中獲得之混合物冷卻至約20℃；及(iv)收集步驟(iii)中獲得之固體材料以獲得化合物(I)琥珀酸鹽。
在用以產生本文所述化合物(I)之鹽或共晶體形式之上述方法之一些實施例中，該方法進一步包含自所得組合物分離鹽或共晶體。可採用業內已知用以自組合物分離鹽或共晶體形式之任何適宜技術或方法。舉例而言，可藉由已知方法(例如過濾及/或蒸發)移除上述方法中所用之溶劑或溶劑混合物以分離自組合物產生之鹽或共晶體。
在一些實施例中，本文所述組合物可包含實質上純的本文所述化合物(I)之鹽或共晶體形式或可實質上不含其他多形體及/或雜質。在一些實施例中，關於本文所述化合物(I)半硫酸鹽、草酸鹽、半乙二磺酸鹽、乙二磺酸鹽、半萘二磺酸鹽、富馬酸鹽或琥珀酸鹽之鹽或共晶體形式之術語「實質上純」或「實質上不含」意指包含本文所述化合物(I)之鹽或共晶體形式的組合物含有小於95重量%、小於90重量%、小於80重量%、小於70重量%、小於65重量%、小於60重量%、小於55重量%、小於50重量%、小於40重量%、小於30重量%、小於20重量%、小於15重量%、小於10重量%、小於重量5%或小於重量1%之其他物質，包括其他多晶型及/或雜質。在某些實施例中，「實質上純的」或「實質上不含」係指物質不含其他物質，包括其他多晶型及/或雜質。雜質可(例 如)包括來自化學反應之副產物或剩下之試劑、污染物、降解產物、其他多晶型、水及溶劑。
在一些實施例中，組合物包含本文所述化合物(I)之鹽或共晶體之多晶型。在某些實施例中，提供包含本文所述化合物(I)之鹽或共晶體形式之組合物，其中組合物內之化合物(I)之鹽或共晶體之多晶型係實質上純的多晶型。在包含本文所述化合物(I)之鹽或共晶體之多晶型的組合物之其他實施例中，至少約50%、至少約60%、至少約70%、至少約80%、至少約85%、至少約90%、至少約95%、至少約96%、至少約97%、至少約98%或至少約99%之組合物中之化合物(I)之鹽或共晶體呈本文所述化合物(I)之鹽或共晶體之多晶型。
在包含本文所述化合物(I)之鹽或共晶體之多晶型的組合物之其他實施例中，小於約50%、小於約40%、小於約30%、小於約20%、小於約10%、小於約5%、小於約4%、小於約3%、小於約2%或小於約1%之存於組合物中之化合物(I)之鹽或共晶體係化合物(I)之鹽或共晶體之其他多晶型及/或雜質。在包含本文所述化合物(I)之鹽或共晶體形式之組合物的其他實施例中，相對於存在之本文所述化合物(I)之鹽或共晶體形式之質量，雜質佔總質量之小於約5%、小於約4%、小於約3%、小於約2%或小於約1%。雜質可(例如)包括自合成本文所述化合物(I)之鹽或共晶體形式產生之副產物、污染物、降解產物、其他多晶型、水及溶劑。
在其他實施例中，包含本文所述化合物(I)之鹽或共晶體形式之組合物具有小於約5重量%、小於約4重量%、小於約3重量%、小於約2重量%或小於約1重量%之化合物(I)之鹽或共晶體之非晶形或非結晶型。在其他實施例中，包含本文所述化合物(I)之鹽或共晶體形式之組合物具有小於約5重量%、小於約4重量%、小於約3重量%、小於約2重量%或小於約1重量%之化合物(I)(亦即，呈其游離形式)。
本文所述化合物(I)之鹽或共晶體形式可作為淨化學物質投與，但通常且較佳投與呈醫藥組合物或調配物形式之化合物。因此，提供醫藥組合物，其包含本文所述化合物(I)之鹽或共晶體形式及一或多種醫藥學上可接受之載劑、賦形劑或其他成分(包括惰性固體稀釋劑及填充劑、稀釋劑(包括無菌水溶液及各種有機溶劑)、滲透增強劑、增溶劑及佐劑)。組合物可包括呈單獨活性劑形式或與其他試劑(例如與一或多種醫藥學上可接受之載劑、賦形劑或其他成分混合之寡核苷酸或多核苷酸、寡肽或多肽、藥物或激素)組合之本文所述化合物(I)之鹽或共晶體形式。只要載劑、賦形劑及其他成分與調配物之其他成分相容且對其接受者無害，則可認為其係醫藥學上可接受的。
本文提供包含本文所述化合物(I)之鹽或共晶體形式及醫藥學上可接受之載劑或賦形劑的醫藥組合物。用於調配及投與醫藥組合物之技術可參見Remington's Pharmaceutical Sciences，第18版，Mack Publishing公司，Easton,Pa.,1990。本文所述醫藥組合物可使用任何習用方法(例如混合、溶解、製粒、製糖衣、磨細、乳化、囊封、截留、熔紡、噴霧乾燥或凍乾過程)製造。可由熟習此項技術者根據投與途徑及期望劑量測定最佳醫藥調配物。該等調配物可影響所投與試劑之物理狀態、穩定性、活體內釋放速率及活體內清除速率。端視所治療之病況而定，該等醫藥組合物可經調配且全身性或局部投與。
醫藥組合物可經調配以含有適宜醫藥學上可接受之載劑，且視情況可包含賦形劑及有利於將本文所述化合物(I)之鹽或共晶體形式處理成可在醫藥學上使用之製劑之輔助劑。投與方式通常決定載劑之性質。舉例而言，非經腸投與之調配物可包括呈水溶形式之活性化合物之水溶液。適於非經腸投與之載劑可選自鹽水、緩衝鹽水、右旋糖、水及其他生理上相容之溶液。非經腸投與之較佳載劑係生理上相容之緩衝液，例如漢克氏溶液(Hanks's solution)、林格氏溶液(Ringer's solution)或生理緩衝鹽水。對於組織或細胞投與，在調配物中使用 適於欲滲透之特定障壁之滲透劑。該等滲透劑通常為業內已知。對於包括蛋白質之製劑，調配物可包括穩定材料，例如多元醇(例如，蔗糖)及/或表面活性劑(例如，非離子型表面活性劑)及諸如此類。
或者，非經腸使用之調配物可包括製備為適當油性注射懸浮液之本文所述化合物(I)之鹽或共晶體形式的分散液或懸浮液。適宜親脂性溶劑或媒劑包括脂肪油(例如芝麻油)或合成脂肪酸酯(例如油酸乙酯或三酸甘油酯)或脂質體。水性注射懸浮液可含有增加懸浮液之黏度之物質，例如羧甲基纖維素鈉、山梨醇、葡聚糖及其混合物。視情況，懸浮液亦可含有適宜穩定劑或增加化合物之溶解度之試劑以容許製備高度濃縮之溶液。提供活性劑之pH敏感性溶解及/或持續釋放之水性聚合物亦可用作包衣或基質結構，例如甲基丙烯酸聚合物，例如自Rohm America公司(Piscataway,N.J.)購得之EUDRAGITTM系列。亦可使用乳液(例如水包油及油包水分散液)，視情況由乳化劑或分散劑(表面活性材料；表面活性劑)穩定。懸浮液亦可含有懸浮劑，例如乙氧基化異硬脂醇、聚氧乙烯山梨糖醇及山梨醇酐酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂-瓊脂、黃蓍膠及其混合物。
含有本文所述化合物(I)之鹽或共晶體形式之脂質體亦可用於非經腸投與。脂質體通常係衍生自磷脂或其他脂質物質。呈脂質體形式之組合物亦可含有其他成分，例如穩定劑、防腐劑、賦形劑及諸如此類。較佳脂質包括磷脂及磷脂醯基膽鹼(卵磷脂)，二者係天然及合成的。形成脂質體之方法為業內已知。參見(例如)Prescott(編輯)，Methods in Cell Biology，第XIV卷，第33頁，Academic Press,New York(1976)。
在一些實施例中，使用業內熟知之醫藥學上可接受之載劑、賦形劑或其他成分調配本文所述化合物(I)之鹽或共晶體形式或本文揭示之其組合物用於經口投與。經調配用於經口投與之製劑可呈錠劑、丸劑、膠囊、扁囊劑、糖 衣錠、菱形錠劑、液體、凝膠、糖漿、漿液、酏劑、懸浮液或粉末形式。為了闡釋，用於經口使用之醫藥製劑可藉由組合活性化合物與固體賦形劑、視情況研磨所得混合物及在添加適宜輔助劑(若期望)後處理混合物以獲得錠劑或糖衣錠核來獲得。經口調配物可採用類似與針對非經腸使用所述之彼等類似之液體載劑，例如緩衝水溶液、懸浮液及諸如此類。
較佳之經口調配物包括錠劑、糖衣錠及明膠膠囊。該等製劑可含有一或多種賦形劑，其包括但不限於：a)稀釋劑，例如微晶纖維素及糖，包括乳糖、右旋糖、蔗糖、甘露醇或山梨醇；b)黏合劑，例如澱粉羥乙酸鈉、交聯羧甲基纖維素鈉、矽酸鋁鎂、來自玉米、小麥、稻穀、馬鈴薯等之澱粉；c)纖維素材料(例如甲基纖維素、羥丙基甲基纖維素及羧甲基纖維素鈉)、聚乙烯基吡咯啶酮、樹膠(例如阿拉伯膠及黃蓍膠)及蛋白質(例如明膠及膠原)；d)崩解或增溶劑，例如交聯聚乙烯吡咯啶酮、澱粉、瓊脂、海藻酸或其鹽(例如海藻酸鈉)或泡騰劑組合物；e)潤滑劑，例如二氧化矽、滑石、硬脂酸或其鎂或鈣鹽及聚乙二醇；f)矯味劑及甜味劑；g)例如用於鑑別產物或表徵活性化合物之量(劑量)之著色劑或顏料；及h)其他成分，例如防腐劑、穩定劑、溶脹劑、乳化劑、促溶劑、用於調節滲透壓之鹽及緩衝液。
舉例而言，提供包含本文所述化合物(I)之鹽或共晶體形式及一或多種醫藥學上可接受之載劑或賦形劑的錠劑。在一個實施例中，錠劑實質上不含化合物(I)之非晶形或非結晶型。在另一實施例中，錠劑實質上不含游離(鹼)化合物(I)。
明膠膠囊包括由明膠製得之推入配合膠囊以及由明膠及諸如甘油或 山梨醇等包衣製得之軟的密封膠囊。推入配合膠囊可含有與填充劑、黏合劑、潤滑劑及/或穩定劑等混合之活性成分。在軟膠囊中，活性化合物可溶解或懸浮於具有或無穩定劑之適宜流體(例如脂肪油、液體石蠟或液體聚乙二醇)中。糖衣錠核可提供有適宜包衣，例如濃縮之糖溶液，其亦可含有阿拉伯膠、滑石、聚乙烯吡咯啶酮、卡波姆凝膠、聚乙二醇及/或二氧化鈦、漆溶液及適宜有機溶劑或溶劑混合物。
組合物較佳調配成單位劑型。術語「單位劑型」係指適於作為單位劑量供人類個體及其他哺乳動物使用之物理離散單位，每一單位含有經計算以產生期望治療效果之預定量的活性物質以及適宜醫藥賦形劑(例如，錠劑、膠囊或安瓿)。本文所述化合物(I)之鹽或共晶體形式在寬劑量範圍內有效且通常以醫藥有效量投與。然而，應理解，本文所述化合物(I)之鹽或共晶體形式之實際投與量通常將由醫師根據包括以下在內之相關情況確定：欲治療之病況、所選投與途徑、接受該治療之個體之年齡、體重及反應、個體症狀之嚴重程度及諸如此類。
本文所述錠劑或丸劑可經塗佈或以其他方式複合以提供得到延長作用之優點之劑型，或保護免於胃之酸條件影響。例如，錠劑或丸劑可包含內部劑量要素及外部劑量要素，後者為前者上之包膜形式。該兩種要素可由腸溶性層分開，該腸溶性層用於抵抗胃內之分解作用並允許內部要素完整地進入十二指腸或延遲釋放。該等腸溶性層或包衣可使用多種材料，該等材料包括多種多晶酸及多晶酸與諸如蟲膠、十六烷醇及乙酸纖維素等材料之混合物。
舉例而言，提供包含本文所述化合物(I)之鹽或共晶體形式的單位劑量。在某些變化形式中，用於人類個體之本文所述化合物(I)之鹽或共晶體形式之實例性單位劑量值可介於約0.01mg至約1000mg之間，或介於約1mg至約200mg之間，或介於約10mg至約200mg之間，或介於約20mg至約160mg 之間，或介於約10mg至約100mg之間，或介於約50mg至約175mg之間，或介於約20mg至約150mg之間，或介於約75mg至約100mg之間，或介於約100mg至約200mg之間。可投與有需要之人類之本文所述化合物(I)之鹽或共晶體形式之個別劑量包括1mg、5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、175mg及200mg之個別劑量。本文所述化合物(I)之鹽或共晶體形式之劑量可如由醫學專業人士所測定投與且可每日一次投與或可每日兩次、每日三次或每日四次遞送。在一個實施例中，本文所述化合物(I)之鹽或共晶體形式係以20mg、40mg、80mg或150mg之劑量每天一次經口投與有需要之個體。在一些實施例中，本文所述化合物(I)之鹽或共晶體形式係以20mg、40mg或75mg之劑量每天兩次經口投與個體。在額外實施例中，本文所述BTK抑制劑之治療有效量係約1mg至約200mg之劑量。在另一實施例中，本文所述BTK抑制劑係以約10mg至約200mg之劑量投與。在另一實施例中，人類中之BTK係以約20mg至約160mg之劑量投與。在另一實施例中，BTK抑制劑係以如下劑量投與人類：a)約10mg至約100mg，b)約50mg至約175mg，c)約20mg至約150mg，d)約75mg至約100mg，及e)約100mg至約200mg。可投與有需要之人類之BTK抑制劑之個別劑量包括1mg、5mg、10mg、20mg、30mg、40mg、50mg、60mg、70mg、75mg、80mg、901mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、175mg及200mg之個別劑量。BTK抑制劑之劑量可如由醫學專業人士所測定投與且可每日一次投與或可每日兩次、每日三次或每日四次遞送。在一個實施例中，本申請案之方法包含以10mg、20mg、40mg、80mg、150mg或200mg之劑量每日投與式(I)-(III)之BTK抑制劑或其組合物。在另一實施例中，本申請案之方法包含以20mg、40mg、80mg或150mg之劑量每日投與式(I)-(III)之BTK抑 制劑或其組合物。
包括本文所述化合物(I)之鹽或共晶體形式之醫藥組合物藉由任何習用方法、包括非經腸及腸內技術投與個體。非經腸投與方式包括藉由除經胃腸道以外之途徑(例如靜脈內、動脈內、腹膜內、髓內、肌內、關節內、鞘內及室內注射)投與組合物之彼等方式。腸內投與方式包括(例如)經口、經頰、舌下及直腸投與。經上皮投與方式包括(例如)經黏膜投與及經皮投與。經黏膜投與包括(例如)腸內投與以及經鼻、吸入及深肺投與；經陰道投與；及經頰及舌下投與。經皮投與包括被動或主動經皮或透皮方式，包括例如貼劑及離子電滲裝置，以及膏糊、油膏或軟膏劑之局部施加。非經腸投與亦可使用高壓技術(例如POWD ERJECTTM)來完成。
可經由臨床前活體外及活體內研究收集關於本文所述化合物(I)之鹽或共晶體形式及本文所述化合物(I)之鹽或共晶體形式之調配物的藥物動力學及藥效學資訊，稍後在臨床試驗過程期間在人類中確認。因此，對於本文所述方法中所用之本文所述化合物(I)之鹽或共晶體形式，可最初自生物化學及/或基於細胞之分析估計治療有效劑量。接著，可在動物模型中調配劑量以達成調節BTK表現或活性之合意之循環濃度範圍。在執行人類研究時，將出現關於對於各種疾病及病況適當劑量值及治療之持續時間的其他資訊。
該等化合物之毒性及治療功效可在細胞培養物或實驗動物中藉由標準醫藥程序來測定，例如測定LD50(可導致群體中之50%死亡之劑量)及ED50(對群體中之50%治療有效之劑量)的程序。毒性及治療效應之間之劑量比率即為「治療指數」，其通常表示為比率LD50/ED50。展現較大治療指數之化合物(亦即毒性劑量實質上高於有效劑量)較佳。可在調配供人類使用之劑量範圍中使用自該等細胞培養分析及額外動物研究獲得之數據。該等化合物之劑量較佳位於具有極 低毒性或無毒性之循環濃度(包括ED50)範圍內。
應理解，可使用調節劑量之時間及順序之任何有效投與方案。本文所述化合物(I)之鹽或共晶體形式及其醫藥組合物可包括其中活性成分係有效量投與以達成其預期目的之彼等。在一些實施例中，「治療有效量」意指足以調節BTK表現或活性(包括)且藉此治療患有適應症之個體(例如，人類)或緩和適應症之現存症狀的量。
人類個體之實例性劑量值係大約約0.001毫克活性劑/公斤體重(mg/kg)至約1000mg/kg。通常，端視(例如)適應症、投與途徑及病況之嚴重程度而定，活性劑之劑量單位包含約0.01mg至約1000mg、較佳約0.1mg至約100mg。端視投與途徑而定，可根據體重/體表面積或器官大小計算適宜劑量。最終劑量方案係由主治醫師鑒於良好醫療實踐考慮各種因素來確定：該等因素改良藥物作用，例如化合物之比活性、疾病狀態之屬性(identity)及嚴重程度、個體之反應性、個體之年齡、病況、體重、性別及飲食及任何感染之嚴重程度。可慮及之額外因素包括投與之時間及頻率、藥物組合、反應敏感性及對療法之耐受性/反應。涉及本文提及之調配物中之任一者之適於治療之劑量之進一步精化通常由熟練從業者而無需過多實驗、尤其鑒於所揭示之劑量資訊及分析以及人類臨床試驗中觀察之藥物動力學數據來進行。適當劑量可經由使用測定體液或其他樣品內之試劑之濃度的確立分析以及劑量反應數據來確定。
投藥頻率取決於試劑之藥物動力學參數及投與途徑。調節劑量及投與以提供足夠量之活性部分或維持期望效應。因此，醫藥組合物可以維持試劑之期望最小量所需之單一劑量、多個離散劑量、連續輸注、持續釋放儲積物或其組合來投與。短效醫藥組合物(即，短的半衰期)可每天一次或每天一次以上(例如，每天兩次、三次或四次)投與。長效醫藥組合物可每3至4天、每週或每兩週一次投與。
提供本文所述化合物(I)之鹽或共晶體形式及或本文所述其組合物用於以治療或預防方式選擇性或特異性抑制BTK活性的用途。方法包含向有需要之個體(例如，人類)投與足以抑制BTK活性之量之本文所述化合物(I)之鹽或共晶體形式或其組合物。方法可用於治療患有或遭受症狀或病狀係由BTK表現或活性介導之病況的人類或動物。
「治療」(「treatment」或「treating」)係獲得有益或期望結果(包括臨床結果)之方法。有益或期望臨床結果可包括以下中之一或多者：(i)減少自該疾病產生之一或多種症狀；(ii)降低疾病之程度及/或穩定疾病(例如，延遲疾病之惡化)；(iii)延遲疾病之擴散(例如，轉移)；(iv)延遲或減緩疾病復發及/或疾病之進展；(v)改善疾病狀態及/或提供疾病之緩解(部分或完全)及/或減少治療疾病所需之一或多種其他藥劑之劑量；(vi)提高生活品質，及/或(vii)延長存活期。
在一些實施例中，「病症」意欲涵蓋(但不限於)醫學病症、疾病、病況、症候群及諸如此類。本申請案中揭示之方法涵蓋治療動物個體、較佳哺乳動物、更佳靈長類動物且仍更佳人類之各種方式。可治療之哺乳動物係(例如)人類；伴侶動物(寵物)，包括動物及貓；農場動物，包括牛、馬、綿羊、豬及山羊；實驗室動物，包括大鼠、小鼠、兔、天竺鼠及非人類靈長類動物；及動物園樣本。可治療之非哺乳動物包括(例如)鳥類、魚、爬行動物及兩棲動物。
在一態樣中，本文所述化合物(I)之鹽或共晶體形式及本文所述其組合物可用於抑製造血來源之癌細胞(例如癌細胞)之生長或增殖的方法中。在一些 實施例中，癌細胞具有淋巴來源，且在具體實施例中，癌細胞與B淋巴球或B淋巴球祖細胞有關或源自B淋巴球或B淋巴球祖細胞。在另一態樣中，本文所述化合物(I)之鹽或共晶體形式及本文所述其組合物可用於治療患有癌症之人類之方法中。
適於使用本申請案中揭示之方法治療之癌症包括(例如)非霍奇金氏淋巴瘤(non-Hodgkin's lymphomas)，其中B細胞非霍奇金氏淋巴瘤尤其適宜，例如柏基特氏淋巴瘤(Burkitt's lymphoma)、AIDS相關之淋巴瘤、邊緣區B細胞淋巴瘤(結節邊緣區B細胞淋巴瘤、結節外邊緣區B細胞淋巴瘤及脾邊緣區B細胞淋巴瘤)、瀰漫性大B細胞淋巴瘤、原發性積液淋巴瘤、淋巴瘤樣肉芽腫病、濾泡性淋巴瘤、B細胞慢性淋巴球性白血病、B細胞前淋巴球性白血病、淋巴漿細胞白血病/華氏巨球蛋白血症(Waldenstrom's macroglobulinemia)、漿細胞瘤、外套細胞淋巴瘤、縱膈大B細胞淋巴瘤、血管內大B細胞淋巴瘤及毛細胞白血病。除了非霍奇金氏淋巴瘤外，本發明中之癌症包括胰臟內分泌腫瘤，例如胰島素瘤、胃泌素瘤、胰升糖素瘤、體抑素瘤、VIP瘤、PP瘤及GRF瘤。亦可藉由投與本文所述化合物(I)之鹽或共晶體形式及本文所述其組合物治療造血來源或其他來源之表現BTK之其他癌細胞。
在另一態樣中，本文所述化合物(I)之鹽或共晶體形式及本文所述其組合物可用於治療自體免疫疾病之方法中。在特定實施例中，自體免疫疾病係發炎性腸病、關節炎、狼瘡、類風濕性關節炎、牛皮癬關節炎、骨關節炎、斯蒂爾氏病(Still's disease)、青少年關節炎、I型糖尿病、重症肌無力、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、奧德氏甲狀腺炎(Ord's thyroiditis)、巴塞杜氏病(Basedow's disease)、薛格連氏症候群(Sjögren's syndrome)、多發性硬化、格林-巴利症候群(Guillain-Barré syndrome)、急性瀰漫性腦脊髓炎、艾迪森氏病(Addison's disease)、視性眼陣攣-肌陣攣症候群、關節黏連性脊椎炎、抗磷脂抗 體症候群、再生障礙性貧血、自體免疫肝炎、乳糜瀉、古巴士德氏症候群(Goodpasture's syndrome)、特發性血小板減少紫斑症、視神經炎、硬皮症、原發性膽汁性肝硬化、雷特氏病(Reiter's disease)、高安動脈炎(Takayasu's arteritis)、顳動脈炎、溫抗體型自體免疫溶血性貧血、韋格納氏肉芽腫(Wegener's granuloma)、牛皮癬、普禿、貝歇氏病(Behget's disease)、慢性疲勞症候群、自主神經機能異常、子宮內膜異位症、間質性膀胱炎、肌強直、陰唇痛症及全身性紅斑狼瘡。
在另一態樣中，提供藉由向患有BTK介導之病症之人類投與本文所述化合物(I)之鹽或共晶體形式來治療該人類的方法。亦提供藉由投與本文所述化合物(I)之鹽或共晶體形式調節個體之BTK的方法。在一種變化形式中，人類患有癌症，例如白血病或淋巴瘤。在另一變化形式中，人類患有自體免疫疾病，例如氣喘、類風濕性關節炎、多發性硬化或狼瘡。
本文所述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、抗纖維變性劑、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、抗體-藥物偶聯物(ADC)、放射性治療劑、抗瘤劑、抗增殖劑、溶瘤病毒、基因修飾劑或編輯劑(例如CRISPR(包括CRISPR Cas9))、鋅指核酸酶或合成核酸酶(TALEN)、CAR(嵌合抗原受體)T-細胞免疫治療劑或其任一組合。該等治療劑可呈化合物、抗體、多肽或多核苷酸形式。在一個實施例中，本申請案提供包含本文所述化合物及額外治療劑之產物，其作為同時、單獨或依序用於療法(例如，治療由BTK介導之疾病、病症或病況之方法)中之組合製劑。
一或多種治療劑包括(但不限於)基因、配體、受體、蛋白質、諸如以下等因子之抑制劑、激動劑、拮抗劑、配體、調節劑、刺激物、阻斷劑、活化劑或阻抑劑：愛柏森(Abelson)鼠類白血病病毒致癌基因同系物1基因(ABL，例如ABL1)、乙醯基-CoA羧化酶(例如ACC1/2)、活化CDC激酶(ACK，例如ACK1)、 腺苷去胺酶、腺苷受體(例如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活化之蛋白激酶、退行發育性淋巴瘤激酶(ALK，例如ALK1)、雄激素受體、血管生成素(例如配體-1、配體-2)、血管緊張素原(AGT)基因、鼠類胸腺瘤病毒致癌基因同系物1(AKT)蛋白激酶(例如AKT1、AKT2、AKT3)、載脂蛋白A-I(APOA1)基因、細胞凋亡誘導因子、細胞凋亡蛋白(例如1、2)、細胞凋亡信號調節激酶(ASK，例如ASK1)、精胺酸酶(I)、精胺酸脫亞胺酶、芳香酶、星樣同系物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、Aurora蛋白激酶(例如1、2)、Axl酪胺酸激酶受體、含桿狀病毒IAP重複5(BIRC5)基因、巴斯金(Basigin)、B細胞淋巴瘤2(BCL2)基因、Bcl2結合組分3、Bcl2蛋白、BCL2L11基因、BCR(斷點簇區)蛋白及基因、β腎上腺素受體、β-連環蛋白、B-淋巴球抗原CD19、B-淋巴球抗原CD20、B-淋巴球細胞黏著分子、B-淋巴球刺激物配體、骨形態演發蛋白-10配體、骨形態演發蛋白-9配體調節劑、Brachyury蛋白、緩激肽受體、B-Raf原癌基因(BRAF)、Brc-Abl酪胺酸激酶、含有溴結構域及外結構域(BET)溴結構域之蛋白(例如BRD2、BRD3、BRD4)、攜鈣蛋白、攜鈣蛋白依賴性蛋白激酶(CaMK，例如CAMKII)、癌睪丸抗原2、癌睪丸抗原NY-ESO-1、癌/睪丸抗原1B(CTAG1)基因、大麻素受體(例如CB1、CB2)、碳酸酐酶、酪蛋白激酶(CK，例如CKI、CKII)、半胱天冬酶(例如半胱天冬酶-3、半胱天冬酶-7、半胱天冬酶-9)、半胱天冬酶8細胞凋亡相關半胱胺酸肽酶CASP8-FADD樣調節劑、半胱天冬酶募集結構域蛋白-15、細胞自溶酶G、CCR5基因、CDK活化激酶(CAK)、檢查點激酶(例如CHK1、CHK2)、趨化介素(C-C基序)受體(例如CCR2、CCR4、CCR5)、趨化介素(C-X-C基序)受體(例如CXCR4、CXCR1及CXCR2)、趨化介素CC21配體、膽囊收縮 素CCK2受體、絨毛膜促性腺激素、c-Kit(酪胺酸-蛋白激酶Kit或CD117)、密連蛋白(例如6、18)、分化簇(CD)，例如CD4、CD27、CD29、CD30、CD33、CD37、CD40、CD40配體受體、CD40配體、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；叢生蛋白(CLU)基因、叢生蛋白、c-Met(肝細胞生長因子受體(HGFR))、補體C3、結締組織生長因子、COP9信號小體亞單位5、CSF-1(群落刺激因子1受體)、CSF2基因、CTLA-4(細胞毒性T-淋巴球蛋白4)受體、週期蛋白D1、週期蛋白G1、週期蛋白依賴性激酶(CDK，例如CDK1、CDK1B、CDK2-9)、環加氧酶(例如1、2)、CYP2B1基因、豪豬半胱胺酸棕櫚醯基轉移酶、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、細胞質異檸檬酸鹽去氫酶、胞嘧啶去胺酶、胞嘧啶DNA甲基轉移酶、細胞毒性T-淋巴球蛋白-4、DDR2基因、δ樣蛋白配體(例如3、4)、去氧核糖核酸酶、Dickkopf-1配體、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，例如DDR1)、DNA結合蛋白(例如HU-β)、DNA依賴性蛋白激酶、DNA迴旋酶、DNA甲基轉移酶、DNA聚合酶(例如α)、DNA引發酶、dUTP焦磷酸酶、L-多巴色素互變異構酶、棘皮動物微管樣蛋白4、EGFR酪胺酸激酶受體、彈性蛋白酶、延長因子1 α 2、延長因子2、內皮因子、內核酸酶、內質網素、內皮唾酸蛋白、內皮抑素、內皮素(例如ET-A、ET-B)、zeste同系物2增強子(EZH2)、Ephrin(EPH)酪胺酸激酶(例如Epha3、Ephb4)、Ephrin B2配體、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、表皮素、上皮細胞黏著分子(EpCAM)、Erb-b2(v-erb-b2禽類成紅血球細胞白血病病毒致癌基因同系物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-選擇蛋白、雌二醇17 β去氫酶、雌激素受體(例如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、細胞外信號相關激酶(例如1、2)、細胞外信號調節激酶(ERK)、因子(例如Xa、VIIa)、類法呢醇(farnesoid)x受體(FXR)、Fas配體、脂肪酸合酶、鐵蛋白、FGF-2配體、FGF-5配體、成纖維細胞生長因子(FGF，例如FGF1、FGF2、FGF4)、纖連蛋白、Fms相關酪胺酸激酶3(Flt3)、黏著斑激酶(FAK，例如FAK2)、葉酸鹽水解酶前列腺特異性膜抗原1(FOLH1)、葉酸鹽受體(例如α)、葉酸鹽、葉酸鹽運輸蛋白1、FYN酪胺酸激酶、成對鹼性胺基酸裂解酶(弗林蛋白酶(FURIN))、β-葡萄糖醛酸苷酶、半乳糖轉移酶、半乳糖凝集素-3、糖皮質激素、糖皮質激素誘導之TNFR相關蛋白GITR受體、麩胺酸鹽羧肽酶II、麩胺醯胺酶、麩胱甘肽S-轉移酶P、肝醣合酶激酶(GSK，例如3-β)、磷脂醯肌醇聚糖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)配體、生長因子受體結合之蛋白2(GRB2)、Grp78(78kDa葡萄糖調節之蛋白)鈣結合蛋白、分子伴護蛋白groEL2基因、熱休克蛋白(例如27、70、90 α、β)、熱休克蛋白基因、熱穩定腸毒素受體、刺蝟(Hedgehog)蛋白、類肝素酶、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、組織蛋白甲基轉移酶(DOT1L)、組織蛋白去乙醯酶(HDAC，例如1、2、3、6、10、11)、組織蛋白H1、組織蛋白H3、HLA I類抗原(A-2 α)、HLA II類抗原、同源異形盒蛋白NANOG、HSPB1基因、人類白血球抗原(HLA)、人類乳頭瘤病毒(例如E6、E7)蛋白、玻尿酸、玻尿酸酶、缺氧誘導之因子-1 α、印跡母系表現轉錄(H19)基因、促分裂原活化之蛋白激酶激酶激酶激酶1(MAP4K1)、酪胺酸-蛋白激酶HCK、I-κ-B激酶(IKK，例如IKKbe)、IL-1 α、IL-1 β、IL-12、IL-12基因、IL-15、IL-17、IL-2基因、IL-2受體α亞單位、IL-2、IL-3受體、IL-4、IL-6、IL-7、IL-8、免疫球蛋白(例如G、G1、G2、 K、M)、免疫球蛋白Fc受體、免疫球蛋白γFc受體(例如I、III、IIIA)、吲哚胺2,3-雙加氧酶(IDO，例如IDO1)、吲哚胺吡咯2,3-雙加氧酶1抑制劑、胰島素受體、胰島素樣生長因子(例如1、2)、整聯蛋白α-4/β-1、整聯蛋白α-4/β-7、整聯蛋白α-5/β-1、整聯蛋白α-V/β-3、整聯蛋白α-V/β-5、整聯蛋白α-V/β-6、細胞間黏著分子1(ICAM-1)、干擾素(例如α、α 2、β、γ)、干擾素誘導蛋白黑色素瘤缺失因子2(AIM2)、干擾素I型受體、介白素1配體、介白素13受體α 2、介白素2配體、介白素-1受體相關之激酶4(IRAK4)、介白素-2、介白素-29配體、異檸檬酸鹽去氫酶(例如IDH1、IDH2)、傑納斯激酶(Janus kinase，JAK，例如JAK1、JAK2)、Jun N末端激酶、激肽釋放酶相關肽酶3(KLK3)基因、殺傷細胞Ig樣受體、激酶插入結構域受體(KDR)、驅動蛋白樣蛋白KIF11、Kirsten大鼠肉瘤病毒致癌基因同系物(KRAS)基因、親吻促動素(KiSS-1)受體、KIT基因、v-kit Hardy-Zuckerman 4貓肉瘤病毒致癌基因同系物(KIT)酪胺酸激酶、乳鐵蛋白、羊毛固醇-14去甲基酶、LDL受體相關蛋白-1、白三烯A4水解酶、李斯特菌素(Listeriolysin)、L-選擇蛋白、黃體促素受體、裂合酶、淋巴球活化基因3蛋白(LAG-3)、淋巴球抗原75、淋巴球功能抗原-3受體、淋巴球特異性蛋白酪胺酸激酶(LCK)、淋巴細胞趨化蛋白、Lyn(Lck/Yes新穎)酪胺酸激酶、離胺酸去甲基酶(例如KDM1、KDM2、KDM4、KDM5、KDM6、A/B/C/D)、溶血磷脂酸(Lysophosphatidate)-1受體、溶酶體相關膜蛋白家族(LAMP)基因、離胺醯氧化酶同系物2、離胺醯氧化酶蛋白(LOX)、離胺醯氧化酶樣蛋白(LOXL，例如LOXL2)、造血祖細胞激酶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)配體、巨噬細胞遷移抑制性因子、MAGEC1基因、MAGEC2基因、窿體主蛋白、MAPK活化之蛋白激酶(例如MK2)、Mas相關G蛋白偶聯受體、基質金屬蛋白酶(MMP，例如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體、黑色素瘤抗原家族A3(MAGEA3)基因、黑色素瘤相關抗原(例如1、2、3、6)、膜銅胺氧化酶、間皮素、MET酪胺酸激酶、促代謝型麩胺酸受體1、金屬還原酶STEAP1(前列腺1之六跨膜上皮抗原)、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、促分裂原活化蛋白激酶(MAPK)、促分裂原活化之蛋白激酶(MEK，例如MEK1、MEK2)、mTOR(雷帕黴素(rapamycin)之機械靶標(絲胺酸/蘇胺酸激酶)、mTOR複合物(例如1、2)、黏蛋白(例如1、5A、16)、mut T同系物(MTH，例如MTH1)、Myc原癌基因蛋白、骨髓細胞白血病1(MCL1)基因、肉豆蔻醯酸化富丙胺酸蛋白激酶C受質(MARCKS)蛋白、NAD ADP核糖基轉移酶、利鈉肽受體C、中性細胞黏著分子1、神經激肽1(NK1)受體、神經激肽受體、跨膜蛋白2、NF κ B活化蛋白、NIMA相關激酶9(NEK9)、一氧化氮合酶、NK細胞受體、NK3受體、NKG2 A B活化NK受體、去甲腎上腺素運輸蛋白、Notch(例如Notch-2受體、Notch-3受體)、核紅血球2相關因子2、核因子(NF)κ B、核仁素、核磷蛋白、核磷蛋白-退行發育性淋巴瘤激酶(NPM-ALK)、2酮戊二酸去氫酶、2,5-寡腺苷酸合成酶、O-甲基鳥嘌呤DNA甲基轉移酶、類鴉片受體(例如δ)、鳥胺酸去羧酶、乳清酸鹽磷酸核糖基轉移酶、孤核激素受體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、p38激酶、p38 MAP激酶、p53腫瘤抑制劑蛋白、副甲狀腺激素配體、過氧化體增殖物活化之受體(PPAR，例如α、δ、γ)、P-醣蛋白(例如1)、磷酸酶及張力蛋白同系物(PTEN)、磷脂醯肌醇3-激酶(PI3K)、磷酸肌醇-3激酶(PI3K，例如α、δ、γ)、磷酸化酶激酶(PK)、PKN3基因、胎盤生長因子、血小板源生長因子(PDGF，例如α、β)、血小板源生長因子(PDGF，例如α、β)、多向性抗藥性運輸蛋白、神經叢蛋白B1、PLK1基因、polo樣激酶(PLK)、Polo樣激酶1、聚ADP核糖聚合酶(PARP，例如PARP1、2及3)、黑色素瘤中優先表 現之抗原(PRAME)基因、異戊二烯基結合蛋白(PrPB)、可能之轉錄因子PML、助孕酮受體、程式化細胞死亡1(PD-1)、程式化細胞死亡配體1抑制劑(PD-L1)、前塞波素(Prosaposin)(PSAP)基因、類前列腺素受體(EP4)、前列腺特異性抗原、前列腺酸磷酸酶、蛋白酶體、蛋白E7、蛋白法尼基轉移酶、蛋白激酶(PK，例如A、B、C)、蛋白酪胺酸激酶、蛋白酪胺酸磷酸酶β、原癌基因絲胺酸/蘇胺酸-蛋白激酶(PIM，例如PIM-1、PIM-2、PIM-3)、P-選擇蛋白、嘌呤核苷磷酸化酶、嘌呤能受體P2X配體門控之離子通道7(P2X7)、丙酮酸鹽去氫酶(PDH)、丙酮酸鹽去氫酶激酶、丙酮酸鹽激酶(PYK)、5-α-還原酶、Raf蛋白激酶(例如1、B)、RAF1基因、Ras基因、Ras GTPase、RET基因、Ret酪胺酸激酶受體、視網膜母細胞瘤相關之蛋白、視黃酸受體(例如γ)、類視色素X受體、Rheb(腦中富含之Ras同系物)GTPase、Rho(Ras同系物)相關之蛋白激酶2、核糖核酸酶、核糖核苷酸還原酶(例如M2亞單位)、核糖體蛋白S6激酶、RNA聚合酶(例如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、肌漿內質鈣ATPase、半胱天冬酶之第二線粒體源活化劑(SMAC)蛋白、分泌型捲曲相關蛋白-2、信號素-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，例如TBK1)、信號轉導及轉錄(STAT，例如STAT-1、STAT-3、STAT-5)、信號傳導淋巴球性活化分子(SLAM)家族成員7、前列腺之六跨膜上皮抗原(STEAP)基因、SL細胞介素配體、平滑(SMO)受體、碘化鈉共運輸蛋白、磷酸鈉共運輸蛋白2B、體抑素受體(例如1、2、3、4、5)、音猥蛋白、特異性蛋白1(Sp1)轉錄因子、鞘磷脂合酶、神經鞘胺醇激酶(例如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、干擾素基因之刺激物(STING)受體、干擾素基因蛋白之刺激物、基質細胞源因子1配體、SUMO(小泛蛋白樣修飾劑)、超 氧化物歧化酶、存活素蛋白、突觸蛋白3、多配體聚醣-1、突觸核蛋白α、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亞單位B(TAF1B)基因、T細胞CD3醣蛋白ζ鏈、T細胞分化抗原CD6、含T細胞免疫球蛋白及黏蛋白-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、端粒酶反轉錄酶(TERT)基因、腱醣蛋白、TGF β 2配體、促血小板生成素受體、胸苷激酶、胸苷磷酸化酶、胸腺嘧啶核苷酸合酶、胸腺嘧啶核苷酸合酶、胸腺素(例如α 1)、甲狀腺激素受體、甲狀腺刺激激素受體、組織因子、TNF相關細胞凋亡誘導配體、TNFR1相關死亡結構域蛋白、TNF相關細胞凋亡誘導配體(TRAIL)受體、TNFSF11基因、TNFSF9基因、類鐸受體(TLR，例如1-13)、拓樸異構酶(例如I、II、III)、轉錄因子、轉移酶、運鐵蛋白、轉變生長因子(TGF，例如β)激酶、轉變生長因子TGF-β受體激酶、轉麩醯胺酸酶、易位相關之蛋白、跨膜醣蛋白NMB、Trop-2鈣信號轉換器、滋養層醣蛋白(TPBG)基因、滋養層醣蛋白、原肌球蛋白受體激酶(Trk)受體(例如TrkA、TrkB、TrkC)、色胺酸5-羥化酶、微管蛋白、腫瘤壞死因子(TNF，例如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、腫瘤抑制劑候選者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(TIE)受體之酪胺酸激酶、酪胺酸蛋白激酶ABL1抑制劑、泛蛋白、泛蛋白羧基水解酶同功酶L5、泛蛋白硫酯酶-14、泛蛋白偶聯酶E2I(UBE2I、UBC9)、尿素酶、尿激酶纖維蛋白溶酶原活化劑、子宮珠蛋白、類香草素VR1、血管細胞黏著蛋白1、血管內皮生長因子受體(VEGFR)、T細胞活化之V-結構域Ig抑制劑(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、威爾姆氏腫瘤(Wilms' tumor)抗原1、威爾姆氏腫瘤蛋白、細胞凋亡蛋白之X鏈接之抑制劑、鋅指蛋白 轉錄因子或其任一組合。
一個態樣提供藉由向患有BTK介導之病症之人類投與式(I)-(III)之BTK抑制劑與一或多種選自以下之群之其他治療劑之組合來治療該人類的方法：細胞凋亡信號調節激酶(ASK)抑制劑、盤狀結構域受體(DDR)抑制劑、組織蛋白去乙醯酶(HDAC)抑制劑、傑納斯激酶(JAK)抑制劑、離胺醯氧化酶樣蛋白2(LOXL2)抑制劑、基質金屬蛋白酶9(MMP9)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、BET-溴結構域4(BRD4)抑制劑、檢查點抑制劑、B細胞慢性淋巴球性白血病(CLL)/淋巴瘤2(BCL-2)抑制劑及CD20抑制劑。在上述方法中之任一者中，式(I)-(III)之BTK抑制劑可作為單位劑量、例如以錠劑形式如本文所述投與個體。同樣，在上述方法中之任一者中，式(I)-(III)之BTK抑制劑及一或多種治療劑可同時或依序投與。
一或多種治療劑之實例包括(但不限於)ASK抑制劑，包括ASK1抑制劑，例如WO 2011/008709及WO 2013/112741中所述之彼等；CD47抑制劑，例如抗CD47 mAbs(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；CDK抑制劑，例如阿博馬昔地(abemaciclib)、阿伏昔地(alvocidib)(HMR-1275、夫拉平度(flavopiridol))、AT-7519、FLX-925、LEE001、帕博西尼(palbociclib)、利泊昔布(ribociclib)、瑞格色替(rigosertib)、塞林克(selinexor)、UCN-01及TG-02；DDR抑制劑，例如PCT專利第WO 2014/047624號、第WO 2013/027802號及第WO 2013/034933號、美國公開專利申請案第2011/0287011號及第2009/0142345中揭示之彼等；HDAC抑制劑，例如阿貝司他(abexinostat)、ACY-241、AR-42、BEBT-908、貝林司他(belinostat)、CKD-581、CS-055(HBI-8000)、CUDC-907、恩替諾特(entinostat)、吉維司他(givinostat)、莫賽替諾司他(mocetinostat)、帕比司他(pracinostat)、普西司他(pracinostat)、奎司司他(quisinostat) (JNJ-26481585)、瑞米司他(resminostat)、瑞可諾司他(ricolinostat)、SHP-141、丙戊酸(VAL-001)、伏立諾他(vorinostat)；IDO1抑制劑，例如BLV-0801、艾帕卡得司他(epacadostat)、F-001287、GBV-1012、GBV-1028、GDC-0919、吲哚西莫(indoximod)、NKTR-218、基於NLG-919之疫苗、PF-06840003、吡喃并萘并醌衍生物(SN-35837)、瑞米司他(resminostat)、SBLK-200802及shIDO-ST；JAK抑制劑，例如AT9283、AZD1480、巴瑞替尼(baricitinib)、BMS-911543、非曲替尼(fedratinib)、非哥替尼(filgotinib)(GLPG0634)、甘多替尼(gandotinib)(LY2784544)、INCB039110、來他替尼(lestaurtinib)、莫羅替尼(momelotinib)(CYT0387)、NS-018、帕克替尼(pacritinib)(SB1518)、派非西替尼(peficitinib)(ASP015K)、魯索替尼、托法替尼(tofacitinib)(先前稱作他索替尼(tasocitinib))及XL019；LOXL抑制劑，例如WO 2009/017833、WO 2009/035791及WO 2011/097513中所述之抗體；MMP9抑制劑，例如馬立馬司他(marimastat)(BB-2516)、西馬司他(cipemastat)(Ro 32-3555)及闡述於PCT公開案第WO 2012/027721號中之彼等；MEK抑制劑，例如安卓奎諾爾(antroquinonol)、比尼替尼(binimetinib)、考比替尼(cobimetinib)(GDC-0973、XL-518)、MT-144、司美替尼(selumetinib)(AZD6244)、索拉菲尼(sorafenib)、曲美替尼(trametinib)(GSK1120212)、阿普色替(uprosertib)+曲美替尼；PI3K抑制劑，例如ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕里斯(buparlisib)(BKM120)、BYL719(alpelisib(alpelisib))、CH5132799、庫潘里斯(copanlisib)(BAY 80-6946)、杜維里斯(duvelisib)、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾代拉里斯(idelalisib)(Zydelig®)、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞格色替、RP5090、他塞里斯(taselisib)、TG100115、TGR-1202、TGX221、WX-037、X-339、X-414、XL147(SAR245408)、XL499、XL756、渥曼青黴素(wortmannin)、ZSTK474及 闡述於PCT公開案第WO 2005/113556號、第WO 2013/052699號、第WO 2013/116562號、第WO 2014/100765號、第WO 2014/100767號及第WO 2014/201409號中之化合物；SYK抑制劑，例如6-(1H-吲唑-6-基)-N-(4-嗎啉基苯基)咪唑并[1,2-a]吡嗪-8-胺、BAY-61-3606、賽杜替尼(cerdulatinib)(PRT-062607)、恩特替尼(entospletinib)、福他替尼(fostamatinib)(R788)、HMPL-523、NVP-QAB 205 AA、R112、R343、他馬替尼(tamatinib)(R406)及闡述於美國專利第8,450,321號及美國公開專利申請案第2015/0175616號中之彼等；TLR8抑制劑，例如E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫德(motolimod)、雷西莫特(resiquimod)、VTX-1463及VTX-763；TLR9抑制劑，例如IMO-2055、IMO-2125、來非特利莫德(lefitolimod)、利尼莫德(litenimod)、MGN-1601及PUL-042；TKI抑制劑，例如阿法替尼(afatinib)、ARQ-087、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、博瑞加替尼(brigatinib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克萊拉尼(crenolanib)、達克替尼(dacomitinib)、達沙替尼(dasatinib)、多韋替尼(dovitinib)、E-6201、厄達替尼(erdafitinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、吉特替尼(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、米哚妥林(midostaurin)、尼達尼布(nintedanib)、ODM-203、奧希替尼(osimertinib)(AZD-9291)、普納替尼(ponatinib)、泊西替尼(poziotinib)、奎紮替尼(quizartinib)、拉多替尼(radotinib)、盧塞替尼(rociletinib)、索凡替尼(sulfatinib)(HMPL-012)、舒尼替尼(sunitinib)及TH-4000。
如本文所用術語「化學治療劑」或「化學治療性」(或在經化學治療劑治療之情形下「化學療法」)意指涵蓋可用於治療癌症之任何非蛋白質性(即非肽性)化學化合物。化學治療劑之實例包括但不限於：烷基化劑，例如噻替派(thiotepa)及環磷醯胺(CYTOXAN®)；磺酸烷基酯，例如白消安(busulfan)、英丙 舒凡(improsulfan)及哌泊舒凡(piposulfan)；氮丙啶，例如苯并多巴(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)及烏瑞替派(uredepa)；次乙亞胺及甲基蜜胺，包括六甲蜜胺(alfretamine)、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羥甲基蜜胺；番荔枝內酯(acetogenin)，尤其係布拉他辛(bullatacin)及布拉他辛酮(bullatacinone)；喜樹鹼(camptothecin)，包括合成類似物托泊替康(topotecan)；苔蘚蟲素(bryostatin)；卡利斯他汀(callystatin)；CC-1065，包括其合成類似物阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)；念珠藻素(cryptophycin)，尤其係念珠藻素1及念珠藻素8；多拉斯他汀(dolastatin)；多卡米星(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)；匍枝珊瑚醇(sarcodictyin)；海綿抑制素(spongistatin)；氮芥，例如氮芥苯丁酸、萘氮芥(chlornaphazine)、環磷醯胺、葡磷醯胺、艾伏磷醯胺(evofosfamide)、苯達莫司汀(bendamustine)、雌氮芥(estramustine)、異環磷醯胺、甲基二氯乙基胺(mechlorethamine)、甲基二氯乙基胺氧化物鹽酸鹽、美法侖(melphalan)、新氮芥(novembichin)、膽甾醇對苯乙酸氮芥(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)及尿嘧啶氮芥；亞硝基脲，例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(foremustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimustine)；抗生素，例如烯二炔抗生素(例如，卡奇黴素(calicheamicin)，尤其係卡奇黴素γII及卡奇黴素φ I1)；達內黴素(dynemicin)，包括達內黴素A；雙膦酸鹽，例如氯膦酸(clodronate)、埃斯波黴素(esperamicin)、新制癌菌素發色團(neocarzinostatin chromophore)及相關色蛋白烯二炔抗生素發色團、阿克拉黴素(aclacinomycin)、放線菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸、博萊黴素(bleomycins)、c放線菌素(cactinomycin)、卡拉黴素(carabicin)、洋紅黴素(carrninomycin)、嗜癌黴素(carzinophilin)、色黴素 (chromomycin)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、多柔比星(doxorubicin)(包括嗎啉基-多柔比星、氰基嗎啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星)、泛艾黴素(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(例如絲裂黴素C)、黴酚酸(mycophenolic acid)、諾拉黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非黴素(porfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(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)、淨司他汀(zinostatin)及佐柔比星(zorubicin)；抗代謝物，例如胺甲喋呤(methotrexate)及5-氟尿嘧啶(5-fluorouracil)(5-FU)；葉酸類似物，例如二甲葉酸(demopterin)、胺甲喋呤、蝶羅呤(pteropterin)及三甲曲沙(trimetrexate)；嘌呤類似物，例如氟達拉濱(fludarabine)、6-巰嘌呤、硫咪嘌呤(thiamiprine)及硫鳥嘌呤；嘧啶類似物，例如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮雜尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)及氟尿苷(floxuridine)；雄激素，例如卡普睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)及睪內酯(testolactone)；抗腎上腺素，例如胺魯米特(aminoglutethimide)、米托坦(mitotane)及曲洛司坦(trilostane)；葉酸補充劑，例如亞葉酸；放射性治療劑，例如鐳-223；單端孢黴烯(trichothecene)，尤其係T-2毒素、疣皰菌素A(verracurin A)、桿孢菌素(roridin A)及蛇形菌素(anguidine)；類紫杉醇(taxoid)，例如太平洋紫杉醇(paclitaxel)(TAXOL®)、亞伯杉烷、多西他賽(TAXOTERE®)、卡巴他賽(cabazitaxel)、BIND-014；鉑類似物，例如順鉑及卡鉑、NC-6004奈米鉑(nanoplatin)；醋葡醛內酯(aceglatone)；醛磷醯胺醣苷(aldophosphamide glycoside)；胺基乙醯丙酸(aminolevulinic acid)；恩尿嘧啶 (eniluracil)；安吖啶；黑斯特氮芥(hestrabucil)；比生群(bisantrene)；依達曲沙(edatraxate)；地磷醯胺(defosfamine)；秋水仙胺(demecolcine)；地吖醌(diaziquone)；依氟鳥胺酸(elformthine)；依利醋銨(elliptinium acetate)；埃博黴素(epothilone)；依託格魯(etoglucid)；硝酸鎵；羥基脲；香菇多醣(lentinan)；甲醯四氫葉酸(leucovorin)；氯尼達明(lonidainine)；類美登素(maytansinoid)，例如美登素(maytansine)及安絲菌素(ansamitocin)；米托胍腙(mitoguazone)；米托蒽醌；莫哌達醇(mopidamol)；硝胺丙吖啶(nitracrine)；噴司他汀(pentostatin)；蛋胺氮芥(phenamet)；吡柔比星(pirarubicin)；洛索蒽醌(losoxantrone)；氟嘧啶；醛葉酸；鬼臼酸；2-乙基醯肼；丙卡巴肼(procarbazine)；多醣-K(PSK)；雷佐生(razoxane)；利索新(rhizoxin)；西左非蘭(sizofiran)；鍺螺胺(spirogermanium)；替奴佐酸(tenuazonic acid)；曲貝替定(trabectedin)、三亞胺醌(triaziquone)；2,2',2"-三氯三乙胺；烏拉坦(urethane)；長春地辛(vindesine)；達卡巴嗪(dacarbazine)；甘露莫司汀(mannomustine)；二溴甘露醇(mitobronitol)；二溴衛矛醇(mitolactol)；哌泊溴烷(pipobroman)；加賽特辛(gacytosine)；阿糖胞苷(arabinoside)(「Ara-C」)；環磷醯胺；噻替派；氮芥苯丁酸；吉西他濱(gemcitabine)(GEMZAR®)；6-硫鳥嘌呤；巰嘌呤；胺甲喋呤；長春鹼(vinblastine)；鉑；依託泊苷(etoposide)(VP-16)；異環磷醯胺(ifosfamide)；米托蒽醌(mitroxantrone)；長春新鹼(vancristine)；長春瑞濱(vinorelbine)(NAVELBINE®)；能滅瘤(novantrone)；替尼泊苷(teniposide)；依達曲沙(edatrexate)；道諾黴素(daunomycin)；胺蝶呤(aminopterin)；截瘤達(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(DMFO)；類視色素，例如視黃酸；卡培他濱(capecitabine)；NUC-1031；FOLFIRI(氟尿嘧啶、甲醯四氫葉酸及伊立替康)；及上述藥劑中任一者之醫藥學上可接受之鹽、酸或衍生物。「化學治療劑」之定義中亦包括抗激素劑，例如抗雌激素及選擇性雌激素受體調節劑(SERM)、酶芳香酶之抑制劑、 抗雄激素劑及上述藥劑中任一者之醫藥學上可接受之鹽、酸或衍生物，其用於調控或抑制對腫瘤之激素作用。抗雌激素及SERM之實例包括(例如)他莫昔芬(tamoxifen)(包括NOLVADEXTM)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(FARESTON®)。酶芳香酶之抑制劑調控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)、福美坦(formestane)、法曲唑(fadrozole)、伏氯唑(vorozole)(RIVISOR®)、來曲唑(FEMARA®)及阿那曲唑(ARIMIDEX®)。抗雄激素之實例包括阿帕魯醯胺(apalutamide)、阿比特龍(abiraterone)、恩雜魯胺(enzalutamide)、氟他胺(flutamide)、蓋樂特龍(galeterone)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、柳培林(leuprolide)、戈舍瑞林(goserelin)、ODM-201、APC-100、ODM-204。助孕酮受體拮抗劑之實例包括奧那司酮。
抗血管生成劑包括(但不限於)類視色素酸及其衍生物、2-甲氧基雌二醇、ANGIOSTATIN®、ENDOSTATIN®、瑞格菲尼(regorafenib)、奈卡帕拉尼(necuparanib)、舒拉明(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劑抑制劑-1、纖維蛋白溶酶原活化劑抑制劑-2、軟骨源抑制劑、太平洋紫杉醇(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)、硫酸化幾丁質衍生物(自雪花蟹外殼製備)、硫酸化多醣肽聚醣複合物(sp-pg)、星狀孢菌素、基質代謝調節劑，包括例如脯胺酸類似物(例如(1-氮雜環丁烷-2-甲酸(LACA)、順羥基脯胺酸、d,I-3,4-脫氫脯胺酸、硫脯胺酸、α,α'-二吡啶基、β-胺基丙腈富馬酸鹽、4-丙基-5-(4-吡啶基)-2(3h)-噁唑酮、胺甲喋呤、米托蒽醌、肝素、干擾素、2巨球蛋白-血清、金屬蛋白酶之雞抑制劑-3(ChIMP-3)、糜蛋白酶抑制素、β-環糊精十四硫酸鹽、依匹黴素(eponemycin)、菸麴黴素(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-氯鄰胺基苯甲酸二鈉或「CCA」、沙利竇邁(thalidomide)；血管生成抑制類固醇、羧基胺基咪唑(cargboxynaminolmidazole)；金屬蛋白酶抑制劑，例如BB-94，S100A9之抑制劑(例如他喹莫德(tasquinimod))。其他抗血管生成劑包括針對該等血管生成生長因子之抗體、較佳單株抗體：β-FGF、α-FGF、FGF-5、VEGF同種型、VEGF-C、HGF/SF及Ang-1/Ang-2。
抗纖維變性劑包括(但不限於)諸如β-胺基丙腈(BAPN)等化合物以及關於離胺醯基氧化酶之抑制劑及其在治療與膠原之異常沈積相關之疾病及病況中之用途之美國專利第4,965,288號及關於抑制LOX用於治療各種病理性纖維變性狀態之化合物之美國專利第4,997,854號中揭示之化合物，該等案件以引用方式併入本文中。其他實例性抑制劑闡述於關於諸如2-異丁基-3-氟-、氯-或溴-烯丙基胺等化合物之美國專利第4,943,593號、關於2-(1-萘基氧基甲基)-3-氟烯丙基胺之美國專利第5,021,456號、第5,059,714號、第5,120,764號、第5,182,297號及第5,252,608號及美國公開專利申請案第2004/0248871號中，該等案件以引用方式併入本文中。實例性抗纖維變性劑亦包括與離胺醯氧化酶之活性位點之羰基反應之一級胺，且更具體而言在與羰基結合後產生藉由共振穩定之產物之彼等，例如以下一級胺：乙烯胺、肼、苯基肼及其衍生物；胺基脲及脲衍生物；胺基腈，例如BAPN或2-硝基乙胺；不飽和或飽和鹵代胺，例如2-溴-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙基胺及對-鹵代苄基胺；及硒基高半胱胺酸內酯。其他抗纖維變性劑係銅螯合劑，其穿透或不穿透細胞。實例性化合物包括阻斷源自離胺醯基及羥基離胺醯基殘基由離胺醯氧化酶之氧化脫胺之醛衍生物的間接抑制劑。實例包括硫醇胺、具體而言D-青黴胺及其類似物，例如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、4-((對-1-二甲基-2-胺基-2-羧基乙基)二硫基) 丁烷硫酸鈉、2-乙醯胺基乙基-2-乙醯胺基乙烷硫醇硫酸鹽及4-巰基丁烷亞硫酸鈉三水合物。
免疫治療劑包括且不限於適於治療患者之治療性抗體。治療性抗體之實例包括阿巴伏單抗(abagovomab)、ABP-980、阿德木單抗(adecatumumab)、阿福圖珠單抗(afutuzumab)、阿倫單抗(alemtuzumab)、阿托珠單抗(altumomab)、阿麥妥昔單抗(amatuximab)、麻安莫單抗(anatumomab)、阿西莫單抗(arcitumomab)、巴維昔單抗(bavituximab)、貝妥莫單抗(bectumomab)、貝伐珠單抗(bevacizumab)、比伐單抗(bivatuzumab)、布利莫單抗(blinatumomab)、貝倫妥單抗、坎妥珠單抗(cantuzumab)、卡妥索單抗(catumaxomab)、CC49、西妥昔單抗(cetuximab)、西他珠單抗(citatuzumab)、西妥木單抗(cixutumumab)、克立瓦妥珠單抗(clivatuzumab)、可那木單抗(conatumumab)、達西珠單抗(dacetuzumab)、達洛珠單抗(dalotuzumab)、達雷木單抗(daratumumab)、地莫單抗(detumomab)、地努圖希單抗(dinutuximab)、卓齊妥單抗(drozitumab)、度利戈妥單抗(duligotumab)、杜昔妥單抗(dusigitumab)、依美昔單抗(ecromeximab)、埃羅妥珠單抗(elotuzumab)、艾米拜土珠單抗(emibetuzumab)、恩司昔單抗(ensituximab)、厄馬索單抗(ertumaxomab)、埃達珠單抗(etaracizumab)、法利珠單抗(farletuzumab)、芬克拉妥珠單抗(ficlatuzumab)、芬妥木單抗(figitumumab)、弗蘭托單抗(flanvotumab)、弗妥昔單抗(futuximab)、蓋尼塔單抗(ganitumab)、吉妥珠單抗(gemtuzumab)、吉瑞妥昔單抗(girentuximab)、格萊木單抗(glembatumumab)、替伊莫單抗(ibritumomab)、伊戈伏單抗(igovomab)、英加妥珠單抗(imgatuzumab)、英達妥昔單抗(indatuximab)、伊珠單抗(inotuzumab)、英妥木單抗(intetumumab)、伊匹單抗(ipilimumab)(YERVOY®、MDX-010、BMS-734016及MDX-101)、伊妥木單抗(iratumumab)、拉貝珠單抗(labetuzumab)、來沙木單抗(lexatumumab)、林妥珠單抗(lintuzumab)、洛伏珠單抗、魯卡木單抗(lucatumumab)、馬帕木單抗 (mapatumumab)、馬妥珠單抗(matuzumab)、米拉珠單抗、明瑞莫單抗(minretumomab)、米妥莫單抗(mitumomab)、莫格木里單抗(mogamulizumab)、莫妥莫單抗(moxetumomab)、那莫單抗(naptumomab)、納那妥單抗(narnatumab)、奈昔木單抗(necitumumab)、尼妥珠單抗(nimotuzumab)、諾非單抗(nofetumomab)、OBI-833、奧妥珠單抗、奧卡妥珠單抗(ocaratuzumab)、奧法木單抗(ofatumumab)、奧拉妥單抗(olaratumab)、昂妥珠單抗(onartuzumab)、莫奧珠單抗(oportuzumab)、奧戈伏單抗(oregovomab)、帕尼單抗(panitumumab)、帕圖珠單抗(parsatuzumab)、帕蘇德托(pasudotox)、帕圖單抗(patritumab)、帕圖莫單抗(pemtumomab)、帕妥珠單抗(pertuzumab)、平妥單抗(pintumomab)、普托木單抗(pritumumab)、拉妥木單抗(racotumomab)、拉圖單抗(radretumab)、雷莫蘆單抗(ramucirumab)(Cyramza®)、利妥木單抗(rilotumumab)、利妥昔單抗(rituximab)、羅妥木單抗(robatumumab)、沙馬珠單抗(samalizumab)、沙妥莫單抗(satumomab)、西羅珠單抗(sibrotuzumab)、司妥昔單抗、索利圖單抗(solitomab)、司妥佐單抗(simtuzumab)、他妥珠單抗(tacatuzumab)、他妥莫單抗(taplitumomab)、替妥莫單抗(tenatumomab)、替普莫單抗(teprotumumab)、替加珠單抗(tigatuzumab)、托西莫單抗(tositumomab)、曲妥珠單抗、托卡珠單抗(tucotuzumab)、烏比利單抗(ubilituximab)、維妥珠單抗(veltuzumab)、沃妥珠單抗(vorsetuzumab)、沃圖莫單抗(votumumab)、紮魯木單抗(zalutumumab)、3F8及諸如此類。利妥昔單抗可用於治療惰性B細胞癌，包括邊緣區淋巴瘤、WM、CLL及小淋巴球性淋巴瘤。利妥昔單抗與化學治療劑之組合尤其有效。所例示治療性抗體可進一步經放射性同位素粒子(例如銦-111、釔-90(90Y-克立瓦妥珠單抗)或碘-131)標記或與其組合。應理解，上述試劑、分子、化合物或抗體可具有額外機制方式且將不限於上述方式；例如，化學治療劑可為抗纖維變性劑。
提供本文所述化合物(I)之鹽或共晶體形式用於製造藥物產品之用途。 本文所述化合物(I)之鹽或共晶體形式可用作製造過程中之中間體以產生藥物產品。
可製備包含本文所述化合物(I)之鹽或共晶體形式且調配於一或多種醫藥學上可接受之載劑、賦形劑或其他成分之組合物，將其放置於適當容器中，且標記用於治療適應病症。因此，亦涵蓋製品，例如包含本文所述化合物(I)之鹽或共晶體形式之劑型及含有化合物之使用說明之標記的容器。
在一些實施例中，製品係包含本文所述化合物(I)之鹽或共晶體形式及一或多種醫藥學上可接受之載劑、賦形劑或其他成分之劑型的容器。在本文所述製品之一個實施例中，劑型係錠劑。
亦涵蓋套組。舉例而言，套組可包含醫藥組合物之劑型及含有組合物在治療醫學病況中之使用說明書之包裝插頁。套組中之使用說明書可為針對治療BTK介導之病症，包括(例如)自體免疫疾病或癌症。在某些實施例中，標記上適應之病況可包括(例如)自體免疫疾病或癌症之治療。
提供以下實例以進一步有助於理解申請案中揭示之實施例，且預料彼等熟習實例所屬領域技術者熟知之習用方法的理解。下文闡述之特定物質及條件意欲例示本文揭示之實施例之特定態樣且不應理解為限制其合理範疇。
藉由各種分析技術(包括X射線粉末繞射圖案(XRPD)、差示掃描量熱法(DSC)及熱重分析(TGA))使用下述程序表徵6-胺基-9-[(3R)-1-(2-丁炔醯基)-3-吡咯啶基]-7-(4-苯氧基苯基)-7,9-二氫-8H-嘌呤-8-酮之鹽及共晶體形式。
X射線粉末繞射(XRPD)：於環境條件下在以下實驗設置下利用PAN分析型XPERT-PRO繞射儀收集XRPD圖案：45KV，40mA，Kα1=1.5406Å，掃描範圍2°至40°，步長0.0084°或0.0167°，量測時間：5min。
差示掃描量熱法(DSC)：利用配備有50位置取樣器之TA儀器Q2000系統收集DSC溫度記錄圖。使用合乎標準之銦實施能量及溫度之校正。通常將針紮孔之鋁盤中之1-5mg每一樣品以10℃/min自25℃加熱至300℃。貫穿量測在樣品上維持50mL/min之乾燥氮之吹掃。熔融吸熱之起始報告為熔點。
熱重分析(TGA)：利用配備有25位置取樣器之TA儀器Q5000系統收集TGA溫度記錄圖。通常將1-5mg每一樣品裝載至預稱重之鋁盤上並以10℃/min自25℃加熱至250℃。貫穿量測在樣品上維持25mL/min之氮吹掃。
動態氣相吸附(DVS)：利用TA儀器Q5000SA系統收集用於測定固體之吸濕性之DVS數據。將溫度控制腔室設定於25℃下且以10mL/min之流速引入乾燥氮。將約1至5mg樣品放置於半球形金屬塗佈之石英坩堝或可棄式鋁盤中。藉由將腔室中之相對濕度(RH)以10%增量自10%控制至90%、接著控制至10%以完成完全吸附/解吸循環來執行25℃下之逐步等溫線實驗。
於約40℃下將5g化合物(I)游離鹼溶解於約50mL乙腈中。將540mg硫酸用約10mL乙腈稀釋，並經約2.5h裝入化合物(I)溶液中。在添加期間形成漿液。其後，將漿液加熱至約70℃且經約2h冷卻至約0℃。過濾混合物，用約10mL乙腈洗滌，且在真空下於約50℃下在烘箱中乾燥過夜。獲得5.05g化合物(I)半硫酸鹽。
將100mg化合物(I)及19.8mg草酸之混合物溶解於丙酮中且於大約室溫下攪拌過夜。形成漿液且藉由XRPD確認為化合物(I)草酸鹽以產生晶種批料。藉由於約20℃下將10g化合物(I)及2g草酸溶解於約50mL丙酮中、之後添加晶種批料之種晶來製備批料。形成漿液且在約2h內裝入約50mL正庚烷。 過濾混合物，用10mL丙酮洗滌且在真空下於約50℃下乾燥。獲得10.7g化合物(I)草酸鹽。
將100mg化合物(I)與24.9mg乙烷-1,2-二磺酸二水合物之混合物在約1mL乙腈、四氫呋喃或丙酮或其混合物中混合。將混合物於大約室溫下攪拌過夜。過濾漿液並在真空下於約50℃下乾燥。藉由XRPD檢查固體以確認化合物(I)半乙二磺酸鹽之形成。
將100mg化合物(I)與49.8mg乙烷-1,2-二磺酸二水合物之混合物在約1mL乙腈、四氫呋喃或丙酮或其混合物中混合。在使用乙腈時，實施加晶種(晶種來自使用此段落中所述之四氫呋喃或丙酮之實驗)。將混合物在室溫下攪拌過夜。過濾漿液並在真空下於約50℃下乾燥。藉由XRPD檢查固體以確認化合物(I)乙二磺酸鹽之形成。
將108.7mg化合物(I)、43.1mg(0.5eq)萘-1,5-二磺酸及約1.5mL乙腈之混合物在密封之4mL琥珀玻璃小瓶中超音波處理約30分鐘。將樣品於約50℃下藉由磁力攪拌棒攪動約1小時，且接著冷卻至室溫，其中樣品保持攪拌約5天。藉由離心分離固體且於約50℃下在真空下乾燥過夜。1H NMR顯示約一半當量之萘-1,5-二磺酸及一些殘餘乙腈。於約125℃下進一步乾燥樣品。
將100.4mg化合物(I)、26.2mg(1eq)富馬酸及0.75mL乙酸異丙酯之混合物在密封之4mL琥珀玻璃小瓶中超音波處理約30分鐘。將樣品於約50℃下藉由磁力攪拌棒攪動約1小時，且接著冷卻至室溫，其中樣品保持攪拌約2週。藉由離心分離固體且於約50℃下在真空下乾燥過夜。1H NMR顯示約1當 量之富馬酸。
藉由於約50℃下將500mg化合物(I)及127.7mg(1eq)富馬酸在5mL乙酸異丙酯及0.5mL水之混合物中攪拌約16小時且接著於室溫下攪拌約2天製備另一批料。過濾樣品，用5mL乙酸異丙酯洗滌並在真空下於約50℃下乾燥過夜。固體之XRPD分析顯示與上述實驗中之樣品相同之圖案。
將99.5mg化合物(I)、27.1mg(1eq)琥珀酸及0.75mL乙酸異丙酯之混合物在密封之4mL琥珀玻璃小瓶中超音波處理約30分鐘。將樣品於約50℃下藉由磁力攪拌棒攪動約1小時，且接著冷卻至室溫，其中樣品保持攪拌約1週。藉由離心分離固體且於約50℃下在真空下乾燥過夜。1H NMR顯示約1當量之琥珀酸。
藉由於室溫下將500mg化合物(I)及129.9mg(1eq)琥珀酸在5mL乙酸異丙酯中攪拌約3天製備另一批料。過濾樣品，用5mL乙酸異丙酯洗滌並在真空下於約50℃下乾燥過夜。固體之XRPD分析顯示與上述實驗中之樣品相同之圖案。
Claims (48)
- 一種化合物(I)之半硫酸鹽，
- 如申請專利範圍第1項之化合物(I)半硫酸鹽，其中X射線粉末繞射圖包含6.6、18.6及23.7°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第2項之化合物(I)半硫酸鹽，其中該繞射圖進一步包含7.1及13.7°2θ±0.2°之峰。
- 如申請專利範圍第2項或第3項之化合物(I)半硫酸鹽，其中另外，差示掃描量熱曲線包含約192℃下之吸熱。
- 一種化合物(I)之草酸鹽，
- 如申請專利範圍第5項之化合物(I)草酸鹽，其中X射線粉末繞射圖包含7.2、18.2及23.3°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測 定。
- 如申請專利範圍第6項之化合物(I)草酸鹽，其中該繞射圖進一步包含13.8及20.2°2θ±0.2°之峰。
- 如申請專利範圍第6項或第7項之化合物(I)草酸鹽，其中另外，差示掃描量熱曲線包含約171℃下之吸熱。
- 一種化合物(I)之半乙二磺酸鹽，
- 如申請專利範圍第9項之化合物(I)半乙二磺酸鹽，其中X射線粉末繞射圖包含5.9、11.8及17.6°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第10項之化合物(I)半乙二磺酸鹽，其中該繞射圖進一步包含21.2及23.6°2θ±0.2°之峰。
- 如申請專利範圍第10項或第11項之化合物(I)半乙二磺酸鹽，其中另外，差示掃描量熱曲線包含約165℃下之吸熱。
- 一種化合物(I)之乙二磺酸鹽，
- 如申請專利範圍第13項之化合物(I)乙二磺酸鹽，其中X射線粉末繞射圖包含5.7、16.6及24.2°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第14項之化合物(I)乙二磺酸鹽，其中該繞射圖進一步包含11.1及22.2°2θ±0.2°之峰。
- 如申請專利範圍第14項或第15項之化合物(I)乙二磺酸鹽，其中另外，差示掃描量熱曲線包含約154℃下之吸熱。
- 一種化合物(I)之半萘二磺酸鹽，
- 如申請專利範圍第17項之化合物(I)半萘二磺酸鹽，其中X射線粉末繞射圖包含15.5、16.5及23.8°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第18項之化合物(I)半萘二磺酸鹽，其中該繞射 圖進一步包含5.6及20.3°2θ±0.2°之峰。
- 如申請專利範圍第18項或第19項之化合物(I)半萘二磺酸鹽，其中另外，差示掃描量熱曲線包含約180℃下之吸熱。
- 一種化合物(I)之富馬酸鹽，
- 如申請專利範圍第21項之化合物(I)富馬酸鹽，其中X射線粉末繞射圖包含13.0、16.6及19.9°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第22項之化合物(I)富馬酸鹽，其中該繞射圖進一步包含8.3及19.0°2θ±0.2°之峰。
- 如申請專利範圍第22項或第23項之化合物(I)富馬酸鹽，其中另外，差示掃描量熱曲線包含約158℃下之吸熱。
- 一種化合物(I)之琥珀酸鹽，
- 如申請專利範圍第25項之化合物(I)琥珀酸鹽，其中X射線粉末繞射圖包含13.2、16.5及18.0°2θ之峰(±0.2°)，如利用繞射儀使用Cu-Kα輻射所測定。
- 如申請專利範圍第26項之化合物(I)琥珀酸鹽，其中該繞射圖進一步包含8.2及18.6°2θ±0.2°之峰。
- 如申請專利範圍第26項或第27項之化合物(I)琥珀酸鹽，其中另外，差示掃描量熱曲線包含約142℃下之吸熱。
- 一種醫藥組合物，其包含醫藥學上可接受之載劑及一或多種選自由以下組成之群之化合物：如申請專利範圍第1項至第4項中任一項之化合物(I)之半硫酸鹽、如申請專利範圍第5項至第8項中任一項之化合物(I)之草酸鹽、如申請專利範圍第9項至第12項中任一項之化合物(I)之半乙二磺酸鹽、如申請專利範圍第13項至第16項中任一項之化合物(I)之乙二磺酸鹽、如申請專利範圍第17項至第20項中任一項之化合物(I)之半萘二磺酸鹽、如申請專利範圍第21項至第24項中任一項之化合物(I)之富馬酸鹽以及如申請專利範圍第25項至第28項中任一項之化合物(I)之琥珀酸鹽。
- 一種治療有需要之人類之至少部分由布魯頓氏酪胺酸激酶(Bruton's Tyrosine Kinase，BTK)介導之疾病的方法，其包含投與治療有效量之如申請專利範圍第1項至第4項中任一項之化合物(I)之半硫酸鹽、如申請專利範圍第5項至第8項中任一項之化合物(I)之草酸鹽、如申請專利範圍第9項至第12項中任一項之化合物(I)之半乙二磺酸鹽、如申請專利範圍第13項至第16項中任一項之化合物(I)之乙二磺酸鹽、如申請專利範圍第17項至第20項中任一項之化合物(I)之半萘二磺酸鹽、如申請專利範圍第21項至第24項中任一項之化合物(I)之富馬酸鹽、如申請專利範圍第25項至第28項中任一項之化合物(I)之琥珀酸鹽或如申請專利範圍第29項之醫藥組合物。
- 如申請專利範圍第30項之方法，其中該疾病係選自癌症、血液惡性病、白血病、淋巴瘤、骨髓增生性病症、骨髓發育不良症候群、漿細胞腫瘤、實體腫瘤、發炎、纖維化、自體免疫病症、過敏病況、過敏、心血管疾病、神經退化疾病、腎病症、病毒感染、肥胖症及自體免疫疾病。
- 一種由以下物質抑制布魯頓氏酪胺酸激酶之活性的方法：如申請專利範圍第1項至第4項中任一項之化合物(I)之半硫酸鹽、如申請專利範圍第5項至第8項中任一項之化合物(I)之草酸鹽、如申請專利範圍第9項至第12項中任一項之化合物(I)之半乙二磺酸鹽、如申請專利範圍第13項至第16項中任一項之化合物(I)之乙二磺酸鹽、如申請專利範圍第17項至第20項中任一項之化合物(I)之半萘二磺酸鹽、如申請專利範圍第21項至第24項中任一項之化合物(I)之富馬酸鹽、如申請專利範圍第25項至第28項中任一項之化合物(I)之琥珀酸鹽或如申請專利範圍第29項之醫藥組合物。
- 一種套組，其包含如申請專利範圍第1項至第13項中任一項之化合物或如申請專利範圍第14項之醫藥組合物或進行使用之標記及/或說明書。
- 一種如申請專利範圍第1項至第29項中任一項之化合物或醫藥組合物的用途，其用於製造用於治療如申請專利範圍第30項至第31項中任一項之疾病或病況的藥劑。
- 一種製造如申請專利範圍第1項至第4項中任一項之化合物(I)之半硫酸鹽的方法，其包含使化合物(I)與硫酸接觸。
- 如申請專利範圍第35項之方法，其中該接觸包含以下步驟：i)將化合物(I)與該硫酸組合於適宜溶劑中以獲得混合物；ii)將步驟i)中獲得之該混合物加熱至約70℃；iii)將步驟ii)中獲得之該混合物冷卻至約0℃；及 iv)收集步驟iii)中獲得之固體材料以獲得該化合物(I)之半硫酸鹽。
- 一種製造如申請專利範圍第5項至第8項中任一項之化合物(I)之草酸鹽的方法，其包含使化合物(I)與草酸接觸。
- 如申請專利範圍第37項之方法，其中該接觸包含以下步驟：i)於室溫下將化合物(I)及該草酸溶解於適宜溶劑中以獲得混合物；及ii)收集步驟i)中獲得之固體材料以獲得該化合物(I)之草酸鹽。
- 一種製造如申請專利範圍第9項至第12項中任一項之化合物(I)之半乙二磺酸鹽的方法，其包含使化合物(I)與乙烷-1,2-二磺酸二水合物接觸。
- 如申請專利範圍第39項之方法，其中該接觸包含以下步驟：i)於室溫下將化合物(I)與該乙烷-1,2-二磺酸二水合物組合於適宜溶劑中以獲得混合物；及ii)收集步驟i)中獲得之固體材料以獲得該化合物(I)之半乙二磺酸鹽。
- 一種製造如申請專利範圍第13項至第16項中任一項之化合物(I)之乙二磺酸鹽的方法，其包含使化合物(I)與乙烷-1,2-二磺酸二水合物接觸。
- 如申請專利範圍第41項之方法，其中該接觸包含以下步驟：i)於室溫下將化合物(I)與該乙烷-1,2-二磺酸二水合物組合於適宜溶劑中以獲得混合物；及ii)收集步驟i)中獲得之固體材料以獲得該化合物(I)之乙二磺酸鹽。
- 一種製造如申請專利範圍第17項至第20項中任一項之化合物(I)之半萘二磺酸鹽的方法，其包含使化合物(I)與萘-1,5-二磺酸接觸。
- 如申請專利範圍第43項之方法，其中該接觸包含以下步驟：i)將化合物(I)與該萘-1,5-二磺酸組合於適宜溶劑中以獲得混合物；ii)將步驟i)中獲得之該混合物加熱至約50℃； iii)將步驟ii)中獲得之該混合物冷卻至室溫；及iv)收集步驟iii)中獲得之固體材料以獲得該化合物(I)之半萘二磺酸鹽。
- 一種製造如申請專利範圍第21項至第24項中任一項之化合物(I)之富馬酸鹽的方法，其包含使化合物(I)與富馬酸接觸。
- 如申請專利範圍第45項之方法，其中該接觸包含以下步驟：i)將化合物(I)與該富馬酸組合於適宜溶劑中；ii)將步驟i)中獲得之該混合物加熱至約50℃；iii)將步驟ii)中獲得之該混合物冷卻至室溫；及iv)收集步驟iii)中獲得之固體材料以獲得該化合物(I)之富馬酸鹽。
- 一種製造如申請專利範圍第25項至第28項中任一項之化合物(I)之琥珀酸鹽的方法，其包含使化合物(I)與琥珀酸接觸。
- 如申請專利範圍第47項之方法，其中該接觸包含以下步驟：i)將化合物(I)與該琥珀酸組合於適宜溶劑中；ii)將步驟i)中獲得之該混合物加熱至約50℃；iii)將步驟ii)中獲得之該混合物冷卻至室溫；及iv)收集步驟iii)中獲得之固體材料以獲得該化合物(I)之琥珀酸鹽。
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| JP6458018B2 (ja) | 2013-07-02 | 2019-01-23 | ファーマサイクリックス エルエルシー | キナーゼ阻害剤としてのプリノン化合物 |
| MA38961A1 (fr) | 2013-09-30 | 2018-05-31 | Pharmacyclics Llc | Composés 3-phenyl-1h-pyrazolo[3,4-d]pyrimidin-4-ylamine substitués inhibiteurs de la tyrosine kinase de bruton utilisés pour traiter par exemple les maladies auto-immunes, respiratoires et inflammatoires, cancer, mastocytose et osteoporose |
| US9290505B2 (en) | 2013-12-23 | 2016-03-22 | Gilead Sciences, Inc. | Substituted imidazo[1,2-a]pyrazines as Syk inhibitors |
| US9937171B2 (en) * | 2014-04-11 | 2018-04-10 | Acerta Pharma B.V. | Methods of blocking the CXCR-4/SDF-1 signaling pathway with inhibitors of bruton's tyrosine kinase |
-
2018
- 2018-02-23 TW TW107106216A patent/TWI754011B/zh not_active IP Right Cessation
- 2018-02-23 AU AU2018224136A patent/AU2018224136B2/en not_active Ceased
- 2018-02-23 WO PCT/US2018/019422 patent/WO2018156895A1/en unknown
- 2018-02-23 CA CA3054403A patent/CA3054403A1/en active Pending
- 2018-02-23 KR KR1020197024651A patent/KR102362646B1/ko active IP Right Grant
- 2018-02-23 CN CN201880012910.8A patent/CN110312720A/zh active Pending
- 2018-02-23 US US15/903,285 patent/US10370381B2/en not_active Expired - Fee Related
- 2018-02-23 AR ARP180100432A patent/AR110998A1/es unknown
- 2018-02-23 JP JP2019545987A patent/JP7014811B2/ja active Active
- 2018-02-23 EP EP18710221.5A patent/EP3585788A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI762939B (zh) * | 2019-05-31 | 2022-05-01 | 大陸商海思科醫藥集團股份有限公司 | Btk抑制劑環衍生物及其製備方法和藥學上的應用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3585788A1 (en) | 2020-01-01 |
| JP7014811B2 (ja) | 2022-02-01 |
| AR110998A1 (es) | 2019-05-22 |
| JP2020508325A (ja) | 2020-03-19 |
| US20180251464A1 (en) | 2018-09-06 |
| KR102362646B1 (ko) | 2022-02-11 |
| WO2018156895A1 (en) | 2018-08-30 |
| AU2018224136B2 (en) | 2021-10-21 |
| TWI754011B (zh) | 2022-02-01 |
| KR20190120211A (ko) | 2019-10-23 |
| CN110312720A (zh) | 2019-10-08 |
| CA3054403A1 (en) | 2018-08-30 |
| WO2018156895A8 (en) | 2019-09-26 |
| US10370381B2 (en) | 2019-08-06 |
| AU2018224136A1 (en) | 2019-09-12 |
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