TW201427666A - Methods of treating a disease or disorder associated with Bruton's tyrosine kinase - Google Patents

Methods of treating a disease or disorder associated with Bruton's tyrosine kinase Download PDF

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TW201427666A
TW201427666A TW102142188A TW102142188A TW201427666A TW 201427666 A TW201427666 A TW 201427666A TW 102142188 A TW102142188 A TW 102142188A TW 102142188 A TW102142188 A TW 102142188A TW 201427666 A TW201427666 A TW 201427666A
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compound
lenalidomide
patient
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Tom Daniel
Kenichi Takeshita
Kenneth Foon
Jay Mei
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Celgene Avilomics Res Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The present invention provides methods of treating, stabilizing or lessening the severity or progression of a disease or disorder associated with BTK.

Description

治療和布魯頓(BRUTON'S)酪胺酸激酶相關之疾病或失調的方法 Method for treating diseases or disorders associated with BRUTON's tyrosine kinase

相關申請案之交叉參考Cross-reference to related applications

本申請案主張2012年11月20日申請之美國臨時申請案第61/728,701號、2012年11月20日申請之第61/728,703號、2013年3月15日申請之第61/799,761號、2013年8月27日申請之第61/870,718號及2013年8月27日申請之第61/870,720號之優先權，該等臨時申請案中之每一者以全文引用的方式併入本文中。 This application claims US Provisional Application No. 61/728,701, filed on November 20, 2012, No. 61/728,703, filed on Nov. 20, 2012, and No. 61/799,761, filed on March 15, 2013, Priority No. 61/870,718, filed on August 27, 2013, and No. 61/870,720, filed on Aug. 27, 2013, each of which is incorporated herein by reference in its entirety. .

本發明提供治療、穩定或減輕與布魯頓酪胺酸激酶(「Bruton's Tyrosine Kinase；BTK」)相關之疾病或失調之嚴重程度或進展的方法。 The present invention provides methods of treating, stabilizing or ameliorating the severity or progression of a disease or disorder associated with Bruton's Tyrosine Kinase (BTK).

近年來，藉由較好地瞭解與疾病相關之酶及其他生物分子之結構，已對尋求新穎治療劑提供極大的幫助。已成為廣泛研究對象之一類重要的酶為蛋白激酶。 In recent years, the search for novel therapeutic agents has been greatly assisted by a better understanding of the structure of enzymes and other biomolecules associated with diseases. One of the most important enzymes that have become a widely studied subject is protein kinases.

蛋白激酶構成負責控制細胞內多種信號轉導過程之結構上相關之酶的大家族。由於蛋白激酶之結構及催化功能保守，因此認為其是自共同祖先基因演化而來。幾乎所有激酶均含有一個類似的250-300個胺基酸的催化域。激酶可根據其磷酸化之受質而分類成各家族(例如蛋白質-酪胺酸、蛋白質-絲胺酸/蘇胺酸、脂質等)。 Protein kinases constitute a large family of structurally related enzymes responsible for controlling multiple signal transduction processes within cells. Since the structure and catalytic function of protein kinases are conserved, they are thought to evolve from common ancestral genes. Almost all kinases contain a similar catalytic domain of 250-300 amino acids. Kinases can be classified into families according to their phosphorylation (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.).

一般而言，蛋白激酶藉由影響在信號傳導路徑中所涉及之自三磷酸核苷至蛋白質受體之磷醯基轉移而介導細胞內信號傳導。此等磷酸化事件充當可調控或調節目標蛋白生物功能之分子開/關轉換器。對多種細胞外刺激及其他刺激之反應最終引發此等磷酸化事件。該等刺激之實例包括環境及化學應力信號(例如滲壓衝擊、熱衝擊、紫外輻射、細菌內毒素及H2O2)、細胞激素(例如介白素-1(IL-1)及腫瘤壞死因子α(TNF-α))及生長因子(例如顆粒球巨噬細胞群落刺激因子(GM-CSF)及纖維母細胞生長因子(FGF))。細胞外刺激可影響與細胞生長、遷移、分化、激素分泌、轉錄因子之活化、葡萄糖代謝、蛋白質合成之控制及細胞週期之調節相關的一或多個細胞反應。 In general, protein kinases mediate intracellular signaling by affecting the phosphoryl transfer from the nucleoside triphosphate to the protein receptor involved in the signaling pathway. These phosphorylation events act as molecular on/off transducers that modulate or regulate the biological function of the target protein. Responses to a variety of extracellular stimuli and other stimuli ultimately trigger these phosphorylation events. Examples of such stimuli include environmental and chemical stress signals (eg, osmotic shock, thermal shock, ultraviolet radiation, bacterial endotoxin and H 2 O 2 ), cytokines (eg, interleukin-1 (IL-1), and tumor necrosis). Factor alpha (TNF-alpha) and growth factors (eg, granule macrophage colony stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimulation can affect one or more cellular responses associated with cell growth, migration, differentiation, hormone secretion, activation of transcription factors, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

多種疾病與由如上文所述之蛋白激酶介導之事件引發的異常細胞反應有關。此等疾病包括(但不限於)自體免疫疾病、發炎疾病、骨病、代謝疾病、神經及神經退化性疾病、癌症、心血管疾病、過敏症及哮喘、阿茲海默氏病(Alzheimer's disease)及激素相關疾病。因此，仍需要尋找適用作治療劑之蛋白激酶抑制劑。 A variety of diseases are associated with abnormal cellular responses elicited by events mediated by protein kinases as described above. Such diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease (Alzheimer's disease) ) and hormone-related diseases. Therefore, there is still a need to find protein kinase inhibitors that are useful as therapeutic agents.

慢性淋巴球性白血病(CLL)為藉由形態上成熟但功能上不全的淋巴細胞在血液、骨髓及淋巴組織中之進行性積聚表徵的淋巴球增生惡性腫瘤。其主要影響中值年齡表現為65至70歲的年長個體。一般將小淋巴球性淋巴瘤(SLL)及CLL視為同一疾病的不同表現。CLL見於血液及骨髓，而SLL主要存在於淋巴結中。CLL/SLL之臨床過程介於長期存活超過12年的惰性疾病至中值存活期為2年之侵襲性疾病。患有CLL/SLL之平均診斷年齡為約60歲。 Chronic lymphocytic leukemia (CLL) is a lymphoid proliferative malignancy characterized by progressive accumulation of morphologically mature but functionally incomplete lymphocytes in blood, bone marrow, and lymphoid tissues. It mainly affects older individuals with a median age of 65 to 70 years. Small lymphocytic lymphoma (SLL) and CLL are generally considered to be different manifestations of the same disease. CLL is found in the blood and bone marrow, while SLL is mainly found in lymph nodes. The clinical course of CLL/SLL is between invasive disease with a long-term survival of more than 12 years and a median survival of 2 years. The mean age of diagnosis with CLL/SLL is approximately 60 years.

儘管新近核准了治療劑及組合療法，CLL/SLL仍為不治之症且大多數患者最終復發及/或死亡。用於需要治療之患有CLL/SLL之個體的經改良之新穎組合治療仍未滿足醫學需要。 Despite the recent approval of therapeutics and combination therapies, CLL/SLL remains incurable and most patients eventually relapse and/or die. Improved novel combination therapies for individuals with CLL/SLL requiring treatment still do not meet medical needs.

布魯頓酪胺酸激酶(Btk)為主要限於B淋巴細胞、單核細胞及肥大細胞或嗜鹼性白血球的限制細胞表現的非受體酪胺酸激酶。Btk為B細胞受體(BCR)信號傳導網之關鍵組分且為B細胞發育之關鍵。調查研究已顯示一些B細胞惡性腫瘤(包括諸如CLL/SLL之疾病)依賴於BCR信號傳導，表明中斷該信號傳導可為有前景之治療機遇。近來，已報導使用抑制脾臟酪胺酸激酶(Syk)及Btk(亦即BCR信號傳導路徑之兩種組分)之藥劑對於各種B細胞非霍奇金氏淋巴瘤(non-Hodgkin's Lymphoma，NHL)及CLL/SLL中之臨床抗腫瘤反應。 Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase that is primarily restricted to B lymphocytes, monocytes, and restricted cell expression of mast cells or basophils. Btk is a key component of the B cell receptor (BCR) signaling network and is critical for B cell development. Investigations have shown that some B cell malignancies (including diseases such as CLL/SLL) rely on BCR signaling, suggesting that disrupting this signaling can be a promising therapeutic opportunity. Recently, agents that inhibit spleen tyrosine kinase (Syk) and Btk (i.e., two components of the BCR signaling pathway) have been reported for various B-cell non-Hodgkin's Lymphoma (NHL). And clinical anti-tumor response in CLL/SLL.

2010年2月4日公開之美國公開專利申請案第US 2010/0029610號(「'610公開案」，其全文特此以引用的方式併入本文中)描述共價及不可逆地抑制一或多種蛋白激酶(包括BTK，亦即TEC激酶之一員)之活性的某些2,4-二取代之嘧啶化合物。該等化合物包括下文稱為化合物1之N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺，其在'610公開案中命名為化合物編號I-182。化合物1之合成詳細描述在'610公開案之實例20。化合物1在多種分析及治療模型中有活性，證明能共價且不可逆地抑制BTK(在酶促及細胞分析中)。值得注意的是，化合物1為經發現抑制B細胞增殖及活化之有效、有選擇性、可口服使用的小分子。化合物1因此適用於治療一或多種與BTK活性相關之失調。 U.S. Published Patent Application No. US 2010/0029610, the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire disclosure Certain 2,4-disubstituted pyrimidine compounds that are active in kinases, including BTK, a member of the TEC kinase. Such compounds include N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)propene, hereinafter referred to as Compound 1 . Indoleamine, which is named Compound No. I-182 in the '610 publication. The synthesis of Compound 1 is described in detail in Example 20 of the '610 publication. Compound 1 is active in a variety of assays and therapeutic models, demonstrating covalent and irreversible inhibition of BTK (in enzymatic and cellular assays). Notably, Compound 1 is an effective, selective, orally administrable small molecule that has been found to inhibit B cell proliferation and activation. Compound 1 is therefore suitable for the treatment of one or more disorders associated with BTK activity.

因此，本發明尤其提供治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法。在一些態樣中，本發明提供治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與醫藥學上可接受之組合物，該組合物包含N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺(1)： Accordingly, the present invention provides, inter alia, methods of treating, stabilizing or ameliorating the severity or progression of one or more diseases and conditions associated with BTK. In some aspects, the invention provides methods of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering to a patient in need thereof a pharmaceutically acceptable composition, The composition comprises N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine ( 1 ):

在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與化合物1與來那度胺(lenalidomide)之組合。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering Compound 1 with lenalidomide to a patient in need thereof ( The combination of lenalidomide).

在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與包含化合物1之組合物與包含來那度胺之組合物之組合。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-associated diseases and conditions, comprising administering to a patient in need thereof a composition comprising Compound 1 and comprising A combination of lenalidomide compositions.

在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中化合物1一天投與一次。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中化合物1一天投與兩次。在一些該等實施例中，來那度胺一天投與一次。因此，在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中化合物1一天投與兩次且來那度胺一天投與一次。 In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide to a patient in need thereof, wherein Compound 1 is administered once a day. In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide to a patient in need thereof, wherein Compound 1 is administered twice a day. In some of these embodiments, lenalidomide is administered once a day. Thus, in some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide to a patient in need thereof, wherein Compound 1 is administered twice a day and lenalidomide is administered once a day.

在一些實施例中，所提供之方法包含向有需要之患者投與包含化合物1及來那度胺之組合物。 In some embodiments, a method is provided comprising administering to a patient in need thereof a composition comprising Compound 1 and lenalidomide.

在一些實施例中，與BTK相關之疾病或病狀係選自慢性淋巴球性白血病及小淋巴球性淋巴瘤。 In some embodiments, the disease or condition associated with BTK is selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma.

在一些實施例中，本發明提供一種治療、穩定或減輕慢性淋巴球性白血病(CLL)之嚴重程度或進展的方法，該方法包含向有需要之患者投與化合物1與來那度胺之組合。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of chronic lymphocytic leukemia (CLL) comprising administering a combination of Compound 1 and lenalidomide to a patient in need thereof .

在一些實施例中，本發明提供一種治療、穩定或減輕小淋巴球性淋巴瘤(SLL)之嚴重程度或進展的方法，該方法包含向有需要之患 者投與化合物1與來那度胺之組合。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of small lymphoplastic lymphoma (SLL) comprising administering Compound 1 with lenalidomide to a patient in need thereof combination.

在一些實施例中，所提供之療法包含向患者經口投與化合物1與來那度胺之組合。在一些實施例中，化合物1及來那度胺各自以醫藥調配物形式投與。在一些該等實施例中，該等調配物為膠囊調配物。 In some embodiments, the therapy provided comprises orally administering to a patient a combination of Compound 1 and lenalidomide. In some embodiments, Compound 1 and lenalidomide are each administered as a pharmaceutical formulation. In some of these embodiments, the formulations are capsule formulations.

在一些實施例中，本發明亦提供向有需要之患者投與化合物1與來那度胺之組合的給藥方案及計劃。 In some embodiments, the invention also provides a dosing regimen and schedule for administering a combination of Compound 1 and lenalidomide to a patient in need thereof.

在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與化合物1、來那度胺及抗CD20抗體(例如利妥昔單抗(rituximab))中之每一者。在一些該等實施例中，與BTK相關之疾病或病狀係選自慢性淋巴球性白血病及小淋巴球性淋巴瘤。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering Compound 1 , lenalidomide, and, to a patient in need thereof Each of the anti-CD20 antibodies (eg, rituximab). In some such embodiments, the disease or condition associated with BTK is selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma.

用於該組合投與之該等方法、給藥方案及計劃進一步詳細描述於下文中。 The methods, dosing regimens and plans for administration of the combination are described in further detail below.

圖1呈現OCI-LY-10細胞株中化合物1苯磺酸鹽與來那度胺(3000nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。化合物1苯磺酸鹽及來那度胺似乎在OCI-LY-10細胞株中展示累加效應。 Figure 1 presents a specific dose response curve for the combination of Compound 1 besylate and lenalidomide (3000 nM) in the OCI-LY-10 cell line. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity. Compound 1 besylate and lenalidomide appeared to exhibit an additive effect in the OCI-LY-10 cell line.

圖2呈現OCI-LY-10細胞株中化合物1苯磺酸鹽(0.2nM-1500nM)與來那度胺(300nM、1000nM及3000nM)之組合的「火山」圖。化合物1苯磺酸鹽及來那度胺似乎在OCI-LY-10細胞株中展示累加效應。 Figure 2 presents a "volcano" plot of the combination of Compound 1 besylate (0.2 nM - 1500 nM) and lenalidomide (300 nM, 1000 nM and 3000 nM) in the OCI-LY-10 cell line. Compound 1 besylate and lenalidomide appeared to exhibit an additive effect in the OCI-LY-10 cell line.

圖3呈現WSU-DLCL2細胞株中化合物1苯磺酸鹽與來那度胺(3333nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。化合物1苯磺酸鹽及來那度胺似乎在WSU-DLCL2細胞株中展示累加效應。 Figure 3 presents a specific dose response curve for the combination of Compound 1 besylate and lenalidomide (3333 nM) in the WSU-DLCL2 cell line. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity. Compound 1 besylate and lenalidomide appeared to exhibit an additive effect in the WSU-DLCL2 cell line.

圖4呈現WSU-DLCL2細胞株中化合物1苯磺酸鹽(0.5nM-3333 nM)與來那度胺(123nM、3333nM及10000nM)之組合的「火山」圖。化合物1苯磺酸鹽及來那度胺似乎在WSU-DLCL2細胞株中展示累加效應。 Figure 4 presents a "volcano" plot of the combination of Compound 1 besylate (0.5 nM - 3333 nM) and lenalidomide (123 nM, 3333 nM and 10000 nM) in the WSU-DLCL2 cell line. Compound 1 and benzenesulfonate lenalidomide seems to show additive effects in cell line WSU-DLCL2.

圖5呈現Riva細胞株中化合物1苯磺酸鹽與來那度胺(3333nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。由箭頭指出明顯的協同效應。 5 presents certain cell lines Dose-response curves of Compound 1 Riva benzenesulfonate and lenalidomide (3333nM) of the combination. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity. Significant synergies are indicated by arrows.

圖6呈現Riva細胞株中化合物1苯磺酸鹽(0.2nM-1000nM)與來那度胺(41nM、1111nM及3333nM)之組合的「火山」圖。由箭頭指出明顯的協同效應。 Figure 6 presents a "volcano" plot of the combination of Compound 1 besylate (0.2 nM - 1000 nM) and lenalidomide (41 nM, 1111 nM and 3333 nM) in the Riva cell line. Significant synergies are indicated by arrows.

圖7呈現Riva細胞株中化合物1苯磺酸鹽與來那度胺(333nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。由箭頭指出明顯的協同作用。 Figure 7 presents a specific dose response curve for the combination of Compound 1 besylate and lenalidomide (333 nM) in the Riva cell line. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity. Significant synergies are indicated by arrows.

圖8呈現Riva細胞株中化合物1苯磺酸鹽(0.2nM-1000nM)與來那度胺(41nM、123nM及370nM)之組合的「火山」圖。由箭頭指出明顯的協同作用。 Figure 8 presents a "volcano" plot of the combination of Compound 1 besylate (0.2 nM - 1000 nM) and lenalidomide (41 nM, 123 nM and 370 nM) in the Riva cell line. Significant synergies are indicated by arrows.

圖9呈現Riva細胞株中化合物1苯磺酸鹽與來那度胺(333nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。 Figure 9 presents a specific dose response curve for the combination of Compound 1 besylate and lenalidomide (333 nM) in the Riva cell line. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity.

圖10呈現Riva細胞株中化合物1苯磺酸鹽(0.2nM-1000nM)與來那度胺(41nM、123nM及370nM)之組合的「火山」圖。化合物1苯磺酸鹽及來那度胺似乎在Riva細胞株中展示累加效應。 Figure 10 presents a "volcano" plot of the combination of Compound 1 besylate (0.2 nM - 1000 nM) and lenalidomide (41 nM, 123 nM and 370 nM) in the Riva cell line. Compound 1 besylate and lenalidomide appeared to exhibit an additive effect in the Riva cell line.

圖11呈現TMD-8細胞株中化合物1苯磺酸鹽與來那度胺(3000nM)之組合的特定劑量反應曲線。●=化合物1苯磺酸鹽；□=來那度胺；△=計算或預期之組合活性；◇=觀測到之組合活性。由箭頭 指出明顯的協同作用。 Figure 11 presents a specific dose response curve for the combination of Compound 1 besylate and lenalidomide (3000 nM) in the TMD-8 cell line. • = compound 1 besylate; □ = lenalidomide; Δ = calculated or expected combined activity; ◇ = observed combined activity. Significant synergies are indicated by arrows.

圖12呈現TMD-8細胞株中化合物1苯磺酸鹽(0.2nM-1500nM)與來那度胺(300nM、1000nM及3000nM)之組合的「火山」圖。由箭頭指出明顯的協同作用。 Figure 12 presents a "volcano" plot of the combination of Compound 1 besylate (0.2 nM - 1500 nM) and lenalidomide (300 nM, 1000 nM and 3000 nM) in the TMD-8 cell line. Significant synergies are indicated by arrows.

圖13呈現到2013年10月16日為止組1中所登記之患者的反應評估。 Figure 13 presents a response assessment of patients enrolled in Group 1 up to October 16, 2013.

圖14呈現到2013年10月16日為止組2中所登記之患者的反應評估。 Figure 14 presents the reaction assessment to date October 16, 2013 Group 2 patients registered.

定義definition

如本文中所用，術語「組合」、「與......組合」或「組合療法」係指兩種或兩種以上不同醫藥劑以重疊方案投與以使得個體同步暴露於兩種藥劑之情況。在一些實施例中，該等組合係指向個體同步投與化合物1及來那度胺之各別劑型。在一些實施例中，該等組合係指向個體同時投與化合物1及來那度胺之各別劑型，其中化合物1在來那度胺投與之前、期間或之後投與。在一些實施例中，經由適於各治療劑之不同給藥方案實現化合物1及來那度胺之同步或同時暴露。舉例而言，在一些實施例中，化合物1每日投與兩次或BID，而來那度胺每日投與一次或QD。或者及/或另外，化合物1可每日投與一或兩次，持續一或多個28天週期，而來那度胺可每日投與一次，持續一或多個28天週期的第1天至第21天。在一些實施例中，化合物1在一或多個28天週期的第8天至第28天每日投與兩次，且來那度胺在一或多個28天週期的第1天至第28天每日投與一次。在一些實施例中，化合物1在一或多個28天週期的第1天至第28天每日投與兩次，且來那度胺在一或多個28天週期的第1天至第28天每日投與一次。 As used herein, the terms "combination", "in combination with" or "combination therapy" mean that two or more different pharmaceutical agents are administered in an overlapping regimen such that the individual is simultaneously exposed to both agents. The situation. In some embodiments, the combinations are directed to the individual dosage form of Compound 1 and lenalidomide administered simultaneously. In some embodiments, the combinations are directed to an individual to simultaneously administer a separate dosage form of Compound 1 and lenalidomide, wherein Compound 1 is administered before, during, or after administration of lenalidomide. In some embodiments, simultaneous or simultaneous exposure of Compound 1 and lenalidomide is achieved via different dosing regimens appropriate to each therapeutic agent. For example, in some embodiments, Compound 1 is administered twice daily or BID, while lenalidomide is administered once daily or QD. Alternatively and/or additionally, Compound 1 may be administered once or twice daily for one or more 28-day cycles, while lenalidomide may be administered once daily for one or more of the first 28 days of the 28-day cycle. Day to the 21st day. In some embodiments, Compound 1 is administered twice daily from day 8 to day 28 of one or more 28 day cycles, and lenalidomide is on day 1 to day of one or more 28 day cycles. Once a day for 28 days. In some embodiments, Compound 1 is administered twice daily from day 1 to day 28 of one or more 28 day cycles, and lenalidomide is on day 1 to day of one or more 28 day cycles. Once a day for 28 days.

如本文中所用之術語「抑制百分比」係指在測試化合物(例如不 可逆BTK抑制劑)存在下，目標活性相對於對照目標活性減小的百分比。應理解，目標(例如激酶)的抑制百分比可用許多方式測定，其中一種描述於下文實例3中。在一些實施例中，抑制百分比表示為%抑制(例如50%抑制)。在一些實施例中，激酶之抑制百分比為平均抑制百分比。 The term "percent inhibition" as used herein refers to a test compound (eg, no Percentage of target activity relative to control target activity decreased in the presence of a reversible BTK inhibitor. It will be appreciated that the percent inhibition of a target (e.g., kinase) can be determined in a number of ways, one of which is described in Example 3 below. In some embodiments, the percent inhibition is expressed as % inhibition (eg, 50% inhibition). In some embodiments, the percent inhibition of the kinase is the average percent inhibition.

如本文中所用，術語「可比較」係指兩種或兩種以上藥劑、實體、情況、條件設置等可能彼此並不相同，但類似到足以允許在其之間比較，以便可基於所觀測到之差異或相似性合理地得出結論。一般熟習此項技術者應瞭解，在上下文中，在任何給定環境中關於兩種或兩種以上該等藥劑、實體、情況、條件設置等需要何種程度之一致性將視為可比較的。如本文中所用，術語「可比較的抑制百分比」或「可比較的平均抑制百分比」分別係指在所觀測到或測定之參考激酶抑制劑之抑制百分比或平均抑制百分比之10%以內的激酶的抑制百分比或平均抑制百分比。舉例而言，若參考激酶抑制劑相對於對照具有激酶之50%抑制，另一抑制劑若相對於對照具有同一激酶之約40%至約60%抑制，則另一抑制劑應視為展示可比較的抑制。在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的抑制百分比，其中該不可逆BTK抑制劑之抑制百分比在所觀測到或測定之參考激酶抑制劑之抑制百分比的9%、8%、7%、6%、5%、4%、3%、2%或1%抑制之內。 As used herein, the term "comparable" means that two or more agents, entities, conditions, conditional settings, etc., may not be identical to each other, but are similar enough to allow comparison therebetween so that they can be based on observations Differences or similarities are reasonably drawn. Those of ordinary skill in the art will appreciate that, in this context, the degree of consistency required for two or more such agents, entities, conditions, conditional settings, etc., in any given environment will be considered comparable. . As used herein, the terms " percent of comparable inhibition " or " percentage of comparable mean inhibition " refer to a kinase within 10% of the percent inhibition or percent inhibition of a reference kinase inhibitor observed or measured, respectively. Percent inhibition or average percent inhibition. For example, if the reference kinase inhibitor has 50% inhibition of the kinase relative to the control and the other inhibitor has about 40% to about 60% inhibition of the same kinase relative to the control, the other inhibitor should be considered as exhibitable. Comparison of inhibition. In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor, wherein the percent inhibition of the irreversible BTK inhibitor is 9%, 8 percent of the percent inhibition of the reference kinase inhibitor observed or determined. %, 7%, 6%, 5%, 4%, 3%, 2% or 1% inhibition.

如本文中所用，「與BTK相關之疾病或失調」或「BTK介導之失調」意指已知或懷疑BTK或其突變體發揮作用之任何疾病或其他有害病狀。因此，本發明之另一實施例係關於預防、治療、穩定或減輕一或多種已知或懷疑BTK或其突變體發揮作用之疾病的嚴重程度或進展。特定言之，本發明係關於一種治療或減輕增生性失調之嚴重程度的方法，其中該方法包含向有需要之患者投與化合物1與來那度胺之 組合。 As used herein, "a disease or disorder associated with BTK" or "a BTK-mediated disorder" means any disease or other deleterious condition in which BTK or a mutant thereof is known or suspected to function. Accordingly, another embodiment of the invention relates to the prevention, treatment, stabilization or amelioration of the severity or progression of one or more diseases known or suspected to function as BTK or a mutant thereof. In particular, the invention relates to a method of treating or ameliorating the severity of a proliferative disorder, wherein the method comprises administering to a patient in need thereof a combination of Compound 1 and lenalidomide.

如本文中所用，術語「不可逆」或「不可逆抑制劑」係指能夠以實質上非可逆的方式共價結合目標蛋白激酶之抑制劑(亦即化合物)。亦即，鑒於可逆抑制劑能夠結合於(但一般不能形成共價結合)目標蛋白激酶，且因此可與目標蛋白激酶解離，而不可逆抑制劑在共價結合形成已發生後將仍實質上結合於目標蛋白激酶。不可逆抑制劑一般顯示時間成賴性，由此抑制程度隨著抑制劑與酶接觸之時間增加。鑑定化合物是否充當不可逆抑制劑之方法為一般熟習此項技術者已知。該等方法包括(但不限於)化合物與蛋白激酶目標之抑制概況之酶動力學分析、使用在抑制劑化合物存在下修飾之蛋白質藥物目標的質譜分析、不連續暴露(亦稱為「洗脫(washout)」)實驗、及使用標記(諸如放射性標記抑制劑)展示酶之共價修飾、以及熟習此項技術者已知之其他方法。 As used herein, the term "irreversible" or "irreversible inhibitor" refers to an inhibitor (ie, a compound) that is capable of covalently binding to a protein kinase of interest in a substantially non-reversible manner. That is, in view of the ability of a reversible inhibitor to bind to (but generally fail to form a covalently bound) target protein kinase, and thus dissociate from a protein kinase of interest, the irreversible inhibitor will still substantially bind after covalent binding has occurred. Target protein kinase. Irreversible inhibitors generally show time dependence , whereby the degree of inhibition increases with the time the inhibitor is in contact with the enzyme. Methods for identifying whether a compound acts as an irreversible inhibitor are known to those of ordinary skill in the art. Such methods include, but are not limited to, enzymatic kinetic analysis of inhibition profiles of compounds and protein kinase targets, mass spectrometric analysis using protein drug targets modified in the presence of inhibitor compounds, discontinuous exposure (also known as "elution ( Washout)) experiments, and the use of labels (such as radiolabeled inhibitors) to display covalent modifications of the enzyme, as well as other methods known to those skilled in the art.

如本文中所用之術語「難治性CLL/SLL」定義為用至少一線先前療法治療(i)未取得對療法之至少部分反應或(ii)在6個月治療內有進展之CLL/SLL。 The term "refractory CLL/SLL" as used herein is defined as CLL/SLL treated with at least one line of prior therapy (i) not achieving at least partial response to therapy or (ii) progressing within 6 months of treatment.

如本文中所用之術語「復發性CLL/SLL」定義為在治療後6個月後，在取得對於療法之部分反應或完全反應後有進展之CLL/SLL。 The term "recurrent CLL/SLL" as used herein is defined as after treatment After 6 months, CLL/SLL progressed after obtaining partial or complete response to the therapy.

如本文中所用之術語「個體」意指哺乳動物且包括人類及動物個體，諸如家畜(例如馬、狗、貓等)。 The term "individual" as used herein means a mammal and includes both human and animal individuals, such as livestock (eg, horses, dogs, cats, etc.).

如本文中所用，「治療有效量」意指引發所需生物反應之物質(例如治療劑、組合物及/或調配物)之量。在一些實施例中，物質之治療有效量為當作為給藥方案之一部分向罹患或易患疾病、失調及/或病狀之個體投與時，足以治療、診斷、預防該疾病、失調及/或病狀及/或延緩其發作之量。一般熟習此項技術者應瞭解，物質之有效量可視諸如所需生物終點、待傳遞之物質、目標細胞或組織等之因素而變 化。舉例而言，調配物中之化合物治療疾病、失調及/或病狀之有效量為緩解、改善、減輕、抑制、預防該疾病、失調及/或病狀之一或多種症狀或特徵、延緩其發作、降低其嚴重程度及/或降低其發病率之量。在一些實施例中，「治療有效量」為化合物或含有化合物之組合物足以用於治療與布魯頓酪胺酸激酶相關之失調或病狀之一或多種症狀的至少最小量。 As used herein, "therapeutically effective amount" means the amount of a substance (eg, a therapeutic, composition, and/or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is sufficient to treat, diagnose, prevent, treat, and/or prevent the disease, disorder, and/or when administered to an individual suffering from or susceptible to a disease, disorder, and/or condition. Or the condition and/or delay the amount of its onset. Those of ordinary skill in the art will appreciate that the effective amount of a substance may vary depending on factors such as the desired biological endpoint, the substance to be delivered, the target cell or tissue, and the like. Chemical. For example, an effective amount of a compound in a formulation to treat a disease, disorder, and/or condition is to alleviate, ameliorate, alleviate, inhibit, prevent, or delay one or more symptoms or characteristics of the disease, disorder, and/or condition. The amount that attacks, reduces its severity, and/or reduces its incidence. In some embodiments, a "therapeutically effective amount" is a compound or a composition comprising a compound that is sufficient to treat at least a minimum amount of one or more symptoms of a disorder or condition associated with Bruton tyrosine kinase.

如本文中所用之術語「治療」係指部分或完全緩解、抑制、延緩發作、預防、改善及/或減輕失調或病狀，或該失調或病狀之一或多種症狀。如本文中所用，術語「治療」係指部分或完全緩解、抑制、延緩發作、預防、改善及/或減輕失調或病狀、或該失調或病狀之一或多種症狀，如本文所述。在一些實施例中，治療可在已發展出一或多種症狀之後投與。在一些實施例中，術語「治療」包括預防疾病或失調或中斷其進展。在其他實施例中，治療可在症狀不存在時投與。舉例而言，治療可在症狀發作之前投與易感個體(例如根據症狀病史及/或根據遺傳或其他易感性因素)。治療亦可在症狀已消退之後繼續進行，例如以預防或延遲其再現。因此，在一些實施例中，術語「治療」包括預防疾病或失調之復發或再現。 The term "treating" as used herein refers to partial or complete alleviation, inhibition, delay of onset, prevention, amelioration and/or alleviation of a disorder or condition, or one or more symptoms of the disorder or condition. As used herein, the term "treating" refers to partial or complete alleviation, inhibition, delay of onset, prevention, amelioration and/or alleviation of a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, the treatment can be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing a disease or disorder or interrupting its progression. In other embodiments, the treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (eg, based on a history of symptoms and/or according to genetic or other susceptibility factors). Treatment can also continue after the symptoms have subsided, for example to prevent or delay their reproduction. Thus, in some embodiments, the term "treatment" includes preventing the recurrence or recurrence of a disease or disorder.

如本文中所用之表述「單位劑型」係指適於待治療個體之治療性調配物之物理離散單位。然而，應瞭解本發明組合物之每日總用量將由主治醫師在合理醫學判斷範疇內決定。任何具體個體或生物體之特定有效劑量將視多種因素而定，包括所治療之失調及該失調之嚴重程度；所用特定活性劑之活性；所用特定組合物；該個體之年齡、體重、一般健康狀況、性別及飲食；投藥時間，及所用特定活性劑之***率；治療持續時間；與所用特定化合物組合或疊合使用之藥物及/或額外療法，及醫學技術中熟知之類似因素。 The expression "unit dosage form" as used herein refers to a physically discrete unit of a therapeutic formulation suitable for the individual to be treated. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The particular effective amount of any particular individual or organism will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular active agent employed; the particular composition employed; the age, weight, and general health of the subject Condition, sex and diet; time of administration, and excretion rate of the particular active agent used; duration of treatment; drugs and/or additional therapies used in combination or superimposed with the particular compound employed, and similar factors well known in the medical arts.

如本文中所用，術語「抗體(antibody)」或其文法變化(亦即抗體 (antibodies))係指能夠結合於抗原決定基之多肽。在一些實施例中，抗體為全長抗體。在一些實施例中，抗體小於全長(亦即抗體片段)但包括至少一個結合位點。在一些該等實施例中，結合位點包含至少一個且較佳至少兩個具有抗體可變區結構之序列。在一些實施例中，術語「抗體」涵蓋結合域與免疫球蛋白結合域同源或大部分同源之任何蛋白質。在具體實施例中，術語「抗體」涵蓋結合域展示與免疫球蛋白結合域至少99%一致性之多肽。在一些實施例中，抗體為結合域展示與免疫球蛋白結合域至少70%、至少80%、至少85%、至少90%或至少95%一致性之任何蛋白質。本發明之抗體多肽可藉由任何可用手段製備，包括例如自天然來源或抗體文庫分離、在宿主系統中或使用宿主系統重組產生、化學合成等、或其組合。在一些實施例中，抗體為單株或多株。在一些實施例中，抗體可為任何免疫球蛋白類別中之成員，包括人類類別IgG、IgM、IgA、IgD及IgE中之任一者。在某些實施例中，抗體為IgG免疫球蛋白類別中之成員。在一些實施例中，術語「抗體」係指具有結合於所關注之抗原決定基之能力之抗體的任何衍生物。在一些實施例中，抗體片段包含例如藉由二硫鍵聯而鍵聯在一起的多條鏈。在一些實施例中，抗體為人類抗體。在一些實施例中，抗體為人類化抗體。在一些實施例中，人類化抗體包括含有來源於非人類免疫球蛋白之最小序列的嵌合免疫球蛋白、免疫球蛋白鏈或抗體片段(Fv、Fab、Fab'、F(ab')2或抗體之其他抗原結合子序列)。在一些實施例中，人類化抗體為人類免疫球蛋白(受體抗體)，其中該受體之互補決定區(CDR)之殘基經具有所需特異性、親和力及能力之非人類物種(供體抗體)，諸如小鼠、大鼠或兔之CDR之殘基置換。在特定實施例中，本發明所用之抗體結合於CD20之特定抗原決定基。在一些實施例中，結合於抗CD20抗體之CD20的抗原決定基包括例如170ANPS173(Binder等人，Blood 2006,108(6)：1975-1978)、FMC7 (Deans等人，Blood 2008,111(4)：2492)、Rp5-L及Rp15-C(CD20之模擬表位)(Perosa等人，J.Immunol.2009,182：416-423)、182YCYSI185(Binder等人，Blood 2006,108(6)：1975-1978)及WEWTI(182YCYSI185之模擬物)(Binder等人，Blood 2006,108(6)：1975-1978)。在一些實施例中，抗CD20抗體對CD20之抗原決定基之結合親和力(Kd)小於12nM、小於11nM、小於10nM、小於9nM、小於8nM、小於7nM、小於6nM、小於5nM、小於4nM、小於3nM、小於2nM或小於1nM。 As used herein, the term "antibody" or a variant thereof (ie, an antibody) refers to a polypeptide that is capable of binding to an epitope. In some embodiments, the antibody is a full length antibody. In some embodiments, the antibody is less than the full length (ie, the antibody fragment) but includes at least one binding site. In some such embodiments, the binding site comprises at least one and preferably at least two sequences having an antibody variable region structure. In some embodiments, the term "antibody" encompasses any protein whose binding domain is homologous or largely homologous to an immunoglobulin binding domain. In a specific embodiment, the term "antibody" encompasses a binding domain that displays a polypeptide that is at least 99% identical to an immunoglobulin binding domain. In some embodiments, the antibody exhibits at least 70%, at least 80%, at least 85%, at least 90%, or at least 95% identity to the immunoglobulin binding domain for the binding domain. The antibody polypeptides of the invention can be prepared by any available means, including, for example, isolation from a natural source or antibody library, recombinant production in a host system or using a host system, chemical synthesis, and the like, or a combination thereof. In some embodiments, the antibody is single or multiple. In some embodiments, the antibody can be a member of any of the immunoglobulin classes, including any of the human classes IgG, IgM, IgA, IgD, and IgE. In certain embodiments, the antibody is a member of the IgG immunoglobulin class. In some embodiments, the term "antibody" refers to any derivative of an antibody that has the ability to bind to an epitope of interest. In some embodiments, antibody fragments comprise a plurality of strands that are linked together, for example, by disulfide linkages. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the humanized antibody comprises a chimeric immunoglobulin, immunoglobulin chain or antibody fragment (Fv, Fab, Fab', F(ab') 2 or comprising a minimal sequence derived from a non-human immunoglobulin or Other antigen binding sequence of the antibody). In some embodiments, the humanized antibody is a human immunoglobulin (receptor antibody), wherein the residues of the complementarity determining regions (CDRs) of the receptor are passed through a non-human species having the desired specificity, affinity, and ability (for Subbody antibodies), such as residues of CDRs of mouse, rat or rabbit. In a particular embodiment, the antibody used in the invention binds to a particular epitope of CD20. In some embodiments, the epitope of CD20 that binds to an anti-CD20 antibody includes, for example, 170 ANPS 173 (Binder et al, Blood 2006, 108(6): 1975-1978), FMC7 (Deans et al, Blood 2008, 111). (4): 2492), Rp5-L and Rp15-C (simulated epitope of CD20) (Perosa et al. , J. Immunol. 2009, 182 : 416-423), 182 YCYSI 185 (Binder et al., Blood 2006, 108(6): 1975-1978) and WEWTI (model of 182 YCYSI 185 ) (Binder et al., Blood 2006, 108(6): 1975-1978). In some embodiments, the anti-CD20 antibody binding affinity of the epitope of the CD20 antigen (K d) of less than 12nM, less than 11 nM, less than 10 nM, less than 9nM, less than 8nM, less than 7 nM, less than 6nM, less than of 5 nM, less than 4nM, less than 3nM, less than 2nM or less than 1nM.

如本文中所用，術語(例如經核准之參考產品/生物學藥物，諸如蛋白質治療劑、抗體等之)「生物類似物」係指基於來源於以下之資料而與參考產品類似之生物產品：(a)分析研究，其證明儘管臨床上非活性組分存在微小差異，但生物產品與參考產品高度類似；(b)動物研究(包括毒性評估)；及/或(c)臨床研究(包括免疫原性及藥物動力學或藥效學之評估)，其足以證明在參考產品經核准且意欲使用及尋求核准之一或多個適當使用條件下之安全性、純度及效能(例如就產品之安全性、純度及效能而言，在生物產品與參考產品之間不存在臨床上有意義的差異)。 As used herein, the term (eg, an approved reference product/biological drug, such as a protein therapeutic, an antibody, etc.) "biological analog" refers to a biological product that is similar to a reference product based on the following information: a) Analytical studies demonstrating that biological products are highly similar to reference products despite minor differences in clinically inactive components; (b) animal studies (including toxicity assessment); and/or (c) clinical studies (including immunogens) Sexual and pharmacodynamic or pharmacodynamic evaluation) sufficient to demonstrate the safety, purity and efficacy of the reference product under approved and intended use and for approval of one or more suitable conditions of use (eg for product safety) In terms of purity and efficacy, there is no clinically meaningful difference between biological products and reference products).

在一些實施例中，對於建議標籤中指定、推薦或提出之使用條件，生物類似性生物產品及參考產品利用相同作用機制，但僅在參考產品之作用機制為已知的情況下。在一些實施例中，生物產品之建議標籤中所指定、推薦或提出之使用條件已早先經核准用於參考產品。在一些實施例中，生物產品之投藥途徑、劑型及/或濃度與參考產品相同。在一些實施例中，製造、加工、包裝或容納生物產品之設施符合經設計以確保生物產品持續安全、純淨且有效之標準。參考產品在美國、歐洲或日本中之至少一者處經核准。生物類似物可為例如具有與市售抗體相同之一級胺基酸序列，但可在不同細胞類型中或藉由不同的產生、純化或調配方法製造之目前已知的抗體。 In some embodiments, the biosimilar biological product and the reference product utilize the same mechanism of action for the conditions of use specified, recommended, or proposed in the proposed label, but only if the mechanism of action of the reference product is known. In some embodiments, the conditions of use specified, recommended, or proposed in the suggested label for the biological product have been previously approved for use in the reference product. In some embodiments, the biopharmaceutical route of administration, dosage form, and/or concentration is the same as the reference product. In some embodiments, the facility that manufactures, processes, packages, or holds the biological product conforms to standards designed to ensure that the biological product remains safe, pure, and effective. The reference product is approved in at least one of the United States, Europe, or Japan. The biological analog can be, for example, a currently known antibody having the same amino acid sequence as the commercially available antibody, but can be produced in different cell types or by different methods of production, purification or formulation.

治療BTK介導之疾病或失調之通用方法A general method for treating BTK-mediated diseases or disorders

在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與不可逆BTK抑制劑及來那度胺。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering an irreversible BTK inhibitor to a patient in need thereof amine.

應瞭解，雖然本文所述之方法係指化合物1及其鹽之調配物、劑量及給藥方案/時程，但該等調配物、劑量及/或給藥方案/時程同樣適用於任何不可逆BTK抑制劑，諸如下文所述之彼等不可逆BTK抑制劑。因此，在一些實施例中，不可逆BTK抑制劑之劑量或給藥方案係選自如本文所述之化合物1之任何劑量或給藥方案。在一些實施例中，所提供之方法包含以選自如本文所述之化合物1之任何劑量的量投與不可逆BTK抑制劑。在一些該等實施例中，根據選自本文所述之化合物1之任何給藥時程的給藥時程投與一定劑量之不可逆BTK抑制劑。在一些實施例中，包含不可逆BTK抑制劑之組合物為如本文所述之任何調配物。 It will be understood that although the methods described herein refer to the formulation, dosage and dosing schedule/time course of Compound 1 and its salts, such formulations, dosages and/or dosing schedules/time schedules are equally applicable to any irreversible BTK inhibitors, such as those described below, are irreversible BTK inhibitors. Thus, in some embodiments, the dosage or dosing regimen of the irreversible BTK inhibitor is selected from any of the doses or dosing regimens of Compound 1 as described herein. In some embodiments, the methods provided comprise administering an irreversible BTK inhibitor in an amount selected from any of the doses of Compound 1 as described herein. In some such embodiments, a dose of an irreversible BTK inhibitor is administered according to the time course of administration of any of the dosing schedules selected from Compound 1 described herein. In some embodiments, the composition comprising an irreversible BTK inhibitor is any formulation as described herein.

在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與不可逆BTK抑制劑、來那度胺及抗CD20抗體(例如利妥昔單抗)。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering an irreversible BTK inhibitor to a patient in need thereof, Amines and anti-CD20 antibodies (eg rituximab).

在一些實施例中，不可逆BTK抑制劑共價結合於BTK之Cys481。 In some embodiments, the irreversible BTK inhibitor is covalently bound to Cys481 of BTK.

在一些實施例中，不可逆BTK抑制劑具有針對選自下表7中所列舉之激酶的一或多種激酶的活性。 In some embodiments, the irreversible BTK inhibitor has activity against one or more kinases selected from the kinases listed in Table 7 below.

在一些實施例中，不可逆BTK抑制劑針對選自表7之激酶或其組合具有與參考激酶抑制劑可比較的抑制百分比。在一些該等實施例中，參考激酶抑制劑為化合物2： In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor for a kinase selected from Table 7 or a combination thereof. In some such embodiments, the reference kinase inhibitor is Compound 2 :

在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對選自表7之一或多種激酶或其組合具有與化合物2可比較的抑制百分比，其中該不可逆激酶抑制劑所具有之抑制百分比在關於化合物2所觀測到之抑制百分比之約10%以內。在一些實施例中，不可逆BTK抑制劑針對選自表7之一或多種激酶或其組合具有與化合物2可比較的抑制百分比，其中該不可逆激酶抑制劑所具有之抑制百分比在關於化合物2所觀測到之抑制百分比之約9%、或約8%、或約7%、或約6%、或約5%、或約4%、或約3%、或約2%或約1%抑制以內。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to Compound 2 for one or more kinases selected from Table 7 or a combination thereof, wherein the percent inhibition of the irreversible kinase inhibitor is observed with respect to Compound 2 Within about 10% of the percent inhibition. In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to Compound 2 for one or more kinases selected from Table 7 or a combination thereof, wherein the percent inhibition of the irreversible kinase inhibitor is observed with respect to Compound 2 Up to about 9%, or about 8%, or about 7%, or about 6%, or about 5%, or about 4%, or about 3%, or about 2% or about 1% inhibition of the percent inhibition.

在一些實施例中，不可逆BTK抑制劑針對選自表7之一或多種激酶具有比關於化合物2所觀測到之抑制百分比大的抑制百分比。在一些實施例中，不可逆BTK抑制劑針對選自表7之一或多種激酶具有比關於化合物2所觀測到之抑制百分比小的抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of one or more kinases selected from Table 7 that is greater than the percent inhibition observed for Compound 2 . In some embodiments, the irreversible BTK inhibitor has a percent inhibition of one or more kinases selected from Table 7 that is less than the percent inhibition observed for Compound 2 .

在一些實施例中，不可逆BTK抑制劑具有一或多種額外激酶之抑制百分比，其中該一或多種激酶之抑制百分比為至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of one or more additional kinases, wherein the percent inhibition of the one or more kinases is at least about 50%, at least about 55%, at least about 60%, at least about 65%, At least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶具有與參考激酶抑制劑可比較的抑制百分比： TXK、BMX/ETK、FLT3、BLK、TEC、ERBB4/HER4、Aurora B、TRKC、RET、LOK/STK10、Aurora C、FLT4/VEGFR3、ROS/ROS1、ARK5/NUAK1、EGFR、DDR1、JAK3、LRRK2、ABL2/ARG、ITK、Aurora A、YES/YES1、FGFR3、TNK1、BRK、FGFR2、PDGFRb、c-SRC、ACK1、FGFR1、STK16、ABL1、AXL、TYK2、ERBB2/HER2、FGR、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor for one or more kinases selected from the group consisting of: TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/ HER4, Aurora B, TRKC, RET, LOK/STK10, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES1, FGFR3 , TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1, FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2 , or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對由以下各物組成之一組激酶具有與參考激酶抑制劑可比較的抑制百分比：TXK、BMX/ETK、FLT3、BLK、TEC、ERBB4/HER4、Aurora B、TRKC、RET、LOK/STK10、Aurora C、FLT4/VEGFR3、ROS/ROS1、ARK5/NUAK1、EGFR、DDR1、JAK3、LRRK2、ABL2/ARG、ITK、Aurora A、YES/YES1、FGFR3、TNK1、BRK、FGFR2、PDGFRb、c-SRC、ACK1、FGFR1、STK16、ABL1、AXL、TYK2、ERBB2/HER2、FGR、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percentage of inhibition comparable to a reference kinase inhibitor for a panel of kinases consisting of: TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B , TRKC, RET, LOK/STK10, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES1, FGFR3, TNK1, BRK , FGFR2, PDGFRb, c-SRC, ACK1, FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or a combination thereof . In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑抑制選自由以下各物組成之群之激酶：TXK、BMX/ETK、FLT3、BLK、TEC、ERBB4/HER4、Aurora B、TRKC、RET、LOK/STK10、Aurora C、FLT4/VEGFR3、ROS/ROS1、ARK5/NUAK1、EGFR、DDR1、JAK3、LRRK2、 ABL2/ARG、ITK、Aurora A、YES/YES1、FGFR3、TNK1、BRK、FGFR2、PDGFRb、c-SRC、ACK1、FGFR1、STK16、ABL1、AXL、TYK2、ERBB2/HER2、FGR、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合，其中該一或多種激酶之抑制作用為至少所觀測到之參考激酶抑制劑的抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor inhibits a kinase selected from the group consisting of: TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STK10, Aurora C, FLT4/VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES1, FGFR3, TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1 , FGFR1, STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or a combination thereof, wherein the inhibition of the one or more kinases The percentage inhibition of at least the reference kinase inhibitor observed. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%、至少約55%、至少約60%、至少65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%抑制：TXK、BMX/ETK、FLT3、BLK、TEC、ERBB4/HER4、Aurora B、TRKC、RET、LOK/STK10、Aurora C、FLT4/VEGFR3、ROS/ROS1、ARK5/NUAK1、EGFR、DDR1、JAK3、LRRK2、ABL2/ARG、ITK、Aurora A、YES/YES1、FGFR3、TNK1、BRK、FGFR2、PDGFRb、c-SRC、ACK1、FGFR1、STK16、ABL1、AXL、TYK2、ERBB2/HER2、FGR、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。 In some embodiments, the irreversible BTK inhibitor has at least about 50%, at least about 55%, at least about 60%, at least 65%, at least about 70%, at least about 75%, at least about a kinase selected from the group consisting of: 80%, at least about 85%, at least about 90% or at least about 95% inhibition: TXK, BMX/ETK, FLT3, BLK, TEC, ERBB4/HER4, Aurora B, TRKC, RET, LOK/STK10, Aurora C, FLT4 /VEGFR3, ROS/ROS1, ARK5/NUAK1, EGFR, DDR1, JAK3, LRRK2, ABL2/ARG, ITK, Aurora A, YES/YES1, FGFR3, TNK1, BRK, FGFR2, PDGFRb, c-SRC, ACK1, FGFR1 STK16, ABL1, AXL, TYK2, ERBB2/HER2, FGR, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶具有與參考激酶抑制劑可比較的抑制百分比：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor for one or more kinases selected from the group consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1 ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對由以下各物組成之一組激酶具有與參考激酶抑制劑可比較的抑制百分比：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor for a panel of kinases consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1 , LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2, and CLK2, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶所具有之抑制百分比至少為所觀測到之參考激酶抑制劑之抑制百分比：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the percent inhibition of the irreversible BTK inhibitor against one or more kinases selected from the group consisting of at least the observed percent inhibition of the reference kinase inhibitor: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2, or combination. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。 In some embodiments, the irreversible BTK inhibitor has at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least a kinase selected from the group consisting of: About 80%, at least about 85%, at least about 90% or at least about 95% inhibition: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1 , AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2, and CLK2, or a combination thereof.

在一些實施例中，本發明提供一種治療、穩定或減輕CLL/SLL之嚴重程度或進展的方法，包含向有需要之患者投與不可逆BTK抑制劑 及來那度胺，其中該不可逆BTK抑制劑具有選自以下各物之激酶之不超過約50%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2，或其組合。 In some embodiments, the invention provides a method of treating, stabilizing or attenuating the severity or progression of CLL/SLL comprising administering an irreversible BTK inhibitor to a patient in need thereof And lenalidomide, wherein the irreversible BTK inhibitor has no more than about 50% inhibition of a kinase selected from the group consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2 /ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2, and CLK2, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11及PKCb2，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約50%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、AXL、TYK2、CHK2、SIK1、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、PKCb2及CLK2。 In some embodiments, the irreversible BTK inhibitor has at least about 50% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, and PKCb2, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 50% inhibition of a panel of kinases consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ ARG, TNK1, STK16, ABL1, AXL, TYK2, CHK2, SIK1, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, PKCb2 and CLK2.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約55%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、CHK2、MLK1/MAP3K9、MLK2/MAP3K10及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約55%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、ABL1、CHK2、MLK1/MAP3K9、MLK2/MAP3K10及MLK3/MAP3K11。 In some embodiments, the irreversible BTK inhibitor has at least about 55% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, MLK2/MAP3K10 and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 55% inhibition by one of a group of kinases: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ ARG, TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, MLK2/MAP3K10 and MLK3/MAP3K11.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約60%抑制：Aurora A、Aurora B、Aurora C、TRKC、 ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約60%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、ABL2/ARG、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11。 In some embodiments, the irreversible BTK inhibitor has at least about 60% inhibition of a kinase selected from the group consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ARG, TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 60% inhibition of a panel of kinases consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, ABL2/ ARG, TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約65%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約65%抑制：Aurora A、Aurora B、Aurora C、TRKC、ROS/ROS1、ARK5/NUAK1、LRRK2、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11。 In some embodiments, the irreversible BTK inhibitor has at least about 65% inhibition of a kinase selected from the group consisting of: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 65% inhibition by one of a group of kinases: Aurora A, Aurora B, Aurora C, TRKC, ROS/ROS1, ARK5/NUAK1, LRRK2, TNK1 STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約70%抑制：Aurora A、Aurora B、Aurora C、ROS/ROS1、ARK5/NUAK1、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約70%抑制：Aurora A、Aurora B、Aurora C、ROS/ROS1、ARK5/NUAK1、TNK1、STK16、CHK2、MLK1/MAP3K9及MLK3/MAP3K11。 In some embodiments, the irreversible BTK inhibitor has at least about 70% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, Aurora C, ROS/ROS1, ARK5/NUAK1, TNK1, STK16, CHK2, MLK1/ MAP3K9 and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 70% inhibition by one of a group of kinases: Aurora A, Aurora B, Aurora C, ROS/ROS1, ARK5/NUAK1, TNK1, STK16, CHK2 MLK1/MAP3K9 and MLK3/MAP3K11.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約75%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1、TNK1、STK16及MLK1/MAP3K9，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約75%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1、TNK1、STK16及 MLK1/MAP3K9。 In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNK1, STK16, and MLK1/MAP3K9, or a combination thereof . In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of a panel of kinases consisting of: Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNK1, STK16, and MLK1/MAP3K9.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約80%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1、TNK1及MLK1/MAP3K9，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約80%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1、TNK1及MLK1/MAP3K9。 In some embodiments, the irreversible BTK inhibitor has at least about 80% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNK1, and MLK1/MAP3K9, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 80% inhibition by one of a group of kinases: Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, TNK1, and MLK1/MAP3K9.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約85%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1及MLK1/MAP3K9，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約85%抑制：Aurora A、Aurora B、ROS/ROS1、ARK5/NUAK1及MLK1/MAP3K9。 In some embodiments, the irreversible BTK inhibitor has at least about 85% inhibition of a kinase selected from the group consisting of Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, and MLK1/MAP3K9, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 85% inhibition by one of a group of kinases: Aurora A, Aurora B, ROS/ROS1, ARK5/NUAK1, and MLK1/MAP3K9.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶具有與參考激酶抑制劑可比較的抑制百分比：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition comparable to a reference kinase inhibitor for one or more kinases selected from the group consisting of: TNK1, STK16, ABL1, AXL, TYK2, CHK2, MLK1/ MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, SIK1, PKCb2, and CLK2, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對由以下各物組成之一組激酶具有與參考激酶抑制劑可比較的抑制百分比：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor is directed against a panel of kinases having a percent inhibition comparable to a reference kinase inhibitor: TNK1, STK16, ABL1, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/ MAP3K10, MLK3/MAP3K11, SIK1, PKCb2, and CLK2, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之 群之一或多種激酶所具有之抑制百分比至少為所觀測到之參考激酶抑制劑之抑制百分比：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the percent inhibition of the irreversible BTK inhibitor against one or more kinases selected from the group consisting of at least the observed percent inhibition of the reference kinase inhibitor: TNK1, STK16, ABL1, AXL , TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, SIK1, PKCb2, and CLK2, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%、至少約55%、至少約60%、至少約65%、至少約70%、至少約75%、至少約80%、至少約85%、至少約90%或至少約95%抑制：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2，或其組合。 In some embodiments, the irreversible BTK inhibitor has at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least at least a kinase selected from the group consisting of: About 80%, at least about 85%, at least about 90%, or at least about 95% inhibition: TNK1, STK16, ABL1, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, SIK1, PKCb2, and CLK2, Or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%抑制：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約50%抑制：TNK1、STK16、ABL1、AXL、TYK2、CHK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、SIK1、PKCb2及CLK2。 In some embodiments, the irreversible BTK inhibitor has at least about 50% inhibition of a kinase selected from the group consisting of: TNK1, STK16, ABL1, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11, SIK1 , PKCb2 and CLK2, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 50% inhibition of a panel of kinases consisting of: TNK1, STK16, ABL1, AXL, TYK2, CHK2, MLK1/MAP3K9, MLK2/MAP3K10, MLK3/MAP3K11 , SIK1, PKCb2 and CLK2.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約55%抑制：TNK1、STK16、ABL1、CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約55%抑制：TNK1、STK16、ABL1、CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。 In some embodiments, the irreversible BTK inhibitor has at least about 55% inhibition of a kinase selected from the group consisting of: TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 55% inhibition by one of a group of kinases: TNK1, STK16, ABL1, CHK2, MLK1/MAP3K9, and MLK3/MAP3K11, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約60%、至少約65%或至少約70%抑制：TNK1、STK16、 CHK2、MLK1/MAP3K9及MLK3/MAP3K11，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約60%、至少約65%或至少約70%抑制：CHK2、MLK1/MAP3K9及MLK3/MAP3K11。 In some embodiments, the irreversible BTK inhibitor has at least about 60%, at least about 65%, or at least about 70% inhibition of a kinase selected from the group consisting of: TNK1, STK16, CHK2, MLK1/MAP3K9 and MLK3/MAP3K11, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 60%, at least about 65%, or at least about 70% inhibition of one of the group consisting of: CHK2, MLK1/MAP3K9, and MLK3/MAP3K11.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之至少約75%抑制：TNK1、STK16及MLK1/MAP3K9，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之至少約75%抑制：TNK1、STK16及MLK1/MAP3K9。 In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of a kinase selected from the group consisting of: TNK1, STK16, and MLK1/MAP3K9, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has at least about 75% inhibition of a panel of kinases consisting of: TNK1, STK16, and MLK1/MAP3K9.

在一些實施例中，本發明所用之不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶具有與參考激酶抑制劑可比較的抑制百分比：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, an irreversible BTK inhibitor for use in the invention has a percentage of inhibition comparable to a reference kinase inhibitor for one or more kinases selected from the group consisting of: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對由以下各物組成之一組激酶具有與參考激酶抑制劑可比較的抑制百分比：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor is directed against a panel of kinases having a percent inhibition comparable to a reference kinase inhibitor: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑針對選自由以下各物組成之群之一或多種激酶所具有之抑制百分比不超過所觀測到之參考激酶抑制劑之抑制百分比：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，參考 激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition against one or more kinases selected from the group consisting of: c-Kit, PDGFRa, RIPK2 HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約50%、不超過約45%、不超過約40%、不超過約35%、不超過約30%、不超過約25%、不超過約20%、不超過約15%、不超過約10%或不超過約5%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。 In some embodiments, the irreversible BTK inhibitor has no more than about 50%, no more than about 45%, no more than about 40%, no more than about 35%, no more than about 30%, no more than a kinase selected from the group consisting of: More than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5% inhibition: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/ MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約50%、不超過約45%、不超過約40%、不超過約35%、不超過約30%、不超過約25%、不超過約20%、不超過約15%、不超過約10%或不超過約5%抑制：RIPK2、HCK、LYN、CSK、LCK、LYN B及FYN，或其組合。 In some embodiments, the irreversible BTK inhibitor has no more than about 50%, no more than about 45%, no more than about 40%, no more than about 35%, no more than about 30%, no more than a kinase selected from the group consisting of: More than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5% inhibition: RIPK2, HCK, LYN, CSK, LCK, LYN B, and FYN, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約50%、不超過約45%、不超過約40%、不超過約35%、不超過約30%、不超過約25%、不超過約20%、不超過約15%、不超過約10%或不超過約5%抑制：EPHA6、LYN B、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS，或其組合。 In some embodiments, the irreversible BTK inhibitor has no more than about 50%, no more than about 45%, no more than about 40%, no more than about 35%, no more than about 30%, no more than a kinase selected from the group consisting of: More than about 25%, no more than about 20%, no more than about 15%, no more than about 10%, or no more than about 5% inhibition: EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS, or combinations thereof .

在一些實施例中，本發明提供一種治療、穩定或減輕CLL/SLL之嚴重程度或進展的方法，包含向有需要之患者投與不可逆BTK抑制劑及來那度胺，其中該不可逆BTK抑制劑具有選自以下各物之激酶之至少約50%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、BRAF、RIPK3、ARAF及SRMS，或其組合。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of CLL/SLL comprising administering to a patient in need thereof an irreversible BTK inhibitor and lenalidomide, wherein the irreversible BTK inhibitor At least about 50% inhibition of a kinase selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, BRAF, RIPK3, ARAF and SRMS, or a combination thereof.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約50%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、 LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約50%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 50% inhibition of a kinase selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 50% inhibition of one of the group consisting of: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約45%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約45%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 45% inhibition of a kinase selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B , FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 45% inhibition of one of the group consisting of: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約40%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約40%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 40% inhibition of a kinase selected from the group consisting of c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B , FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 40% inhibition by one of a group of kinases: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約35%抑制：c-Kit、RIPK2、HCK、EPHA6、LYN、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下 各物組成之一組激酶之不超過約35%抑制：c-Kit、RIPK2、HCK、EPHA6、LYN、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 35% inhibition of a kinase selected from the group consisting of: c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5 , FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has the following No more than about 35% inhibition of one of the various components of the kinase: c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF, and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約30%抑制：c-Kit、RIPK2、HCK、EPHA6、LYN、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約30%抑制：c-Kit、RIPK2、HCK、EPHA6、LYN、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 30% inhibition of a kinase selected from the group consisting of c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5 , FYN, RIPK3, BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 30% inhibition of one of the group consisting of: c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK /PTK5, FYN, RIPK3, BRAF, ARAF and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約25%抑制：c-Kit、RIPK2、EPHA6、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約25%抑制：c-Kit、IPK2、EPHA6、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 25% inhibition of a kinase selected from the group consisting of: c-Kit, RIPK2, EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3 , BRAF, ARAF and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 25% inhibition of one of the group consisting of: c-Kit, IPK2, EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN , RIPK3, BRAF, ARAF and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約20%抑制：EPHA6、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約20%抑制：EPHA6、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 20% inhibition of a kinase selected from the group consisting of: EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF, and SRMS , or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 20% inhibition of one of the group consisting of: EPHA6, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, RIPK3, BRAF, ARAF And SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約15%抑制：EPHA6、LYN B、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有 由以下各物組成之一組激酶之不超過約15%抑制：EPHA6、LYN B、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 15% inhibition of a kinase selected from the group consisting of: EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has No more than about 15% inhibition by one of the following groups of kinases: EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約10%抑制：EPHA6、LYN B、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約10%抑制：EPHA6、LYN B、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 10% inhibition of a kinase selected from the group consisting of: EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 10% inhibition by one of a group of kinases: EPHA6, LYN B, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS.

在一些實施例中，不可逆BTK抑制劑具有選自以下各物之激酶之不超過約5%抑制：EPHA6、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS，或其組合。在一些實施例中，不可逆BTK抑制劑具有由以下各物組成之一組激酶之不超過約5%抑制：EPHA6、FRK/PTK5、RIPK3、BRAF、ARAF及SRMS。 In some embodiments, the irreversible BTK inhibitor has no more than about 5% inhibition of a kinase selected from the group consisting of: EPHA6, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS, or a combination thereof. In some embodiments, the irreversible BTK inhibitor has no more than about 5% inhibition by one of the group consisting of: EPHA6, FRK/PTK5, RIPK3, BRAF, ARAF, and SRMS.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的LYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之LYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約20-30%之LYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約25-30%之LYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約25-28%之LYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約25%、不超過約26%、不超過約27%、不超過約28%、不超過約29%、不超過約30%、不超過約31%、不超過約32%或不超過約33%之LYN之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of no more than the observed KIN of the reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN of about 20-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN of about 25-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN of about 25-28%. In some embodiments, the irreversible BTK inhibitor has no more than about 25%, no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about Percent inhibition of LYN of 31%, no more than about 32%, or no more than about 33%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的c-Kit之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不 超過所觀測到之參考激酶抑制劑之c-Kit之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約15-25%之c-Kit之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約20-25%之c-Kit之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約20-23%之c-Kit之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約15%、不超過約16%、不超過約17%、不超過約18%、不超過約19%、不超過約20%、不超過約21%、不超過約22%、不超過約23%、不超過約24%或不超過約25%之c-Kit之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit of about 15-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit of about 20-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of c-Kit of about 20-23%. In some embodiments, the irreversible BTK inhibitor has no more than about 15%, no more than about 16%, no more than about 17%, no more than about 18%, no more than about 19%, no more than about 20%, no more than about Percent inhibition of c-Kit of 21%, no more than about 22%, no more than about 23%, no more than about 24%, or no more than about 25%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的PDGFRa之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之PDGFRa之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約30-40%之PDGFRa之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約35-40%之PDGFRa之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約35-38%之PDGFRa之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約30%、不超過約31%、不超過約32%、不超過約33%、不超過約34%、不超過約35%、不超過約36%、不超過約37%、不超過約38%、不超過約39%或不超過約40%之PDGFRa之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa of about 30-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa of about 35-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of PDGFRa of between about 35 and 38%. In some embodiments, the irreversible BTK inhibitor has no more than about 30%, no more than about 31%, no more than about 32%, no more than about 33%, no more than about 34%, no more than about 35%, no more than about Percent inhibition of PDGFRa of 36%, no more than about 37%, no more than about 38%, no more than about 39%, or no more than about 40%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的RIPK2之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之RIPK2之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約20-30%之RIPK2之抑制百分比。在 一些實施例中，不可逆BTK抑制劑具有約20-25%之RIPK2之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約22-25%之RIPK2之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約18%、不超過約19%、不超過約20%、不超過約21%、不超過約22%、不超過約23%、不超過約24%、不超過約25%、不超過約26%或不超過約27%之RIPK2之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 of about 20-30%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 of from about 20% to about 25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of RIPK2 of about 22-25%. In some embodiments, the irreversible BTK inhibitor has no more than about 18%, no more than about 19%, no more than about 20%, no more than about 21%, no more than about 22%, no more than about 23%, no more than about Percent inhibition of RIPK2 of 24%, no more than about 25%, no more than about 26%, or no more than about 27%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的HCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之HCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約25-35%之HCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約27-32%之HCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約28-31%之HCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約26%、不超過約27%、不超過約28%、不超過約29%、不超過約30%、不超過約31%、不超過約32%、不超過約33%或不超過約34%之HCK之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK of between about 25 and 35%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK of about 27-32%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of HCK of about 28-31%. In some embodiments, the irreversible BTK inhibitor has no more than about 26%, no more than about 27%, no more than about 28%, no more than about 29%, no more than about 30%, no more than about 31%, no more than about Percent inhibition of HCK of 32%, no more than about 33% or no more than about 34%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的EPHA6之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之EPHA6之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-10%之EPHA6之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-5%之EPHA6之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-3%之EPHA6之抑制 百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約0.5%、不超過約0.6%、不超過約0.7%、不超過約0.8%、不超過約0.9%、不超過約1%、不超過約2%、不超過約3%或不超過約4%之EPHA6之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of EPHA6 that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of about 0-10% EPHA6. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of from about 0% to about 5% of EPHA6. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of from about 0% to about 3% of EPHA6. In some embodiments, the irreversible BTK inhibitor has no more than about 0.5%, no more than about 0.6%, no more than about 0.7%, no more than about 0.8%, no more than about 0.9%, no more than about 1%, no more than about Percent inhibition of 25%, no more than about 3%, or no more than about 4% of EPHA6. In some embodiments, the kinase inhibitor is the reference compound 2. In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的CSK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之CSK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約10-20%之CSK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約15-20%之CSK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約16-19%之CSK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約15%、不超過約16%、不超過約17%、不超過約18%、不超過約19%、不超過約20%、不超過約21%、不超過約22%或不超過約23%之CSK之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK of about 10-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK of about 15-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of CSK of about 16-19%. In some embodiments, the irreversible BTK inhibitor has no more than about 15%, no more than about 16%, no more than about 17%, no more than about 18%, no more than about 19%, no more than about 20%, no more than about Percent inhibition of CSK of 21%, no more than about 22%, or no more than about 23%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的LCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之LCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約30-40%之LCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約32-37%之LCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約34-37%之LCK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約34%、不超過約35%、不超過約36%、不超過約37%、不超過約38%、不超過約39%、 不超過約40%、不超過約41%或不超過約42%之LCK之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK of about 30-40%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK of about 32-37%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LCK of about 34-37%. In some embodiments, the irreversible BTK inhibitor has no more than about 34%, no more than about 35%, no more than about 36%, no more than about 37%, no more than about 38%, no more than about 39%, no more than about Percent inhibition of LCK of 40%, no more than about 41% or no more than about 42%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的ZAK/MLTK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之ZAK/MLTK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約10-20%之ZAK/MLTK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約12-17%之ZAK/MLTK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約14-17%之ZAK/MLTK之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約12%、不超過約13%、不超過約14%、不超過約15%、不超過約16%、不超過約17%、不超過約18%、不超過約19%或不超過約20%之ZAK/MLTK之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK of about 10-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK of about 12-17%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of ZAK/MLTK of about 14-17%. In some embodiments, the irreversible BTK inhibitor has no more than about 12%, no more than about 13%, no more than about 14%, no more than about 15%, no more than about 16%, no more than about 17%, no more than about Percent inhibition of ZAK/MLTK of 18%, no more than about 19% or no more than about 20%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的LYN B之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之LYN B之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-10%之LYN B之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約3-8%之LYN B之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約4-7%之LYN B之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約1%、不超過約2%、不超過約3%、不超過約4%、不超過約5%、不超過約6%、不超過約7%、不超過約8%、不超過約9%或不超過約10%之LYN B之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在 一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B of from about 0% to about 10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of LYN B of from about 3 to 8%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of about 4-7% of LYN B. In some embodiments, the irreversible BTK inhibitor has no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, no more than about 5%, no more than about 6%, no more than about Percent inhibition of 7% B of 7%, no more than about 8%, no more than about 9%, or no more than about 10%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的FRK/PTK5之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之FRK/PTK5之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-10%之FRK/PTK5之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-5%之FRK/PTK5之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-3%之FRK/PTK5之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約0.5%、不超過約0.6%、不超過約0.7%、不超過約0.8%、不超過約0.9%、不超過約1%、不超過約1.5%、不超過約2%、不超過約3%或不超過約4%之FRK/PTK5之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 of from about 0% to about 10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 of from about 0% to about 5%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FRK/PTK5 of from about 0% to about 3%. In some embodiments, the irreversible BTK inhibitor has no more than about 0.5%, no more than about 0.6%, no more than about 0.7%, no more than about 0.8%, no more than about 0.9%, no more than about 1%, no more than about Percent inhibition of FRK/PTK5 of 1.5%, no more than about 2%, no more than about 3%, or no more than about 4%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的FYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之FYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約15-25%之FYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約15-20%之FYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約17-20%之FYN之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約15%、不超過約16%、不超過約17%、不超過約18%、不超過約19%、不超過約20%、不超過約21%、不超過約22%或不超過約23%之FYN之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of no more than the observed FYN of the reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN of about 15-25%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN of about 15-20%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of FYN of about 17-20%. In some embodiments, the irreversible BTK inhibitor has no more than about 15%, no more than about 16%, no more than about 17%, no more than about 18%, no more than about 19%, no more than about 20%, no more than about Percent inhibition of FYN of 21%, no more than about 22%, or no more than about 23%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

在一些實施例中，不可逆BTK抑制劑具有與參考激酶抑制劑可比較的BRAF之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過所觀測到之參考激酶抑制劑之BRAF之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0-10%之BRAF之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0.1-5%之BRAF之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有約0.2-3%之BRAF之抑制百分比。在一些實施例中，不可逆BTK抑制劑具有不超過約0.1%、不超過約0.2%、不超過約0.3%、不超過約0.4%、不超過約0.5%、不超過約0.6%、不超過約0.7%、不超過約0.8%、不超過約0.9%、不超過約1%、不超過約2%、不超過約3%、不超過約4%或不超過約5%之BRAF之抑制百分比。在一些實施例中，參考激酶抑制劑為化合物2。在一些實施例中，參考激酶抑制劑之抑制百分比為實例3中關於化合物2所展示之抑制百分比。 In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF comparable to a reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF that does not exceed the observed reference kinase inhibitor. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF of from about 0% to about 10%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF of from about 0.1% to about 5%. In some embodiments, the irreversible BTK inhibitor has a percent inhibition of BRAF of from about 0.2% to about 3%. In some embodiments, the irreversible BTK inhibitor has no more than about 0.1%, no more than about 0.2%, no more than about 0.3%, no more than about 0.4%, no more than about 0.5%, no more than about 0.6%, no more than about Percent inhibition of BRAF of 0.7%, no more than about 0.8%, no more than about 0.9%, no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, or no more than about 5%. In some embodiments, the reference kinase inhibitor is Compound 2 . In some embodiments, the percent inhibition of the reference kinase inhibitor is the percent inhibition exhibited by Compound 2 in Example 3.

化合物1為不可逆BTK抑制劑Compound 1 is an irreversible BTK inhibitor

如上所述，布魯頓酪胺酸激酶(Btk)為主要限於B淋巴細胞、單核細胞及肥大細胞或嗜鹼性白血球的限制細胞表現的非受體酪胺酸激酶。Btk為B細胞受體(BCR)信號傳導網之關鍵組分且為B細胞發育之關鍵。調查研究已顯示一些B細胞惡性腫瘤(包括CLL/SLL)依賴於BCR信號傳導，表明中斷該信號傳導可為有前景之治療機遇。近來，已報導使用抑制脾臟酪胺酸激酶(Syk)及Btk(亦即BCR信號傳導路徑之兩種組分)之藥劑對於各種B細胞非霍奇金氏淋巴瘤(NHL)及CLL/SLL中之臨床抗腫瘤反應。 As noted above, Bruton's tyrosine kinase (Btk) is a non-receptor tyrosine kinase that is primarily restricted to B lymphocytes, monocytes, and limiting cell expression of mast cells or basophils. Btk is a key component of the B cell receptor (BCR) signaling network and is critical for B cell development. Investigations have shown that some B cell malignancies (including CLL/SLL) are dependent on BCR signaling, suggesting that disrupting this signaling can be a promising therapeutic opportunity. Recently, agents that inhibit spleen tyrosine kinase (Syk) and Btk (ie, two components of the BCR signaling pathway) have been reported for use in various B-cell non-Hodgkin's lymphomas (NHL) and CLL/SLL. Clinical anti-tumor response.

化合物1在多種分析及治療模型中有活性，證明能共價且不可逆地抑制BTK(在酶促及細胞分析中)。化合物1藉由以高親和力結合於Btk之三磷酸腺苷(ATP)結合位點且與Btk蛋白形成目標共價結合來抑制Btk活性，提供活體外及活體內迅速、完全及延長的Btk活性抑制。 Compound 1 is active in a variety of assays and therapeutic models, demonstrating covalent and irreversible inhibition of BTK (in enzymatic and cellular assays). Compound 1 by high affinity binding to the Btk adenosine triphosphate (ATP) binding site and forms a Btk target protein covalently bound to inhibition of Btk activity, in vitro and in vivo to provide rapid, complete and prolonged inhibition of Btk activity.

藉由在達到50%抑制(EC50)所需之1nM至10nM之有效濃度下的化合物1抑制Ramos細胞(人類伯基特淋巴瘤細胞株，human Burkitt lymphoma cell line)中Btk上之自體磷酸化位點(Tyr223)及PLCγ2上之Btk反應位點(Tyr1217)的磷酸化。化合物1顯示在細胞分析系統中針對相關激酶之高度選擇性。 Inhibition of autophosphoric acid on Btk in Ramos cells (human Burkitt lymphoma cell line) by Compound 1 at an effective concentration of 1 nM to 10 nM required to achieve 50% inhibition (EC 50 ) Phosphorylation of the Btk reaction site (Tyr1217) at the chemistry site (Tyr223) and PLCγ2. Compound 1 shows high selectivity for related kinases in cell analysis systems.

在健康個體之單次劑量研究中，證明化合物1足夠安全，可預測藥物動力學(PK)且在大於0.5mg/kg之劑量下，正常人類外周血液B細胞之Btk受體目標佔有率達80%至100%。目前正在對不同血液學惡性腫瘤(包括CLL/SLL)進行單一藥劑化合物1之I期劑量遞增研究。 In a single-dose study of healthy individuals, Compound 1 was shown to be sufficiently safe to predict pharmacokinetics (PK) and at a dose greater than 0.5 mg/kg, Btk receptor target occupancy in normal human peripheral blood B cells was 80. % to 100%. A phase I dose escalation study of single agent compound 1 is currently underway for different hematological malignancies (including CLL/SLL).

來那度胺Lenalidomide

來那度胺(REVLIMID®)屬於稱為免疫調節藥物(IMiDsP®)之醫藥化合物類別。其治療潛能的關鍵在於以下事實：其具有多個作用機制，該等機制起作用以產生消炎及抗腫瘤效應。此等效應視細胞類型及觸發刺激物而定。迄今，來那度胺已與腫瘤壞死因子(TNF)-α抑制、T細胞協同刺激、抗增殖及抗血管生成活性相關。 Lenalidomide (REVLIMID®) belongs to the class of pharmaceutical compounds known as immunomodulatory drugs (IMiDsP®). The key to its therapeutic potential lies in the fact that it has multiple mechanisms of action that act to produce anti-inflammatory and anti-tumor effects. These effects depend on the cell type and trigger stimuli. To date, lenalidomide has been associated with tumor necrosis factor (TNF)-alpha inhibition, T cell co-stimulation, anti-proliferative and anti-angiogenic activities.

來那度胺已經多個全球健康管理機構(包括美國食品及藥物管理局(the United States Food and Drug Administration)，但不包括歐盟(European Union))核准，用於因與缺失5q細胞遺傳異常(具有或不具有其他細胞遺傳異常)相關之低危或中危-1骨髓發育不良症候群而患有輸血依賴性貧血之患者的治療。來那度胺亦已經多個全球健康管理機構(值得注意的是包括US及EU)核准與***(dexamethasone)組合用於患有先前經治療之多發性骨髓瘤(MM)的患者。 Lenalidomide has been approved by several global health authorities (including the United States Food and Drug Administration, but not the European Union) for the genetic abnormality of the 5q cell Treatment of patients with low- or medium-risk-1 myelodysplastic syndromes with or without transfusion-dependent anemia associated with other cytogenetic abnormalities. Lenalidomide has also been approved by several global health authorities (notably US and EU) for use in combination with dexamethasone for patients with previously treated multiple myeloma (MM).

來那度胺正作為各種腫瘤學適應症(包括MM、NHL及實體腫瘤)之治療劑而加以調查研究。已亦對非腫瘤學適應症進行研究。 Lenalidomide is being investigated as a therapeutic agent for a variety of oncological indications including MM, NHL and solid tumors. Non-oncological indications have also been studied.

已提出腫瘤壞死因子-α為穿過CLL細胞上之TNF-α受體的自分泌生長因子。亦已報導高血清血管內皮生長因子(VEGF)含量及CLL細胞 上之血管內皮生長因子受體1(VEGFR-1)及血管內皮生長因子受體2(VEGFR-2)表現。已證明來那度胺具有調控及調節生長因子/細胞激素(包括VEGF、TNF-α、介白素(IL)-10及IL-6)之能力。已證明免疫調節藥物協同刺激免疫效應細胞(T細胞及自然殺手細胞)。此等觀測結果及沙力度胺(thalidomide)與來那度胺在另一B細胞惡性腫瘤多發性骨髓瘤中之已知活性提供研究來那度胺在CLL/SLL中之初始基本原理。 Tumor necrosis factor-α has been proposed as an autocrine growth factor that crosses the TNF-α receptor on CLL cells. High serum vascular endothelial growth factor (VEGF) levels and CLL cells have also been reported Vascular Endothelial Growth Factor Receptor 1 (VEGFR-1) and Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2). Lenalidomide has been shown to have the ability to regulate and regulate growth factors/cytokines including VEGF, TNF-[alpha], interleukin (IL)-10 and IL-6. Immunomodulatory drugs have been shown to synergistically stimulate immune effector cells (T cells and natural killer cells). These observations and the known activity of thalidomide and lenalidomide in another B-cell malignant multiple myeloma provide an initial rationale for studying lenalidomide in CLL/SLL.

已在復發性/難治性CLL中研究單一藥劑來那度胺。個體用來那度胺25mg治療每28天週期之21天。總反應率為53%(18%完全反應[CR]，36%部分反應[PR])。在47%具有del(11)(q23)及/或del(17)(p13.1)不利細胞遺傳之個體及30%對氟達拉濱(fludarabine)難治性個體中觀察到臨床反應(CR或PR)。達到最佳反應之中值時間為5.9個月(1.6-18.3個月)且中值無進展存活(PFS)時間為19.4個月(1.2至31.8個月)。另外，患有復發性/難治性CLL之個體藉由在28天週期中每日投與來那度胺來治療直至疾病進展。 The single agent lenalidomide has been studied in relapsed/refractory CLL. Individuals were given lenalidomide 25 mg for 21 days per 28 day cycle. The overall response rate was 53% (18% complete response [CR], 36% partial reaction [PR]). Clinical response (CR or was observed in 47% of individuals with del(11)(q23) and/or del(17)(p13.1) unfavorable cytogenes and 30% of fludarabine refractory individuals PR). The median time to optimal response was 5.9 months (1.6-18.3 months) and the median progression-free survival (PFS) time was 19.4 months (1.2 to 31.8 months). In addition, individuals with relapsed/refractory CLL were treated by daily administration of lenalidomide over a 28 day period until disease progression.

大量臨床資料表明來那度胺在復發性/難治性侵襲性B細胞惡性腫瘤中具有活性。此外，Btk作為下游組分之B細胞受體(BCR)路徑已與B細胞增殖、活化及存活之發病機制有關聯。Btk在CLL/SLL中之作用受到涉及Btk抑制劑之臨床研究的早期報告支持。 A large number of clinical data indicate that lenalidomide is active in relapsed/refractory aggressive B cell malignancies. In addition, the B cell receptor (BCR) pathway of Btk as a downstream component has been linked to the pathogenesis of B cell proliferation, activation and survival. The role of Btk in CLL/SLL is supported by early reports of clinical studies involving Btk inhibitors.

抗CD20抗體anti-CD20 antibody

CD20(由單株抗體托西莫單抗(tositumomab)界定之第一個B細胞特異性抗原)在B細胞發育中發揮關鍵作用。人類CD20為具有由位於染色體11q12.2上之基因MS4A1編碼之四個跨膜域之297個胺基酸(30至35kDa)的磷蛋白。CD20在B細胞發育中發揮關鍵作用且為靶向B細胞源性疾病之免疫療法的生物標記。CD20為由分化早期之B淋巴細胞及由大多數B細胞淋巴瘤，而不是由分化漿細胞表現之整合膜蛋白。 CD20在抗體結合後保留在B細胞膜上而未解離或內化。儘管結合於酪胺酸激酶之Src家族(諸如Lyn、Fyn及Lck)，但CD20仍起作用，且因此咸信涉及細胞內蛋白質之磷酸化級聯。抗CD20抗體大致分為I型及II型抗體。兩種類型之抗CD 20抗體在活化Fc-FcγR相互作用，諸如抗體依賴性細胞毒性(ADCC)及吞噬作用方面顯示出相當的能力。I型抗CD20抗體將CD20再分佈於膜脂筏中且強效活化補體依賴性細胞毒性(CDC)。II型抗CD20抗體微弱地活化CDC，但更強效地誘發直接漸進式細胞死亡。 CD20 (the first B cell-specific antigen defined by the monoclonal antibody tositumomab) plays a key role in B cell development. Human CD20 is a phosphoprotein having 297 amino acids (30 to 35 kDa) in four transmembrane domains encoded by the gene MS4A1 located on chromosome 11q12.2. CD20 plays a key role in B cell development and is a biomarker for immunotherapy targeting B cell-derived diseases. CD20 is an integral membrane protein expressed by early differentiation of B lymphocytes and by most B cell lymphomas, but not by differentiated plasma cells. CD20 remains on the B cell membrane after antibody binding without dissociation or internalization. Despite the binding to the Src family of tyrosine kinases (such as Lyn, Fyn, and Lck), CD20 still functions, and thus is involved in the phosphorylation cascade of intracellular proteins. Anti-CD20 antibodies are broadly classified into type I and type II antibodies. Both types of anti-CD20 antibodies show considerable ability to activate Fc-FcyR interactions, such as antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. Type I anti-CD20 antibodies redistribute CD20 in membrane lipid rafts and potently activate complement dependent cytotoxicity (CDC). Type II anti-CD20 antibodies weakly activate CDC, but more potently induce direct progressive cell death.

在一些實施例中，本發明涵蓋BTK抑制劑(例如化合物1)與來那度胺及抗CD20抗體一起適用於治療BTK介導之疾病或失調的認知。因此，在一些實施例中，本發明包含一種治療BTK介導之疾病或失調的方法，該方法包含向有需要之患者投與化合物1、來那度胺及抗CD20抗體中之每一者。一般熟習此項技術者可易於鑑定及選擇適用於本發明之額外抗CD20抗體。舉例而言，在一些實施例中，該等抗體描述於例如美國專利第8,153,125號、第8,147,832號、第8,101,179號、第8,084,582號、第8,057,793號及第7,879,984號，及美國專利公開案第2011/0129412號、第2012/0183545號、第2012/0134990號及第2012/0034185號中。 In some embodiments, the invention contemplates that a BTK inhibitor (eg, Compound 1 ), together with lenalidomide and an anti-CD20 antibody, is useful for treating a BTK-mediated disease or disorder. Accordingly, in some embodiments, the invention comprises a method of treating a BTK mediated disease or disorder, the method comprising administering to each patient in need thereof a compound 1 , a lenalidomide, and an anti-CD20 antibody. Those skilled in the art will readily be able to identify and select additional anti-CD20 antibodies suitable for use in the present invention. For example, in some embodiments, such antibodies are described in, for example, U.S. Patent Nos. 8,153,125, 8,147,832, 8,101,179, 8,084,582, 8,057,793, and 7,879,984, and U.S. Patent Publication No. 2011/ No. 0129412, No. 2012/0183545, No. 2012/0134990 and No. 2012/0034185.

在一些實施例中，本發明所用之抗CD20抗體為I型抗體。在一些實施例中，本發明所用之抗CD20抗體為II型抗體。 In some embodiments, the anti-CD20 antibody used in the invention is a type I antibody. In some embodiments, the anti-CD20 antibody used in the invention is a Type II antibody.

在一些實施例中，抗CD20抗體為結合於選自170ANPS173及182YCYSI185之CD20抗原決定基的抗體。 In some embodiments, the anti-CD20 antibody is an antibody that binds to a CD20 epitope selected from the group consisting of 170 ANPS 173 and 182 YCYSI 185 .

在一些實施例中，抗CD20抗體對CD20之抗原決定基之結合親和力(Kd)小於12nM、小於11nM、小於10nM、小於9nM、小於8nM、小於7nM、小於6nM、小於5nM、小於4nM、小於3nM、小於2nM或小於1nM。 In some embodiments, the anti-CD20 antibody binding affinity of the epitope of the CD20 antigen (K d) of less than 12nM, less than 11 nM, less than 10 nM, less than 9nM, less than 8nM, less than 7 nM, less than 6nM, less than of 5 nM, less than 4nM, less than 3nM, less than 2nM or less than 1nM.

利妥昔單抗僅為抗CD20抗體之一個實例。在一些實施例中，本發明所用之抗CD20抗體包括例如利妥昔單抗(Rituxan®或MabThera®)、Gazyva®(亦即歐碧奴單抗(obinutuzumab))及Arzerra®(奧法木單抗(ofatumumab))。為便於參考，所提供之方法及本文中詳述之方案係指例示性抗CD20抗體(亦即利妥昔單抗)；然而，該參考並不意欲將本發明侷限於單一抗CD20抗體。實際上，熟習此項技術者將閱讀關於利妥昔單抗或其生物類似物之所有參考文獻以涵蓋抗CD20抗體之類別。舉例而言，應理解在提及利妥昔單抗之每一情形中，可作為替代投與抗CD20抗體奧法木單抗(Arzerra®)或歐碧奴單抗(Gazyva®)。因此，在一些實施例中，所提供之方法包含投與化合物1、來那度胺及/或奧法木單抗。在一些該等實施例中，根據以下時程以12次劑量投與奧法木單抗：300mg首劑量，接著1週以後每週7次2000mg劑量，接著4週以後每4週4次2000mg劑量。在一些實施例中，所提供之方法包含投與化合物1、來那度胺及/或歐碧奴單抗。在一些該等實施例中，如下歷經六個28天週期投與歐碧奴單抗：在第1週期第1天100mg；在第1週期第2天900mg；在第1週期第8天及第15天1000mg；及在第2-6週期第1天1000mg。因此，在一些實施例中，術語「利妥昔單抗」涵蓋滿足在選自由美國、歐洲及日本組成之一組國家之國家或領土獲得作為相同或生物類似產品之銷售授權所需之要求的所有相應抗CD20抗體。 Rituximab is only one example of an anti-CD20 antibody. In some embodiments, anti-CD20 antibodies for use in the invention include, for example, rituximab (Rituxan® or MabThera®), Gazyva® (i.e., obinutuzumab), and Arzerra® (Orpheus Anti (ofatumumab)). For ease of reference, the methods provided and the protocols detailed herein refer to exemplary anti-CD20 antibodies (i.e., rituximab); however, this reference is not intended to limit the invention to a single anti-CD20 antibody. In fact, those of skill in the art will read all references to rituximab or a biological analog thereof to encompass classes of anti-CD20 antibodies. For example, it should be understood that in each case where rituximab is mentioned, the anti-CD20 antibody arfazumab (Arzerra®) or oubizumab (Gazyva®) may be administered instead. Accordingly, in some embodiments, the methods provided comprise administering Compound 1 , lenalidomide, and/or orfarizumab. In some of these embodiments, orfarizumab was administered in 12 doses according to the following schedule: 300 mg first dose, followed by 7 doses of 2000 mg dose per week after 1 week, followed by 4 weeks, 4 doses of 2000 mg dose every 4 weeks . In some embodiments, the methods provided comprise administering Compound 1 , lenalidomide, and/or opiconumab. In some of these examples, the following two 28-day cycles were administered to opiconumab: 100 mg on the first day of the first cycle; 900 mg on the second day of the first cycle; on the eighth day of the first cycle and 1000 mg for 15 days; and 1000 mg on the first day of the 2-6th cycle. Thus, in some embodiments, the term "rituximab" encompasses the requirement to obtain a sales authorization for the same or biosimilar product in a country or territory selected from a group of countries consisting of the United States, Europe, and Japan. All corresponding anti-CD20 antibodies.

在一些實施例中，抗CD20抗體具有與利妥昔單抗或其生物類似物相同或類似的活性。在一些實施例中，抗CD20抗體結合於與利妥昔單抗或其片段相同或類似的區或抗原決定基。在一些實施例中，抗CD20抗體與利妥昔單抗或其片段競爭結合於CD20。在一些實施例中，抗CD20抗體與利妥昔單抗或其片段生物等效。在一些實施例中，抗CD20抗體為利妥昔單抗或其片段之生物類似物。在一些實施 例中，抗CD20抗體為利妥昔單抗之變化形式或衍生物，包括功能片段、衍生物或抗體結合物。 In some embodiments, the anti-CD20 antibody has the same or similar activity as rituximab or a biological analog thereof. In some embodiments, the anti-CD20 antibody binds to a region or epitope that is identical or similar to rituximab or a fragment thereof. In some embodiments, the anti-CD20 antibody competes with rituximab or a fragment thereof for binding to CD20. In some embodiments, the anti-CD20 antibody is bioequivalent to rituximab or a fragment thereof. In some embodiments, the anti-CD20 antibody is a biological analog of rituximab or a fragment thereof. In some implementations In one embodiment, the anti-CD20 antibody is a variant or derivative of rituximab, including a functional fragment, derivative or antibody conjugate.

利妥昔單抗Rituximab

利妥昔單抗(Rituxan®或MabThera®)為針對正常B淋巴細胞及B細胞CLL中及大多數形式之非霍奇金氏B細胞淋巴瘤中存在之CD20細胞表面分子的經遺傳工程改造之細胞溶解型嵌合鼠類/人類單株IgG1κ抗體。利妥昔單抗對CD20抗原具有約8.0nM之結合親和力。利妥昔單抗可誘發補體依賴性細胞毒性(CDC)及抗體依賴性細胞毒性(ADCC)，產生其針對淋巴瘤細胞之臨床活性。利妥昔單抗亦可在結合於CD20後導致B細胞凋亡，由此直接抑制細胞生長。 Rituxan® or MabThera® is a genetically engineered CD20 cell surface molecule present in normal B lymphocytes and B cell CLL and in most forms of non-Hodgkin's B cell lymphoma. Cell lytic chimeric murine/human monoclonal IgG 1 κ antibody. Rituximab has a binding affinity of about 8.0 nM for the CD20 antigen. Rituximab induces complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), resulting in its clinical activity against lymphoma cells. Rituximab also causes B cell apoptosis upon binding to CD20, thereby directly inhibiting cell growth.

利妥昔單抗由含有抗生素慶大黴素(gentamicin)之營養培養基中的哺乳動物細胞(中國倉鼠卵巢)懸浮培養物產生。慶大黴素在最終產物中不可偵測。利妥昔單抗為用於靜脈內投藥之無菌、澄清、無色、無防腐劑之液體濃縮物。利妥昔單抗以10mg/mL之濃度供應在100mg/10mL或500mg/50mL之單次使用小瓶中。在聚山梨醇酯80(0.7mg/mL)、二水合檸檬酸鈉(7.35mg/mL)、氯化鈉(9mg/mL)及注射用水中調配利妥昔單抗。Rituxan®(或MabThera®)之pH值為6.5。 Rituximab is produced from a suspension culture of mammalian cells (Chinese hamster ovaries) in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration. Rituximab was supplied at a concentration of 10 mg/mL in a single use vial of 100 mg/10 mL or 500 mg/50 mL. Rituximab was formulated in polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL), sodium chloride (9 mg/mL), and water for injection. Rituxan® (or MabThera®) has a pH of 6.5.

利妥昔單抗已在臨床研究中加以調查且經核准用於與氟達拉濱及環磷醯胺(cyclophosphamide)一起治療患有CLL之患者，以及與甲胺喋呤(methotrexate)一起治療患有類風濕性關節炎之患者。利妥昔單抗亦經核准用於治療非霍奇金氏淋巴瘤、韋格納肉芽腫病(Wegener's Granulomatosis)及顯微鏡下多血管炎(Microscopic Polyangiitis)。另外，研究已展示利妥昔單抗及苯達莫司汀(bendamustine)亦有效用於治療復發性或難治性CLL及NHL，例如惰性淋巴瘤及套細胞淋巴瘤。應瞭解且理解，當利妥昔單抗與化合物1及來那度胺一起投與時，利妥昔單抗可作為單一藥劑或與(i)氟達拉濱及環磷醯胺(「FCR」)或(ii) 苯達莫司汀(「BR」)一起使用。因此，在一些實施例中，所提供之方法包含投與化合物1、來那度胺、利妥昔單抗、氟達拉濱及環磷醯胺中之每一者。在一些實施例中，所提供之方法包含投與化合物1、來那度胺、利妥昔單抗及苯達莫司汀中之每一者。 Rituximab has been investigated in clinical studies and approved for the treatment of patients with CLL with fludarabine and cyclophosphamide, as well as with methotrexate A patient with rheumatoid arthritis. Rituximab is also approved for the treatment of non-Hodgkin's lymphoma, Wegener's Granulomatosis and Microscopic Polyangiitis. In addition, studies have shown that rituximab and bendamustine are also effective in the treatment of relapsed or refractory CLL and NHL, such as indolent lymphoma and mantle cell lymphoma. It is understood and understood that when rituximab is administered with Compound 1 and lenalidomide, rituximab can be used as a single agent or with (i) fludarabine and cyclophosphamide ("FCR"") or (ii) Bendamustine ("BR") is used together. Accordingly, in some embodiments, the methods provided comprise administering each of Compound 1 , lenalidomide, rituximab, fludarabine, and cyclophosphamide. In some embodiments, the methods provided comprise administering each of Compound 1 , lenalidomide, rituximab, and bendamustine.

I.通用給藥計劃I. General dosing plan

如本文所述，所提供之方法包含投與兩種或兩種以上治療劑(亦即化合物1、來那度胺及/或抗CD20抗體)。應理解，各治療劑可作為給藥方案之一部分同步或依次(例如化合物1可在來那度胺及/或抗CD20抗體之前、期間或之後投與，反之亦然)投與。舉例而言，化合物1可在來那度胺或抗CD20抗體投與前一或多個小時、一或多天或一或多週投與。在其他實施例中，化合物1及來那度胺各自可在抗CD20抗體投與前一或多個小時、一或多天或一或多週投與。在其他實施例中，化合物1及抗CD20抗體各自可在來那度胺投與前一或多個小時、一或多天或一或多週投與。 As described herein, the methods provided comprise administering two or more therapeutic agents (i.e., Compound 1 , lenalidomide, and/or anti-CD20 antibodies). It should be understood, each therapeutic agent can be synchronized as part of the program or sequence of administration (e.g. Compound 1 may lenalidomide and / or anti-CD20 antibody before, during or after the administration, and vice-versa) and administered. For example, Compound 1 can be administered one or more hours, one or more days, or one or more weeks prior to administration of lenalidomide or an anti-CD20 antibody. In other embodiments, each of Compound 1 and lenalidomide can be administered one or more hours, one or more days, or one or more weeks prior to administration of the anti-CD20 antibody. In other embodiments, each of Compound 1 and the anti-CD20 antibody can be administered one or more hours, one or more days, or one or more weeks prior to administration of lenalidomide.

在一些實施例中，本發明提供用於治療、穩定或減輕一或多種與BTK相關之疾病或病狀之嚴重程度或進展的方法。在一些實施例中，本發明提供用於預防與BTK相關之疾病或失調之進展的方法。在一些實施例中，與BTK相關之疾病或失調係選自慢性淋巴球性白血病(CLL)及小淋巴球性淋巴瘤(SLL)。 In some embodiments, the invention provides methods for treating, stabilizing or ameliorating the severity or progression of one or more diseases or conditions associated with BTK. In some embodiments, the invention provides methods for preventing progression of a disease or disorder associated with BTK. In some embodiments, the disease or disorder associated with BTK is selected from the group consisting of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

在一些實施例中，與BTK相關之疾病或失調為難治性CLL。在一些實施例中，與BTK相關之疾病或失調為復發性CLL。在一些實施例中，與BTK相關之疾病或失調為難治性SLL。在一些實施例中，與BTK相關之疾病或失調為復發性SLL。 In some embodiments, the disease or disorder associated with BTK is refractory CLL. In some embodiments, the disease or disorder associated with BTK is recurrent CLL. In some embodiments, the disease or disorder associated with BTK is a refractory SLL. In some embodiments, the disease or disorder associated with BTK is a recurrent SLL.

在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合。在一些該等實施例中，化合物1及來那度胺各自以另外包含一或多種醫藥學上可接受之賦形劑之組合物形式投與。 在一些實施例中，所提供之方法另外包含投與抗CD20抗體，例如利妥昔單抗。在一些實施例中，所提供之方法包含投與化合物1、來那度胺及抗CD20抗體(例如利妥昔單抗)中之每一者。 In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide to a patient in need thereof. In some such embodiments, Compound 1 and lenalidomide in each composition additionally comprises one or more pharmaceutically acceptable excipients and administered in the form of. In some embodiments, the methods provided additionally comprise administering an anti-CD20 antibody, such as rituximab. In some embodiments, the methods provided comprise administering each of Compound 1 , lenalidomide, and an anti-CD20 antibody (eg, rituximab).

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之化合物1與治療有效量之來那度胺之組合。因此，在一些實施例中，本發明提供一種治療、穩定或減輕一或多種與BTK相關之疾病之嚴重程度或進展的方法，該方法包含向有需要之患者投與治療有效量之化合物1與治療有效量之來那度胺之組合。在一些實施例中，所提供之方法另外包含投與抗CD20抗體，例如利妥昔單抗。在一些實施例中，所提供之方法包含投與治療有效量之化合物1、來那度胺及抗CD20抗體(例如利妥昔單抗)中之每一者。 In some embodiments, a method is provided comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 in combination with a therapeutically effective amount of lenalidomide. Accordingly, in some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more diseases associated with BTK, the method comprising administering to a patient in need thereof a therapeutically effective amount of Compound 1 and A combination of a therapeutically effective amount of lenalidomide. In some embodiments, the methods provided additionally comprise administering an anti-CD20 antibody, such as rituximab. In some embodiments, the methods provided comprise administering a therapeutically effective amount of each of Compound 1 , lenalidomide, and an anti-CD20 antibody (eg, rituximab).

在一些實施例中，所提供之方法包含投與化合物1與來那度胺之組合，其中化合物1及來那度胺每日各投與一次(「QD」)。在一些實施例中，所提供之方法包含投與化合物1與來那度胺之組合，其中化合物1每日投與兩次(「BID」)。在一些實施例中，所提供之方法另外包含投與抗CD20抗體，例如利妥昔單抗。在一些實施例中，所提供之方法包含投與化合物1、來那度胺及抗CD20抗體(例如利妥昔單抗)中之每一者，其中化合物1投與BID。在一些該等實施例中，來那度胺投與QD。出於明瞭之目的，投與375mg劑量之化合物1「BID」意指在一天內向患者投與兩個單獨的375mg劑量。 In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide, wherein Compound 1 and lenalidomide are administered once daily ("QD"). In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide, wherein Compound 1 is administered twice daily ("BID"). In some embodiments, the methods provided additionally comprise administering an anti-CD20 antibody, such as rituximab. In some embodiments, the methods provided comprise administering each of Compound 1 , lenalidomide, and an anti-CD20 antibody (eg, rituximab), wherein Compound 1 is administered BID. In some of these embodiments, lenalidomide is administered to QD. For the sake of clarity, administration of a 375 mg dose of Compound 1 "BID" means that two separate doses of 375 mg are administered to the patient within one day.

在一些實施例中，所提供之方法包含投與化合物1與來那度胺之組合，其中來那度胺每日投與一次。在一些實施例中，所提供之方法包含投與化合物1與來那度胺之組合，其中化合物1每日投與兩次且來那度胺每日投與一次。在一些實施例中，所提供之方法另外包含投與抗CD20抗體，例如利妥昔單抗，其中該抗CD20抗體在28天週期內投與一次。在一些該等實施例中，在第1週期之第1天或第2天投與抗 CD20抗體。在一些該等實施例中，在28天週期之第1天投與抗CD20抗體。在一些實施例中，在第2-6週期之第1天投與抗CD20抗體。在一些實施例中，所提供之方法包含投與化合物1、來那度胺及抗CD20抗體中之每一者，其中該抗CD20抗體在28天週期內投與一次。在一些該等實施例中，在28天週期之第1天或第2天投與抗CD20抗體。應瞭解，雖然本文所述之方法係指投與化合物1，但該等方法同樣適用於投與化合物1之鹽形式(例如化合物1之苯磺酸鹽)的方法。 In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide, wherein lenalidomide is administered once daily. In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide, wherein Compound 1 is administered twice daily and lenalidomide is administered once daily. In some embodiments, the methods provided additionally comprise administering an anti-CD20 antibody, such as rituximab, wherein the anti-CD20 antibody is administered once in a 28 day period. In some of these embodiments, the anti-CD20 antibody is administered on the first or second day of the first cycle. In some of these examples, the anti-CD20 antibody was administered on day 1 of the 28 day cycle. In some embodiments, the anti-CD20 antibody is administered on day 1 of cycles 2-6. In some embodiments, the methods provided comprise administering each of Compound 1 , lenalidomide, and an anti-CD20 antibody, wherein the anti-CD20 antibody is administered once in a 28 day period. In some of these embodiments, the anti-CD20 antibody is administered on day 1 or day 2 of the 28 day cycle. It should be appreciated that while the method herein refers to administration of the compound 1, but these methods are equally applicable to the administration of the compound in the form of a salt (e.g. benzenesulfonate salt of Compound 1) method.

在一些實施例中，化合物1及來那度胺各自以醫藥學上可接受之組合物形式投與。在一些該等實施例中，將各醫藥學上可接受之組合物調配成口服劑型。在一些實施例中，該等口服劑型為膠囊。在一些實施例中，所提供之方法另外包含投與抗CD20抗體(例如利妥昔單抗)之醫藥學上可接受之組合物。在一些實施例中，所提供之方法包含投與化合物1、來那度胺及抗CD20抗體(例如利妥昔單抗)中之每一者之醫藥學上可接受之組合物。在一些該等實施例中，將抗CD20抗體之醫藥學上可接受之組合物調配成靜脈內組合物。 In some embodiments, Compound 1 and lenalidomide are each administered as a pharmaceutically acceptable composition. In some such embodiments, each pharmaceutically acceptable composition is formulated into an oral dosage form. In some embodiments, the oral dosage forms are capsules. In some embodiments, the methods provided additionally comprise a pharmaceutically acceptable composition for administration of an anti-CD20 antibody (eg, rituximab). In some embodiments, a method provided comprises administering a pharmaceutically acceptable composition of each of Compound 1 , lenalidomide, and an anti-CD20 antibody (eg, rituximab). In some such embodiments, a pharmaceutically acceptable composition of an anti-CD20 antibody is formulated into an intravenous composition.

在一些實施例中，以組合物之總重量計，包含化合物1之醫藥學上可接受之組合物包含約5%至約60%之化合物1或其醫藥學上可接受之鹽。在一些實施例中，以組合物之總重量計，包含化合物1之醫藥學上可接受之組合物包含約5%至約15%、或約7%至約15%、或約7%至約10%、或約9%至約12%之化合物1。在一些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，以調配物之總重量計，該組合物包含約25%至約75%、或約30%至約60%、或約40%至約50%、或約40%至約45%之化合物1。在某些實施例中，所提供之方案包含向有需要之患者投與醫藥學上可接受之組合物，以給定組合物或調配物之總重量計，該組合物包含約6%、約7%、約8%、約9%、約10%、約11%、約12%、約13%、約20%、約30%、約40%、約 41%、約42%、約43%、約44%、約45%、約50%、約60%、約70%、或約75%之化合物1。 In some embodiments, the pharmaceutically acceptable composition comprising Compound 1 comprises from about 5% to about 60% of Compound 1 or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the pharmaceutically acceptable composition comprising Compound 1 comprises from about 5% to about 15%, or from about 7% to about 15%, or from about 7% to about, based on the total weight of the composition. 10%, or about 9% to about 12% of Compound 1 . In some embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25% to about 75%, or about 30, based on the total weight of the formulation. From about 60%, or from about 40% to about 50%, or from about 40% to about 45% of Compound 1 . In certain embodiments, the regimen provided comprises administering to a patient in need thereof a pharmaceutically acceptable composition comprising about 6%, based on the total weight of the given composition or formulation. 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 20%, about 30%, about 40%, about 41%, about 42%, about 43% About 44%, about 45%, about 50%, about 60%, about 70%, or about 75% of Compound 1 .

在一些實施例中，以組合物之總重量計，包含來那度胺之醫藥學上可接受之組合物包含約2.5%至約6.25%之來那度胺。在一些實施例中，以組合物之總重量計，醫藥學上可接受之組合物包含約2.5%、約3.75%或約6.25%之來那度胺或其醫藥學上可接受之鹽。在一些實施例中，來那度胺之組合物為可購自Celgene Corporation之組合物。在一些實施例中，來那度胺之醫藥學上可接受之組合物為表2或表3中所述之組合物。 In some embodiments, the pharmaceutically acceptable composition comprising lenalidomide comprises from about 2.5% to about 6.25% lenalidomide, based on the total weight of the composition. In some embodiments, the pharmaceutically acceptable composition comprises about 2.5%, about 3.75%, or about 6.25% lenalidomide or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In some embodiments, the composition of lenalidomide is a composition commercially available from Celgene Corporation. In some embodiments, the pharmaceutically acceptable composition of lenalidomide is the composition described in Table 2 or Table 3.

利妥昔單抗以包含檸檬酸鈉、聚山梨醇酯80、氯化鈉、氫氧化鈉、鹽酸及水之10mg/mL溶液形式市售。市售小瓶包含100mg/10mL或500mg/50mL。 Rituximab is commercially available as a 10 mg/mL solution comprising sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid and water. Commercially available vials contain 100 mg/10 mL or 500 mg/50 mL.

在一些實施例中，醫藥學上可接受之組合物包含約1mg/mL至約4mg/mL利妥昔單抗。在一些實施例中，醫藥學上可接受之組合物包含約1mg/mL、約2mg/mL、約3mg/mL或約4mg/mL利妥昔單抗。在一些實施例中，醫藥學上可接受之組合物包含10mg/mL。 In some embodiments, the pharmaceutically acceptable composition comprises from about 1 mg/mL to about 4 mg/mL rituximab. In some embodiments, the pharmaceutically acceptable composition comprises about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, or about 4 mg/mL rituximab. In some embodiments, the pharmaceutically acceptable composition comprises 10 mg/mL.

在一些實施例中，所提供之方法包含每日投與化合物1與來那度胺之組合，持續1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27或28天之時間。在一些實施例中，治療方案包含至少一個28天週期。如本文中所用，術語「28天週期」意指向有需要之患者投與化合物1及來那度胺之組合，持續28個連續日。在一些實施例中，每日投與化合物1與來那度胺之組合一次，持續至少一個28天週期。在一些實施例中，投與化合物1與來那度胺之組合至少兩個、至少三個、至少四個、至少五個或至少六個28天週期。在一些實施例中，每日投與化合物1與來那度胺之組合一次，持續至少七個、至少八個、至少九個、至少十 個、至少十一個或至少十二個28天週期。在一些實施例中，每日投與化合物1與來那度胺之組合一次，持續至少十三個、至少十四個、至少十五個、至少十六個、至少十七個、至少十八個、至少十九個或至少二十個28天週期。在一些實施例中，向患者投與化合物1與來那度胺之組合，持續患者一生。在一些實施例中，在一或多個28天週期之第1天至第28天投與化合物1(例如每天一次劑量或每天兩次劑量)，且在一或多個28天週期之第1天至第21天投與來那度胺(例如每天一次劑量)。在一些實施例中，在一或多個28天週期之第8天至第28天投與化合物1，且在一或多個28天週期之第1天至第28天投與來那度胺。在一些實施例中，在一或多個28天週期之第1天至第28天投與化合物1，且在一或多個28天週期之第1天至第28天投與來那度胺。 In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days. In some embodiments, the treatment regimen comprises at least one 28 day period. As used herein, the term "28 day cycle" is intended to mean that a patient in need thereof is administered a combination of Compound 1 and lenalidomide for 28 consecutive days. In some embodiments, the combination of Compound 1 and lenalidomide is administered once a day for at least one 28 day period. In some embodiments, the combination of Compound 1 and lenalidomide is administered for at least two, at least three, at least four, at least five, or at least six 28 day cycles. In some embodiments, the combination of Compound 1 and lenalidomide is administered once a day for at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve 28-day cycles. . In some embodiments, the combination of Compound 1 and lenalidomide is administered once a day for at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen At least nineteen or at least twenty 28-day cycles. In some embodiments, a combination of Compound 1 and lenalidomide is administered to a patient for a lifetime. In some embodiments, Compound 1 is administered on Day 1 to Day 28 of one or more 28-day cycles (eg, once daily or twice daily) and is 1 in one or more 28-day cycles Lenalidomide is administered on day 21 (eg, once daily). In some embodiments, Compound 1 is administered from day 8 to day 28 of one or more 28 day cycles, and lenalidomide is administered from day 1 to day 28 of one or more 28 day cycles. . In some embodiments, Compound 1 is administered from Day 1 to Day 28 of one or more 28-day cycles, and lenalidomide is administered on Days 1 to 28 of one or more 28-day cycles. .

在一些實施例中，向患者投與化合物1及來那度胺中之每一者持續一個、兩個或三個28天週期，隨後減小來那度胺之劑量。在一些實施例中，向患者投與化合物1及來那度胺中之每一者持續一個、兩個或三個28天週期，隨後減小來那度胺之劑量至先前組劑量。在一些實施例中，向患者投與化合物1及來那度胺中之每一者直至達到所需反應(例如完全反應)為止，隨後減小來那度胺之劑量。 In some embodiments, each of Compound 1 and lenalidomide is administered to the patient for one, two or three 28 day cycles, followed by a reduction in the dose of lenalidomide. In some embodiments, each of Compound 1 and lenalidomide is administered to the patient for one, two or three 28 day cycles, followed by a reduction in the dose of lenalidomide to the previous group dose. In some embodiments, each of Compound 1 and lenalidomide is administered to the patient until the desired response (eg, complete response) is reached, followed by a reduction in the dose of lenalidomide.

在一些實施例中，投與化合物1、來那度胺及利妥昔單抗中之每一者，持續至少六個28天週期，且另外投與化合物1及來那度胺中之每一者，再持續至少一個28天週期。在一些實施例中，投與化合物1、來那度胺及利妥昔單抗中之每一者，持續至少六個28天週期，且另外投與化合物1及來那度胺中之每一者，再持續兩個、三個、四個、五個、六個、七個、八個、九個、十個、十一個、十二個、十三個或十四個28天週期。在一些實施例中，投與化合物1、來那度胺及利妥昔單抗中之每一者，持續至少六個28天週期，且另外投與化合物1及來那度胺中之每一者，持續患者一生。在一些實施例中，在一或 多個28天週期之第1天至第28天投與化合物1及來那度胺中之每一者(例如每天一次劑量或每天兩次劑量)，且在28天週期之第1天投與利妥昔單抗。在一些實施例中，在一或多個28天週期之第1天至第28天投與化合物1及來那度胺中之每一者，且在28天週期之第1天或第2天投與利妥昔單抗。 In some embodiments, each of Compound 1 , lenalidomide, and rituximab is administered for at least six 28-day cycles, and each of Compound 1 and lenalidomide is additionally administered. Continue for at least one 28-day cycle. In some embodiments, each of Compound 1 , lenalidomide, and rituximab is administered for at least six 28-day cycles, and each of Compound 1 and lenalidomide is additionally administered. Then, continue for two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen 28-day cycles. In some embodiments, each of Compound 1 , lenalidomide, and rituximab is administered for at least six 28-day cycles, and each of Compound 1 and lenalidomide is additionally administered. For the rest of the patient's life. In some embodiments, each of Compound 1 and lenalidomide is administered from Day 1 to Day 28 of one or more 28-day cycles (eg, once daily or twice daily), and Rituximab was administered on the first day of the 28-day cycle. In some embodiments, each of Compound 1 and lenalidomide is administered from Day 1 to Day 28 of one or more 28-day cycles, and on Day 1 or Day 2 of the 28-day cycle Invested in rituximab.

在一些實施例中，在一或多個週期內向患者投與化合物1及利妥昔單抗中之每一者，隨後在後續週期內向患者投與化合物1、利妥昔單抗及來那度胺中之每一者。在一些實施例中，在第1週期內向患者投與化合物1及利妥昔單抗中之每一者，隨後在第2-6週期內向患者投與化合物1、利妥昔單抗及來那度胺中之每一者。在一些實施例中，所提供之方法包含(i)在第一個28天週期內向有需要之患者投與化合物1及利妥昔單抗中之每一者；(ii)在第2-6週期內向該患者投與化合物1、利妥昔單抗及來那度胺中之每一者；及(iii)在此後一或多個28天週期內向該患者投與化合物1及/或來那度胺。 In some embodiments, each of Compound 1 and rituximab is administered to a patient in one or more cycles, followed by administration of Compound 1 , Rituximab, and Lenazide to the patient over a subsequent cycle. Each of the amines. In some embodiments, each of Compound 1 and rituximab is administered to the patient during the first cycle, followed by administration of Compound 1 , Rituximab, and Laina to the patient during Cycles 2-6. Each of the amines. In some embodiments, the methods provided comprise (i) administering to each of the patients in need thereof, Compound 1 and rituximab, during the first 28-day period; (ii) at 2-6 Each of Compound 1 , Rituximab, and Lenalidomide is administered to the patient during the cycle; and (iii) Compound 1 is administered to the patient over a period of one or more 28 days thereafter and/or Amine.

在一些實施例中，兩個相鄰28天週期可藉由休息期隔開。此類休息期可為一天、兩天、三天、四天、五天、六天、七天或七天以上，在此期間，不向患者投與化合物1及來那度胺中之任一者或兩者。在一較佳實施例中，兩個相鄰28天週期為連續的。 In some embodiments, two adjacent 28 day periods may be separated by a rest period. Such rest periods may be one day, two days, three days, four days, five days, six days, seven days or more, during which no one of Compound 1 and lenalidomide is administered to the patient or Both. In a preferred embodiment, two adjacent 28 day periods are continuous.

在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中該患者已失敗至少一個先前療法。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1、來那度胺及利妥昔單抗中之每一者，其中該患者已失敗至少一個先前療法。 In some embodiments, a method is provided comprising administering to a patient in need thereof a combination of Compound 1 and lenalidomide, wherein the patient has failed at least one prior therapy. In some embodiments, a method is provided comprising administering to a patient in need thereof each of Compound 1 , lenalidomide, and rituximab, wherein the patient has failed at least one prior therapy.

單位劑型Unit dosage form

本發明所用之醫藥組合物可製備成單位劑型。一般技術者應瞭解，本文所述之單位劑型係指組分呈其游離鹼形式之量。熟習此項技 術者另外應瞭解，當醫藥組合物包含一種組分之鹽形式(例如化合物1之苯磺酸鹽形式)時，該組合物中所存在之鹽形式的量為與該組分(亦即化合物1)之游離鹼之單位劑量等效的量。舉例而言，包含化合物1之苯磺酸鹽之醫藥組合物將含有傳遞等效的25mg單位劑量化合物1之游離鹼所必需的34.97mg苯磺酸鹽形式。 The pharmaceutical compositions used in the present invention can be prepared in unit dosage form. One of ordinary skill in the art will appreciate that the unit dosage form described herein refers to the amount of the component in its free base form. It will be further understood by those skilled in the art that when the pharmaceutical composition comprises a salt form of one component (e.g., the besylate form of Compound 1 ), the amount of the salt form present in the composition is the same as the component ( That is, the unit dose equivalent amount of the free base of Compound 1 ). For example, a pharmaceutical composition comprising a besylate salt of Compound 1 will contain the 34.97 mg besylate salt form necessary to deliver an equivalent equivalent of 25 mg unit dose of Compound 1 free base.

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之化合物1，其中化合物1之治療有效量為約250mg至約1250mg。在一些實施例中，以一或多個離散劑量形式投與治療有效量之化合物1。舉例而言，在一些實施例中，化合物1之治療有效量為250mg，其中該治療有效量以125mg形式每日投與兩次(BID)。在一些實施例中，化合物1之治療有效量為500mg，其中該治療有效量以250mg形式每日投與兩次(BID)。在一些實施例中，化合物1之治療有效量為750mg，其中該治療有效量以375mg形式每日投與兩次(BID)。在一些實施例中，化合物1之治療有效量為1000mg，其中該治療有效量以500mg形式每日投與兩次(BID)。 In some embodiments, the method comprises providing to a patient in need there of administering a therapeutically effective amount of a compound, wherein the therapeutically effective amount of a compound is from about 250mg to about 1250mg. In some embodiments, a therapeutically effective amount of Compound 1 is administered in one or more discrete dosage forms. For example, in some embodiments, the therapeutically effective amount of Compound 1 is 250 mg, wherein the therapeutically effective amount is administered twice daily (BID) in the form of 125 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 500 mg, wherein the therapeutically effective amount is administered twice daily (BID) in the form of 250 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 750 mg, wherein the therapeutically effective amount is administered twice daily (BID) in the form of 375 mg. In some embodiments, the therapeutically effective amount of Compound 1 is 1000 mg, wherein the therapeutically effective amount is administered twice daily (BID) in the form of 500 mg.

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之化合物1，其中化合物1之該治療有效量為約125mg至約1250mg、或約125mg至約1125mg、或約125mg至約1000mg、或約125mg至約875mg、或約125mg至約750mg、或約125mg至約625mg、或約125mg至約500mg、或約125mg至約375mg、或約125mg至約250mg、或約250mg至約1250mg、或約250mg至約1125mg、或約250mg至約1000mg、或約250mg至約875mg、或約250mg至約750mg、或約250mg至約625mg、或約250mg至約500mg、或約250mg至約375mg、或約375mg至約1250mg、或約375mg至約1125mg、或約375mg至約1000mg、或約375mg至約875mg、或約375mg至約750mg、或約375mg至約625mg、或約375mg至約500mg、或約500 mg至約1250mg、或約500mg至約1125mg、或約500mg至約1000mg、或約500mg至約875mg、或約500mg至約750mg、或約500mg至約625mg、或約625mg至約1250mg、或約625mg至約1125mg、或約625mg至約1000mg、或約625mg至約875mg、或約625mg至約750mg、或約750mg至約1250mg、或約750mg至約1125mg、或約750mg至約1000mg、或約875mg至約1250mg、或約875mg至約1125mg、或約875mg至約1000mg。 In some embodiments, the methods provided comprise to have administered to treat a patient in need of an effective amount of a compound, wherein the compound therapeutically effective amount of a is from about 125mg to about 1250 mg, or from about 125mg to about 1125 mg, or about 125mg To about 1000 mg, or about 125 mg to about 875 mg, or about 125 mg to about 750 mg, or about 125 mg to about 625 mg, or about 125 mg to about 500 mg, or about 125 mg to about 375 mg, or about 125 mg to about 250 mg, or about 250 mg to About 1250 mg, or about 250 mg to about 1125 mg, or about 250 mg to about 1000 mg, or about 250 mg to about 875 mg, or about 250 mg to about 750 mg, or about 250 mg to about 625 mg, or about 250 mg to about 500 mg, or about 250 mg to about 375 mg, or from about 375 mg to about 1250 mg, or from about 375 mg to about 1125 mg, or from about 375 mg to about 1000 mg, or from about 375 mg to about 875 mg, or from about 375 mg to about 750 mg, or from about 375 mg to about 625 mg, or from about 375 mg to about 500 mg. Or from about 500 mg to about 1250 mg, or from about 500 mg to about 1125 mg, or from about 500 mg to about 1000 mg, or from about 500 mg to about 875 mg, or from about 500 mg to about 750 mg, or from about 500 mg to about 625 mg, or from about 625 mg to about 1250 mg Or from about 625 mg to about 1125 mg, or from about 625 mg to about 1000 mg, or about 625 mg to 875 mg, or from about 625 mg to about 750 mg, or from about 750 mg to about 1250 mg, or from about 750 mg to about 1125 mg, or from about 750 mg to about 1000 mg, or from about 875 mg to about 1250 mg, or from about 875 mg to about 1125 mg, or from about 875 mg to about 1000 mg .

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之化合物1，其中化合物1之該治療有效量為約125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg、705mg、710mg、715mg、720mg、725 mg、730mg、735mg、740mg、745mg、750mg、755mg、760mg、765mg、770mg、775mg、780mg、785mg、790mg、795mg、800mg、805mg、810mg、815mg、820mg、825mg、830mg、835mg、840mg、845mg、850mg、855mg、860mg、865mg、870mg、875mg、880mg、885mg、890mg、895mg、900mg、905mg、910mg、915mg、920mg、925mg、930mg、935mg、940mg、945mg、950mg、955mg、960mg、965mg、970mg、975mg、980mg、985mg、990mg、995mg、1000mg、1005mg、1010mg、1015mg、1020mg、1025mg、1030mg、1035mg、1040mg、1045mg、1050mg、1055mg、1060mg、1065mg、1070mg、1075mg、1080mg、1085mg、1090mg、1095mg、1100mg、1105mg、1110mg、1115mg、1120mg、1125mg、1130mg、1135mg、1140mg、1145mg、1150mg、1155mg、1160mg、1165mg、1170mg、1175mg、1180mg、1185mg、1190mg、1195mg、1200mg、1205mg、1210mg、1215mg、1220mg、1225mg、1230mg、1235mg、1240mg、1245mg或1250mg。 In some embodiments, the methods provided comprise to have administered to treat a patient in need of an effective amount of a compound, wherein the compound of the therapeutically effective amount is about 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg, 285mg 290mg, 295mg, 300mg, 305mg, 310mg, 315mg, 320mg, 325mg, 330mg, 335mg, 340mg, 345mg, 350mg, 355mg, 360mg, 365mg, 370mg, 375mg, 380mg, 385mg, 390mg, 395mg, 400mg, 405mg, 410mg 415mg, 420mg, 425mg, 430mg, 435mg, 440mg, 445mg, 450mg, 455mg, 460mg, 465mg, 470mg, 475mg, 480mg, 485mg, 490mg, 495mg, 500mg, 505mg, 510mg, 515mg, 520mg, 525mg, 530mg, 535mg 540mg, 545mg, 550mg, 555mg, 560mg, 565mg, 570mg, 575mg, 580mg, 585mg, 590mg, 595mg, 600mg, 605mg, 610mg, 615mg, 620mg, 625mg, 630mg, 635mg, 640mg, 645mg, 650mg, 65 5mg, 660mg, 665mg, 670mg, 675mg, 680mg, 685mg, 690mg, 695mg, 700mg, 705mg, 710mg, 715mg, 720mg, 725mg, 730mg, 735mg, 740mg, 745mg, 750mg, 755mg, 760mg, 765mg, 770mg, 775mg , 780mg, 785mg, 790mg, 795mg, 800mg, 805mg, 810mg, 815mg, 820mg, 825mg, 830mg, 835mg, 840mg, 845mg, 850mg, 855mg, 860mg, 865mg, 870mg, 875mg, 880mg, 885mg, 890mg, 895mg, 900mg 905mg, 910mg, 915mg, 920mg, 925mg, 930mg, 935mg, 940mg, 945mg, 950mg, 955mg, 960mg, 965mg, 970mg, 975mg, 980mg, 985mg, 990mg, 995mg, 1000mg, 1005mg, 1010mg, 1015mg, 1020mg, 1025mg 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105 mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg, 1145 mg, 1150 mg 1,155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg, 1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg 1250mg.

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之來那度胺，其中來那度胺之該治療有效量為約2.5mg至約25mg。 In some embodiments, a method is provided comprising administering to a patient in need thereof a therapeutically effective amount of lenalidomide, wherein the therapeutically effective amount of lenalidomide is from about 2.5 mg to about 25 mg.

在一些實施例中，所提供之方法包含向有需要之患者投與治療有效量之來那度胺，其中來那度胺之該治療有效量為約2.5mg至約25mg、或約2.5mg至約20mg、或約2.5mg至約15mg、或約2.5mg至約10mg、或約2.5mg至約7.5mg、或約2.5mg至約5mg、或約5mg至約25mg、或約5mg至約20mg、或約5mg至約15mg、或約5mg至約10mg、或約5mg至約7.5mg、或約7.5mg至約25mg、或約7.5mg至約20mg、或約7.5mg至約15mg、或約7.5mg至約10mg、或約10mg至 約25mg、或約10mg至約20mg、或約10mg至約15mg、或約15mg至約25mg、或約15mg至約20mg、或約20mg至約25mg。 In some embodiments, the methods provided comprise administering to a patient in need thereof a therapeutically effective amount of lenalidomide, wherein the therapeutically effective amount of lenalidomide is from about 2.5 mg to about 25 mg, or about 2.5 mg to About 20 mg, or about 2.5 mg to about 15 mg, or about 2.5 mg to about 10 mg, or about 2.5 mg to about 7.5 mg, or about 2.5 mg to about 5 mg, or about 5 mg to about 25 mg, or about 5 mg to about 20 mg, Or from about 5 mg to about 15 mg, or from about 5 mg to about 10 mg, or from about 5 mg to about 7.5 mg, or from about 7.5 mg to about 25 mg, or from about 7.5 mg to about 20 mg, or from about 7.5 mg to about 15 mg, or about 7.5 mg To about 10 mg, or about 10 mg to About 25 mg, or from about 10 mg to about 20 mg, or from about 10 mg to about 15 mg, or from about 15 mg to about 25 mg, or from about 15 mg to about 20 mg, or from about 20 mg to about 25 mg.

在一些實施例中，所提供之方法包含向有需要之患者投與約2.5mg、5mg、約7.5mg、10mg、15mg、20mg、25mg之來那度胺。 In some embodiments, the methods provided comprise administering about 2.5 mg, 5 mg, about 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg of lenalidomide to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與包含單位劑量之化合物1與單位劑量之來那度胺之組合的醫藥組合物。在一些該等實施例中，化合物1之單位劑量為約25mg、約50mg、約75mg、約100mg、約125mg、約150mg、約175mg、約200mg、約225mg或約250mg。 In some embodiments, a method is provided comprising administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1 in combination with a unit dose of lenalidomide. In some such embodiments, the unit dosage of Compound 1 is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

在一些實施例中，來那度胺之單位劑量為約2.5mg、約5mg、約7.5mg、約10mg、約15mg或約25mg。 In some embodiments, the unit dose of lenalidomide is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, or about 25 mg.

在一些實施例中，所提供之方法包含向有需要之患者投與包含利妥昔單抗之醫藥組合物，其中利妥昔單抗以50mg/h之速率以輸注形式投與。在一些實施例中，利妥昔單抗之輸注速率每30分鐘增加50mg/h，達到最大400mg/h。在一些實施例中，利妥昔單抗之輸注速率每30分鐘增加100mg/h，達到最大400mg/h。因此，在一些實施例中，利妥昔單抗之輸注速率為100mg/h。在一些實施例中，利妥昔單抗之輸注速率為150mg/h。在一些實施例中，利妥昔單抗之輸注速率為200mg/h。在一些實施例中，利妥昔單抗之輸注速率為250mg/h。在一些實施例中，利妥昔單抗之輸注速率為300mg/h。在一些實施例中，利妥昔單抗之輸注速率為350mg/h。在一些實施例中，利妥昔單抗之輸注速率為400mg/h。 In some embodiments, a method is provided comprising administering to a patient in need thereof a pharmaceutical composition comprising rituximab, wherein rituximab is administered as an infusion at a rate of 50 mg/h. In some embodiments, the infusion rate of rituximab is increased by 50 mg/h every 30 minutes to a maximum of 400 mg/h. In some embodiments, the infusion rate of rituximab is increased by 100 mg/h every 30 minutes to a maximum of 400 mg/h. Thus, in some embodiments, the infusion rate of rituximab is 100 mg/h. In some embodiments, the infusion rate of rituximab is 150 mg/h. In some embodiments, the infusion rate of rituximab is 200 mg/h. In some embodiments, the infusion rate of rituximab is 250 mg/h. In some embodiments, the infusion rate of rituximab is 300 mg/h. In some embodiments, the infusion rate of rituximab is 350 mg/h. In some embodiments, the infusion rate of rituximab is 400 mg/h.

II.化合物及醫藥學上可接受之組合物的用途II. Use of Compounds and Pharmaceutically Acceptable Compositions

本文所述之化合物1及組合物一般適用於抑制一或多種酶之蛋白激酶活性。由本文所述之化合物1及組合物抑制且本文所述之方法適用之激酶的實例包括BTK及其他TEC-激酶，包括ITK、TEC、BMX及 RLK，或其突變體。 The compounds 1 and compositions described herein are generally suitable for inhibiting the protein kinase activity of one or more enzymes. Examples of kinases that are inhibited by the compounds 1 and compositions described herein and which are suitable for use in the methods described herein include BTK and other TEC-kinases, including ITK, TEC, BMX, and RLK, or mutants thereof.

布魯頓酪胺酸激酶(「BTK」，TEC激酶之成員)為在B淋巴細胞、單核細胞及肥大細胞或嗜鹼性白血球中表現之關鍵信號傳導酶。BTK在連接細胞表面B細胞受體(BCR)刺激與下游細胞內反應的B細胞信號傳導路徑中發揮必要作用。 Bruton tyrosine kinase ("BTK", a member of TEC kinase) is a key signaling enzyme that is expressed in B lymphocytes, monocytes, and mast cells or basophils. BTK plays an essential role in the B cell signaling pathway that links cell surface B cell receptor (BCR) stimulation with downstream intracellular responses.

BTK為B細胞發育、活化、信號傳導及存活之關鍵調節劑(Kurosaki,Curr.Op.Imm.,2000,276-281；Schaeffer及Schwartzberg,Curr.Op.Imm.2000,282-288)。此外，BTK在許多其他造血細胞信號傳導路徑中起作用，例如巨噬細胞中之Toll樣受體(Toll like receptor；TLR)及細胞激素受體介導之TNF-α產生、肥大細胞中之IgE受體(Fc_ε_RI)信號傳導、抑制B譜系淋巴樣細胞中之Fas/APO-1細胞凋亡信號傳導、及膠原蛋白刺激之血小板凝集。參見例如C.A.Jeffries，等人，(2003),Journal of Biological Chemistry 278：26258-26264；N.J.Horwood，等人，(2003),The Journal of Experimental Medicine 197：1603-1611；Iwaki等人(2005),Journal of Biological Chemistry 280(48)：40261-40270；Vassilev等人(1999),Journal of Biological Chemistry 274(3)：1646-1656及Quek等人(1998),Current Biology 8(20)：1137-1140。 BTK is a key regulator of B cell development, activation, signaling and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op . Imm . 2000, 282-288). In addition, BTK plays a role in many other hematopoietic signaling pathways, such as Toll like receptor (TLR) in macrophages and cytokine receptor-mediated TNF-α production, IgE in mast cells. Receptor (Fc_ε_RI) signaling, inhibition of Fas/APO-1 cell apoptosis signaling in B lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, for example, CA Jeffries, et al, (2003), Journal of Biological Chemistry 278: 26258-26264; NJ Horwood, et al, (2003), The Journal of Experimental Medicine 197: 1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48): 40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3): 1646-1656 and Quek et al. (1998), Current Biology 8(20): 1137-1140.

具有BTK遺傳失活突變之患者在B細胞發育方面具有極大阻礙，導致幾乎完全不存在成熟B淋巴細胞及漿細胞，嚴重減少Ig含量且極大地抑制對回憶抗原之體液性反應(在Vihinen等人Frontiers in Bioscience 5：d917-928中有評述)。缺乏BTK之小鼠亦具有減少的周邊B細胞數量及大為降低的IgM及IgG3血清含量。小鼠缺失BTK對由抗IgM誘發之B細胞增殖具有極大影響，且抑制對於非胸腺依賴性II型抗原的免疫反應(Ellmeier等人，J Exp Med 192：1611-1623(2000))。BTK亦在經由高親和力IgE受體(Fc_ε_RI)活化肥大細胞中發揮關鍵作用。 BTK缺陷型鼠類肥大細胞在Fc_ε_RI交聯後減少脫粒作用且降低促炎性細胞激素產生(Kawakami等人Journal of Leukocyte Biology 65：286-290)。 Patients with BTK genetically inactivating mutations have significant barriers to B cell development, resulting in the almost complete absence of mature B lymphocytes and plasma cells, severely reducing Ig content and greatly inhibiting humoral responses to recall antigens (in Vihinen et al. Frontiers in Bioscience 5: reviewed in d917-928). Mice lacking BTK also had a reduced number of peripheral B cells and a greatly reduced serum IgM and IgG3 levels. Deletion of BTK in mice has a profound effect on anti-IgM-induced B cell proliferation and inhibits immune responses to non-thymus-dependent type II antigens (Ellmeier et al, J Exp Med 192:1611-1623 (2000)). BTK also plays a key role in the activation of mast cells via the high affinity IgE receptor (Fc_ε_RI). BTK-deficient murine mast cells reduce degranulation and reduce pro-inflammatory cytokine production following Fc_ε_RI cross-linking (Kawakami et al . Journal of Leukocyte Biology 65: 286-290).

化合物1為BTK抑制劑且因此適用於治療一或多種與BTK活性相關之失調。因此，在一些實施例中，本發明提供一種治療、穩定或減輕BTK介導之失調之嚴重程度或進展的方法，包含向有需要之患者投與化合物1與來那度胺之組合的步驟。 Compound 1 is a BTK inhibitor and is therefore suitable for the treatment of one or more disorders associated with BTK activity. Accordingly, in some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a BTK mediated disorder comprising the step of administering a combination of Compound 1 and lenalidomide to a patient in need thereof.

慢性淋巴球性白血病及小淋巴球性淋巴瘤Chronic lymphocytic leukemia and small lymphocytic lymphoma

B細胞失調慢性淋巴球性白血病(CLL)及小淋巴球性淋巴瘤(SLL)表示在血液/骨髓受累(CLL)與淋巴結受累(SLL)程度上有差異之同一疾病過程範圍的兩端。CLL為藉由形態上成熟但功能上不全的淋巴細胞在血液、骨髓及淋巴組織中之進行性積聚表徵的淋巴球增生惡性腫瘤。其主要影響中值年齡表現為65至70歲的年長個體。CLL之臨床過程介於長期存活超過12年的惰性疾病至中值存活期為2年之侵襲性疾病。 B cell dysregulation Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) indicate both ends of the same disease process range where blood/bone marrow involvement (CLL) and lymph node involvement (SLL) differ. CLL is a lymphoid proliferative malignancy characterized by progressive accumulation of morphologically mature but functionally incomplete lymphocytes in blood, bone marrow, and lymphoid tissues. It mainly affects older individuals with a median age of 65 to 70 years. The clinical course of CLL is between invasive disease with a long-term survival of more than 12 years and a median survival of 2 years.

慢性淋巴球性白血病為美國最常見的白血病且通常以免疫表型方式表徵為CD5+、CD23+、CD10-、CD19+、CD20弱表現(dim)、sIg弱表現及細胞週期素D1-(後者指出與套細胞淋巴瘤之區別特徵)。慢性淋巴球性白血病亦必須與單株B淋巴球增多區別開(絕對單株B細胞計數<5000/μL且不存在腺病或淋巴球增生失調之其他臨床特徵)。近來，已由Lanasa、Furman及美國國家綜合癌症網絡(National Comprehensive Cancer Network)NHL專門小組回顧瞭解CLL/SLL生物學及預後因素，及在制定危險分層方法以治療CLL/SLL方面的進步。 Chronic lymphocytic leukemia is the most common leukemia in the United States and is usually characterized by immunophenotype as CD5+, CD23+, CD10-, CD19+, CD20 weak manifestation (dim), sIg weak manifestation, and cyclin D1- (the latter indicated with the set) The distinguishing feature of cell lymphoma). Chronic lymphocytic leukemia must also be distinguished from single B lymphocytosis (absolute single B cell count <5000/μL and no other clinical features of adenosis or lymphocytosis disorders). Recently, Lanasa, Furman, and the National Comprehensive Cancer Network NHL panel have reviewed the biology and prognostic factors of CLL/SLL and the advances in the development of a risk stratification approach to treat CLL/SLL.

Btk之細胞表現受限且主要限於B淋巴細胞、單核細胞及肥大細胞或嗜鹼性白血球。調查研究已顯示一些B細胞淋巴瘤及CLL/SLL依賴於BCR信號傳導，表明中斷該信號傳導可為有前景之治療機遇。近 來，已報導所有CLL中之一半保有活體外BCR信號傳導，且免疫球蛋白重鏈基因體細胞突變(IgVH)為BCR反應之重要決定因素。實際上，CLL中BCR之突變狀態為疾病進展最有力之預測因子之一，因為侵襲性疾病通常顯示由未突變免疫球蛋白可變重鏈編碼之BCR。 The cell expression of Btk is limited and is mainly limited to B lymphocytes, monocytes and mast cells or basophils. Investigations have shown that some B-cell lymphomas and CLL/SLL are dependent on BCR signaling, suggesting that disrupting this signaling may be a promising therapeutic opportunity. near In addition, one of the CLLs has been reported to have in vitro BCR signaling, and immunoglobulin heavy chain gene somatic mutation (IgVH) is an important determinant of BCR response. In fact, the mutation status of BCR in CLL is one of the most powerful predictors of disease progression, as invasive disease usually shows a BCR encoded by an unmutated immunoglobulin variable heavy chain.

兩組已報導突變及未突變CLL細胞區別響應於BCR之IgM連接，其中未突變(而非突變)CLL細胞藉由增加總體酪胺酸磷酸化及上調幾個與細胞週期調節相關之基因而響應於BCR刺激，且允許細胞生長及擴增。此等資料突出BCR信號傳導在CLL生理機能方面發揮之有差異的作用依賴於IgVH突變狀態，且可表明CLL對BCR信號傳導抑制劑之反應可能有差異。其他活體外研究已報導使用研究中藥劑PCI-32765之特異性Btk抑制在CLL細胞中產生實質上相對於正常B細胞更多的細胞凋亡及細胞毒性；以及面臨抗細胞凋亡微環境信號誘發細胞凋亡，減少趨化因子CCL3及CCL4之分泌，及減少朝著趨化因子CXCL12及CXCL13之趨化性。尚未報導Btk在WM之來源及/或維持中之病理生理作用的詳細研究。然而，調查研究轉殖基因小鼠模型之最新報導顯示組成性活性Btk表現引起B-1細胞之選擇性擴增或存活，驅使生發中心非依賴性漿細胞分化，如由脾臟及骨髓中之IgM+漿細胞數目增加及顯著升高的血清IgM所證明。亦觀測到抗核小體自體抗體及腎小球IgM沈積。然而，對19名患有低伽瑪球蛋白血症G及/或A之WM患者的一個序列分析研究未能發現Btk之啟動子、側翼內含子或外顯子之任何新穎變體。 Mutant and unmutated CLL cells have been reported to be differentially responsive to ICR junctions in BCR, in which unmutated (rather than mutated) CLL cells respond by increasing overall tyrosine phosphorylation and up-regulating several genes involved in cell cycle regulation. Stimulated by BCR and allowed for cell growth and expansion. These data highlight the differential role of BCR signaling in the physiological function of CLL depending on the IgVH mutation status and may indicate that CLL may have a different response to BCR signaling inhibitors. Other in vitro studies have reported that the specific Btk inhibition of the agent PCI-32765 in the study produces more apoptosis and cytotoxicity in CLL cells than in normal B cells; and is induced by anti-apoptotic microenvironmental signals. Apoptosis, reduced secretion of chemokines CCL3 and CCL4, and decreased chemotaxis toward the chemokines CXCL12 and CXCL13. A detailed study of the pathophysiological effects of Btk in the source and/or maintenance of WM has not been reported. However, a recent report investigating the transgenic mouse model shows that constitutively active Btk expression causes selective expansion or survival of B-1 cells, driving germinal center-independent plasma cell differentiation, such as IgM+ in the spleen and bone marrow. Increased plasma cell numbers and significantly elevated serum IgM were demonstrated. Anti-nucleosome autoantibodies and glomerular IgM deposition were also observed. However, a sequence analysis study of 19 WM patients with low gamma globulinemia G and/or A failed to find any novel variants of the Btk promoter, flanking intron or exon.

同種異體幹細胞移植為唯一可能治癒CLL之治療，但70%之患病患者在診斷出時65歲，患有限制該療法適用性之併發病狀，且可在存在或不存在特異性治療之情況下顯示出延長的自然病史。CLL之實際預後可變且主要視臨床階段及某些遺傳及分子特徵而定。Rai及Binet臨床分期系統能夠以範圍介於最晚期(血小板減少)之19個月至最 早期(無腺病、內臟增大或所界定之貧血/血小板減少之血液及骨髓淋巴球增多)之>150個月之中值OS區分患者預後組。藉由IgVH之存在或不存在及藉由探查後天性染色體異常之間期螢光原位雜交(iFISH)分析分類增加額外預後鑑別以便臨床分期，其中未突變之IgVH及del(11q)及del(17p)細胞遺傳學預示較不良的結果。 Allogeneic stem cell transplantation is the only treatment that may cure CLL, but 70% of patients are diagnosed 65 years old, suffering from a combined disease that limits the applicability of the therapy, and exhibits an extended natural history in the presence or absence of specific treatment. The actual prognosis of CLL is variable and depends primarily on the clinical stage and certain genetic and molecular characteristics. The Rai and Binet clinical staging systems are able to range from the most advanced (thrombocytopenia) from 19 months to the earliest (no adenosis, visceral enlargement or defined anemia/thrombocytopenia in blood and bone marrow lymphocytes) The 150-month median OS differentiated the patient prognosis group. Additional prognostic differentiation was added for clinical staging by the presence or absence of IgVH and by profiling of inferior fluorescence in situ hybridization (iFISH) analysis of acquired chromosomal abnormalities, with unmutated IgVH and del(11q) and del ( 17p) Cytogenetics predicts poorer results.

CLL治療策略複雜且需要首先決定治療(例如存在諸如疲勞或盜汗；大體積腺病/內臟增大；進行性貧血/血小板減少之症狀)；且其次選擇治療方案，一般涉及以下一或多者：嘌呤核苷(氟達拉濱)、烷基化劑(環磷醯胺、苯丁酸氮芥(chlorambucil)、苯達莫司汀)、皮質類固醇、抗CD20單株抗體(利妥昔單抗/奧法木單抗)或抗CD52單株抗體(阿倫單抗(alemtuzumab))。特異性療法之選擇視患者年齡、疾病模式(例如主要為結點與非結點)、預期耐藥性及禁忌，以及存在或不存在不利預後特徵(諸如del(11q)或del(17p))而定。儘管有許多療法，但治療選項最終受藥物毒性及耐受性限制，且未死於其他病之患者忍受與血細胞減少症有關之進行性併發症、淋巴腺病及內臟增大之影響、全身性症狀及感染性併發症。考慮到患者群體常常年老的特徵，利用CLL之新弱點之經口可用、良好耐受之治療應為受歡迎的。 CLL treatment strategies are complex and require first treatment (eg, such as fatigue or night sweats; large adenopathy/visceral enlargement; symptoms of progressive anemia/thrombocytopenia); and second choice of treatment options, generally involving one or more of the following: Purine nucleoside (fludarabine), alkylating agent (cyclophosphamide, chlorambucil, bendamustine), corticosteroids, anti-CD20 monoclonal antibody (rituximab) /ofolimumab) or anti-CD52 monoclonal antibody (alemtuzumab). The choice of specific therapy depends on the patient's age, disease patterns (eg, primarily node and non-node), expected drug resistance and contraindications, and the presence or absence of adverse prognostic features (such as del(11q) or del(17p)) And set. Although there are many therapies, the treatment options are ultimately limited by drug toxicity and tolerance, and patients who have not died of other diseases endure the progressive complications associated with cytopenia, lymphadenopathy and visceral enlargement, systemic Symptoms and infectious complications. Given the ageing characteristics of patient populations, oral and well tolerated treatments that exploit the new weaknesses of CLL should be welcome.

在CLL及SLL中靶向Btk之基本原理及與來那度胺之組合The basic principle of targeting Btk in CLL and SLL and its combination with lenalidomide

特異性靶向B細胞之策略(例如B細胞耗盡抗CD20單株抗體利妥昔單抗及奧法木單抗)已在B細胞淋巴瘤及CLL中顯示臨床功效。脾臟酪胺酸激酶(Syk)為BCR信號傳導路徑中接近於Btk之激酶。使用經口可用的Syk抑制劑福他替尼二鈉(fostamatinib disodium)抑制Syk在DLBCL、CLL及套細胞淋巴瘤中產生臨床反應。最有說服力的是，Btk抑制概念之臨床證據已藉由經口可用Btk抑制劑PCI-32765之臨床調查顯示，該等臨床調查已報導患有DLBCL；套細胞、邊緣區/黏膜相關淋巴組織(MALT)及濾泡性淋巴瘤(FL)、瓦爾登斯特倫巨球蛋白 血症(Waldenstrom's macroglobulinemia，WM)及CLL/SLL之患者的客觀抗腫瘤反應及良好耐受性。 Strategies that specifically target B cells (eg, B cell depletion of the anti-CD20 monoclonal antibody rituximab and orfarizumab) have shown clinical efficacy in B cell lymphoma and CLL. Spleen tyrosine kinase (Syk) is a kinase close to Btk in the BCR signaling pathway. The use of the orally available Syk inhibitor fostamatinib disodium inhibits the clinical response of Syk in DLBCL, CLL and mantle cell lymphoma. Most convincingly, the clinical evidence for the concept of Btk inhibition has been shown by clinical investigation of the orally available Btk inhibitor PCI-32765, which has been reported to have DLBCL; mantle cells, marginal/mucosa-associated lymphoid tissue (MALT) and follicular lymphoma (FL), Waldenstrom macroglobulin Objective anti-tumor response and good tolerance of patients with blood (Waldenstrom's macroglobulinemia, WM) and CLL/SLL.

因此，基於經由Btk介導之BCR信號傳導對於各種惡性B細胞之存活及增殖的關鍵重要性；B細胞、巨噬細胞及單核細胞中Btk之限制性細胞表現；及所顯示之Btk抑制產生有益抗淋巴瘤、CLL及WM效應及可接受之臨床耐受性之觀念的臨床前及早期臨床證據，使用選擇性Btk抑制劑靶向Btk為有前景的且適於進一步臨床調查研究之治療策略。最新研究中已展示化合物1(以其苯磺酸鹽形式)作為單一治療劑安全且針對CLL有效。到2012年9月11日為止，43名CLL患者中之35名的疾病已穩定且繼續用N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽單一療法治療。23名患者中之15名的淋巴結尺寸已減小，且33名患者中之28名的絕對淋巴細胞計數(ALC)已及早增加。參見美國專利申請案第13/661,678號及國際專利申請案第PCT/US2012/062133號，兩者皆於2012年10月26日申請，其各自特此以全文引用的方式併入。該資料強烈支持使用BTK抑制劑且尤其化合物1來治療CLL。化合物1作為單一藥劑一般在高達750mgPO QD下得到良好耐受且尚未達到最大耐受劑量(MTD)。研究仍在進行中且目前正在調查研究之額外劑量包括：1000mg QD、1250mg QD、375mg BID及500mg BID。亦已展示來那度胺顯示出針對復發性/難治性CLL患者之良好活性。 Therefore, based on the critical importance of Btk-mediated BCR signaling for the survival and proliferation of various malignant B cells; restricted cell expression of Btk in B cells, macrophages and monocytes; and the shown inhibition of Btk production Preclinical and early clinical evidence for the concept of anti-lymphoma, CLL and WM effects and acceptable clinical tolerance, targeting Btk with selective Btk inhibitors is a promising therapeutic strategy for further clinical investigations . Compound 1 (in its besylate form) has been shown to be safe as a single therapeutic agent and effective against CLL in the latest studies. As of September 11, 2012, 35 of 43 CLL patients had stable disease and continued to use N- (5-fluoro-2-(4-(2-methoxyethoxy)aniline) Monopyridyl-4-pyrimidinyl)phenyl)propenylamine besylate monotherapy. The lymph node size of 15 of the 23 patients has decreased, and the absolute lymphocyte count (ALC) of 28 of the 33 patients has increased early. See U.S. Patent Application Serial No. 13/661,678, the disclosure of which is hereby incorporated by reference in its entirety in its entirety in the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all all all all all This data strongly supports the use of BTK inhibitors and in particular Compound 1 to treat CLL. Compound 1 as a single agent is generally well tolerated up to 750 mg PO QD and has not yet reached the maximum tolerated dose (MTD). Additional doses that are still under investigation and currently under investigation include: 1000 mg QD, 1250 mg QD, 375 mg BID, and 500 mg BID. Lenalidomide has also been shown to exhibit good activity against patients with relapsed/refractory CLL.

亦已展示利妥昔單抗顯示出針對復發性/難治性CLL患者之良好活性。在一項研究中，在408名CLL患者中評估利妥昔單抗、氟達拉濱及環磷醯胺且展示86%之反應率，與關於氟達拉濱/環磷醯胺單獨所觀測到之73%反應率相比。中值無進展存活期為39.8個月，與關於氟達拉濱/環磷醯胺單獨所觀測到之31.5個月相比。 Rituximab has also been shown to exhibit good activity against patients with relapsed/refractory CLL. In one study, rituximab, fludarabine, and cyclophosphamide were evaluated in 408 CLL patients and demonstrated a 86% response rate as observed with fludarabine/cyclophosphamide alone. Compared to the 73% response rate. The median progression-free survival was 39.8 months compared to 31.5 months observed for fludarabine/cyclophosphamide alone.

因此，在一些實施例中，本發明涵蓋諸如化合物1之BTK抑制劑 與來那度胺之組合適用於治療CLL及SLL之認知。在一些實施例中，本發明涵蓋諸如化合物1之BTK抑制劑連同來那度胺及利妥昔單抗一起適用於治療CLL及SLL之認知。可發現化合物1作為單一藥劑或以組合形式均對CLL患者有效，該等CLL患者包括(但不限於)已表現以下預後/遺傳標記及細胞遺傳風險因素中之一或多者的患者：染色體11q、17p或13q缺失、或第12對染色體三體症(Trisomy 12)及第14q對染色體三體症、ζ鏈締合之蛋白激酶70(ZAP 70)或免疫球蛋白重鏈可變區(IgVH)未突變。 Thus, in some embodiments, the invention contemplates the use of a combination of a BTK inhibitor such as Compound 1 and lenalidomide for the treatment of CLL and SLL. In some embodiments, the invention contemplates the use of a BTK inhibitor such as Compound 1 in combination with lenalidomide and rituximab for the treatment of CLL and SLL. Compound 1 can be found to be effective as a single agent or in combination for patients with CLL, including but not limited to patients who have demonstrated one or more of the following prognosis/genetic markers and cytogenetic risk factors: chromosome 11q , 17p or 13q deletion, or 12th trisomy 13 (Trisomy 12) and 14q versus trisomy, ζ chain associated protein kinase 70 (ZAP 70) or immunoglobulin heavy chain variable region (IgVH ) No mutation.

在一些實施例中，本發明涵蓋以下認知：來那度胺及Btk抑制劑在彌漫性大B細胞淋巴瘤(DLBCL)模型中為協同的，或許由於兩種藥劑對IκB激酶(IKK)及下游核因子κB(NFkB)信號傳導之伴隨性抑制。因此，本發明提供治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與化合物1與來那度胺之組合。在一些實施例中，所提供之方法另外包含向有需要之患者投與利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1、來那度胺及利妥昔單抗中之每一者。 In some embodiments, the invention encompasses the recognition that lenalidomide and a Btk inhibitor are synergistic in a diffuse large B-cell lymphoma (DLBCL) model, perhaps due to the two agents acting against IκB kinase (IKK) and downstream Concomitant inhibition of nuclear factor kappa B (NFkB) signaling. Accordingly, the present invention provides a method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-associated diseases and conditions, comprising administering a combination of Compound 1 and lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering rituximab to a patient in need thereof. In some embodiments, the methods provided comprise administering to each of the patients in need, Compound 1 , lenalidomide, and rituximab.

III.治療與BTK相關之疾病或失調的方法III. Methods of treating diseases or disorders associated with BTK

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與化合物1與來那度胺之組合。在一些實施例中，所提供之方法另外包含向有需要之患者投與利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1、來那度胺及利妥昔單抗中之每一者。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered a combination of Compound 1 and lenalidomide. In some embodiments, the methods provided additionally comprise administering rituximab to a patient in need thereof. In some embodiments, the methods provided comprise administering to each of the patients in need, Compound 1 , lenalidomide, and rituximab.

在一些實施例中，本發明提供化合物1與來那度胺之組合，其中該組合顯示協同效應。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中所投與之化合物1及/或 來那度胺之量小於在各別治療方案給藥時一種或兩種化合物之投與量。在一些實施例中，所提供之方法另外包含向有需要之患者投與利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與治療劑化合物1、來那度胺及利妥昔單抗中之每一者，其中該等治療劑顯示協同效應。 In some embodiments, the invention provides a combination of Compound 1 and lenalidomide, wherein the combination exhibits a synergistic effect. In some embodiments, the methods provided comprise administering a combination of Compound 1 and lenalidomide to a patient in need thereof, wherein the amount of Compound 1 and/or lenalidomide administered is less than in each of the treatment regimens The amount of one or both compounds administered at the time of administration. In some embodiments, the methods provided additionally comprise administering rituximab to a patient in need thereof. In some embodiments, a method is provided comprising administering to a patient in need thereof each of the therapeutic agents Compound 1 , Lenalidomide, and Rituximab, wherein the therapeutic agents exhibit a synergistic effect.

在一些實施例中，所提供之方法包含向有需要之患者投與包含化合物1之組合物與包含來那度胺之組合物之組合。在一些實施例中，所提供之方法另外包含向有需要之患者投與包含利妥昔單抗之組合物。在一些實施例中，所提供之方法包含向有需要之患者投與包含化合物1、來那度胺及利妥昔單抗中之每一者之組合物。 In some embodiments, the methods provided comprise administering to a patient in need, a combination comprising a composition comprising Compound 1 and a composition comprising lenalidomide. In some embodiments, the methods provided additionally comprise administering to a patient in need thereof a composition comprising rituximab. In some embodiments, a method is provided comprising administering to a patient in need thereof a composition comprising each of Compound 1 , Lenalidomide, and Rituximab.

在一些實施例中，包含化合物1之組合物另外包含一或多種醫藥學上可接受之賦形劑。在一些該等實施例中，將包含化合物1之組合物調配成口服劑型。在一些實施例中，口服劑型為膠囊。 In some embodiments, the composition comprising Compound 1 additionally comprises one or more pharmaceutically acceptable excipients. In some of these embodiments, the composition comprising Compound 1 is formulated into an oral dosage form. In some embodiments, the oral dosage form is a capsule.

在一些實施例中，包含來那度胺之組合物另外包含一或多種醫藥學上可接受之賦形劑。在一些該等實施例中，將包含來那度胺之組合物調配成口服劑型。在一些實施例中，口服劑型為膠囊。 In some embodiments, the composition comprising lenalidomide additionally comprises one or more pharmaceutically acceptable excipients. In some of these embodiments, the composition comprising lenalidomide is formulated into an oral dosage form. In some embodiments, the oral dosage form is a capsule.

在一些實施例中，化合物1與來那度胺之組合以單一醫藥學上可接受之組合物形式投與。 In some embodiments, the compound 1 in combination with an amine of lenalidomide in combination on a single pharmaceutically acceptable composition is administered.

在一些實施例中，所提供之方法包含向有需要之患者投與單位劑量之化合物1與單位劑量之來那度胺之組合。在一些實施例中，所提供之方法另外包含向有需要之患者投與單位劑量之利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與單位劑量之化合物1、單位劑量之來那度胺及單位劑量之利妥昔單抗。在一些實施例中，所提供之方法另外包含向有需要之患者投與單位劑量之利妥昔單抗。在一些實施例中，化合物1之單位劑量為約25mg、約50mg、約75mg、約100mg、約125mg、約150mg、約175mg、約200mg、 約225mg或約250mg。在一些實施例中，來那度胺之單位劑量為約2.5mg、約5mg、約7.5mg、約10mg、約15mg或約25mg。 In some embodiments, a method is provided comprising administering a unit dose of Compound 1 to a unit dose of lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering a unit dose of rituximab to a patient in need thereof. In some embodiments, the methods provided comprise administering a unit dose of Compound 1 , a unit dose of lenalidomide, and a unit dose of rituximab to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering a unit dose of rituximab to a patient in need thereof. In some embodiments, the unit dosage of Compound 1 is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg. In some embodiments, the unit dose of lenalidomide is about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, or about 25 mg.

在一些實施例中，所提供之方法包含向有需要之患者投與包含利妥昔單抗之醫藥組合物，其中利妥昔單抗以50mg/h之速率以輸注形式投與。在一些實施例中，利妥昔單抗之輸注速率每30分鐘增加50mg/h，達到最大400mg/h。在一些實施例中，利妥昔單抗之輸注速率每30分鐘增加100mg/h，達到最大400mg/h。因此，在一些實施例中，利妥昔單抗之輸注速率為100mg/h。在一些實施例中，利妥昔單抗之輸注速率為150mg/h。在一些實施例中，利妥昔單抗之輸注速率為200mg/h。在一些實施例中，利妥昔單抗之輸注速率為250mg/h。 在一些實施例中，利妥昔單抗之輸注速率為300mg/h。在一些實施例中，利妥昔單抗之輸注速率為350mg/h。在一些實施例中，利妥昔單抗之輸注速率為400mg/h。 In some embodiments, a method is provided comprising administering to a patient in need thereof a pharmaceutical composition comprising rituximab, wherein rituximab is administered as an infusion at a rate of 50 mg/h. In some embodiments, the infusion rate of rituximab is increased by 50 mg/h every 30 minutes to a maximum of 400 mg/h. In some embodiments, the infusion rate of rituximab is increased by 100 mg/h every 30 minutes to a maximum of 400 mg/h. Thus, in some embodiments, the infusion rate of rituximab is 100 mg/h. In some embodiments, the infusion rate of rituximab is 150 mg/h. In some embodiments, the infusion rate of rituximab is 200 mg/h. In some embodiments, the infusion rate of rituximab is 250 mg/h. In some embodiments, the infusion rate of rituximab is 300 mg/h. In some embodiments, the infusion rate of rituximab is 350 mg/h. In some embodiments, the infusion rate of rituximab is 400 mg/h.

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與化合物1與來那度胺之組合，其中該患者已失敗至少一個先前療法。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1、來那度胺及利妥昔單抗中之每一者，其中該患者已失敗至少一個先前療法。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered a combination of Compound 1 and lenalidomide, wherein the patient has failed at least one prior therapy. In some embodiments, a method is provided comprising administering to a patient in need thereof each of Compound 1 , lenalidomide, and rituximab, wherein the patient has failed at least one prior therapy.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg至約1250mg化合物1與約2.5mg至約25mg來那度胺之組合。在一些實施例中，所提供之方法包含向有需要之患者投與約500mg至約1250mg化合物1與約2.5mg至約25mg來那度胺之組合。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg至約1250mg化合物1、約2.5mg至約25mg來那度胺及約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering to a patient in need thereof a combination of from about 250 mg to about 1250 mg of Compound 1 and from about 2.5 mg to about 25 mg of lenalidomide. In some embodiments, the methods provided comprise administering to a patient in need thereof a combination of from about 500 mg to about 1250 mg of Compound 1 and from about 2.5 mg to about 25 mg of lenalidomide. In some embodiments, the methods provided comprise administering from about 250 mg to about 1250 mg of Compound 1 , from about 2.5 mg to about 25 mg of lenalidomide, and from about 375 mg/m 2 to about 500 mg/m 2 of lysine to a patient in need thereof. Waximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約2.5mg至約10mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約2.5mg至約15mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約5mg至約10mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約5mg至約15mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約7.5mg至約10mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約7.5mg至約15mg來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約750mg至約1000mg化合物1及約10mg至約15mg來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 2.5 mg to about 10 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 2.5 mg to about 15 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 5 mg to about 10 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 5 mg to about 15 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 7.5 mg to about 10 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 7.5 mg to about 15 mg of lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from about 750 mg to about 1000 mg of Compound 1 and from about 10 mg to about 15 mg of lenalidomide to a patient in need thereof. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1與約2.5mg QD至約15mg QD來那度胺之組合。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1、約2.5mg QD至約15mg QD來那度胺及約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered a combination of about 125 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 500 mg BID Compound 1 , about 2.5 mg QD to about 15 mg QD lenalidomide, and about 375 mg/m 2 to about 500 mg/ m 2 rituximab.

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與約125mg BID至 約500mg BID化合物1與約5mg QD至約15mg QD來那度胺之組合。 在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1、約2.5mg QD至約15mg QD來那度胺及約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered a combination of about 125 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab. In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising the patient administered from about 125mg BID and 500mg BID compound to about 1, to about 2.5mg QD about 15mg QD lenalidomide and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約500mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125 mg BID至約500mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 500 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約375mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 375 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約125 mg BID至約250mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID至約250mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg BID to about 250 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 125 mg BID to about 250 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 125 mg BID to about 250 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 125 mg BID to about 250 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide. In some embodiments, the methods provided comprise administering to a patient in need thereof about 125 mg BID to about 250 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250 mg BID至約500mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約500mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 250 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 250 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 500 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250 mg BID至約375mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID至約375mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 250 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 250 mg BID to about 375 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering to a patient in need thereof about 250 mg BID to about 375 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約2.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約2.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約2.5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約2.5mg QD至約5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375 mg BID至約500mg BID化合物1及約5mg QD至約7.5mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約7.5mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約7.5mg QD至約10mg QD來那度胺。在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID至約500mg BID化合物1及約10mg QD至約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2至約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 10 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 2.5 mg QD to about 5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from a patient in need thereof about 375 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 10 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 5 mg QD to about 7.5 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided comprise administering from a patient in need thereof about 375 mg BID to about 500 mg BID Compound 1 and about 7.5 mg QD to about 10 mg QD lenalidomide. In some embodiments, the methods provided comprise administering about 375 mg BID to about 500 mg BID Compound 1 and about 10 mg QD to about 15 mg QD lenalidomide to a patient in need thereof. In some embodiments, the method further comprising providing to a patient in need there of administration and about 375mg / m 2 to about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID化合物1及約2.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg of BID Compound 1 and about 2.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID化合物1及約5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg of BID Compound 1 and about 5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID化合物1及約7.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg of BID Compound 1 and about 7.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the method provided further comprises administering to a patient in need of and about 375mg / m 2 or from about 500mg / m 2 rituximab.

在一些實施例中，所提供之方法包含向有需要之患者投與約125mg BID化合物1及約10mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg of BID Compound 1 and about 10 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約125 mg BID化合物1及約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 125 mg of BID Compound 1 and about 15 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID化合物1及約2.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg of BID Compound 1 and about 2.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID化合物1及約5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg of BID Compound 1 and about 5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID化合物1及約7.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg of BID Compound 1 and about 7.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID化合物1及約10mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg of BID Compound 1 and about 10 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約250mg BID化合物1及約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 250 mg of BID Compound 1 and about 15 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID化合物1及約2.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥 昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg of BID Compound 1 and about 2.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID化合物1及約5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg of BID Compound 1 and about 5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID化合物1及約7.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg of BID Compound 1 and about 7.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID化合物1及約10mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg of BID Compound 1 and about 10 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約375mg BID化合物1及約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 375 mg of BID Compound 1 and about 15 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約500mg BID化合物1及約2.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 500 mg of BID Compound 1 and about 2.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約500mg BID化合物1及約5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 500 mg of BID Compound 1 and about 5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約500 mg BID化合物1及約7.5mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 500 mg of BID Compound 1 and about 7.5 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約500mg BID化合物1及約10mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 500 mg of BID Compound 1 and about 10 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，所提供之方法包含向有需要之患者投與約500mg BID化合物1及約15mg QD來那度胺。在一些實施例中，所提供之方法另外包含向有需要之患者投與約375mg/m2或約500mg/m2利妥昔單抗。 In some embodiments, the methods provided comprise administering about 500 mg of BID Compound 1 and about 15 mg of QD lenalidomide to a patient in need thereof. In some embodiments, the methods provided additionally comprise administering about 375 mg/m 2 or about 500 mg/m 2 of rituximab to a patient in need thereof.

在一些實施例中，經28個連續日(「28天週期」)之時間投與化合物1與來那度胺之組合。在一些實施例中，投與化合物1與來那度胺之組合兩個、三個、四個、五個或六個28天週期。在一些實施例中，投與化合物1與來那度胺之組合七個、八個、九個、十個、十一個、十二個或十二個以上28天週期。在一些實施例中，每日投與化合物1與來那度胺之組合一次，持續至少十三個、至少十四個、至少十五個、至少十六個、至少十七個、至少十八個、至少十九個或至少二十個28天週期。在一些實施例中，向患者投與化合物1與來那度胺之組合，持續患者一生。在一些實施例中，向患者投與化合物1與來那度胺之組合一或多個28天週期，且另外再向該患者投與化合物1或來那度胺中之任一者一或多個28天週期。在一些實施例中，所提供之方法另外包含在第1週期之第1天或第2天向有需要之患者投與利妥昔單抗。在一些實施例中，所提供之方法另外包含在第2週期、第3週期、第4週期、第5週期及第6週期之第1天向有需要之患者投與利妥昔單抗。在一些實施例中，所提供之方法包含向有需要之患者投與化合物1、來 那度胺及利妥昔單抗中之每一者，其中向患者投與化合物1及來那度胺中之每一者一或多個28天週期且在第1週期、第2週期、第3週期、第4週期、第5週期及/或第6週期之第1天或第2天投與利妥昔單抗。 In some embodiments, the combination of Compound 1 and lenalidomide is administered over a period of 28 consecutive days ("28 day cycle"). In some embodiments, a combination of Compound 1 and lenalidomide is administered for two, three, four, five or six 28 day cycles. In some embodiments, a combination of Compound 1 and lenalidomide is administered for seven, eight, nine, ten, eleven, twelve or twelve or more 28 day cycles. In some embodiments, the combination of Compound 1 and lenalidomide is administered once a day for at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen At least nineteen or at least twenty 28-day cycles. In some embodiments, a combination of Compound 1 and lenalidomide is administered to a patient for a lifetime. In some embodiments, the patient is administered a combination of Compound 1 and lenalidomide for one or more 28-day cycles, and the patient is additionally administered one or more of Compound 1 or Lenalidomide. A 28-day cycle. In some embodiments, the methods provided additionally comprise administering rituximab to a patient in need on the first or second day of the first cycle. In some embodiments, the method provided additionally comprises administering rituximab to a patient in need on the first, second, fourth, fifth, and sixth cycles. In some embodiments, the methods provided comprise administering to a patient in need thereof, each of Compound 1 , Lenalidomide, and Rituximab, wherein Compound 1 and lenalidomide are administered to the patient. Each of the one or more 28-day cycles and the first day, the second cycle, the third cycle, the fourth cycle, the fifth cycle, and/or the first or second day of the sixth cycle Waximab.

在一些實施例中，兩個相鄰28天週期可藉由休息期隔開。此類休息期可為一天、兩天、三天、四天、五天、六天、七天或七天以上，在此期間，不向患者投與化合物1及來那度胺中之任一者或兩者。在一較佳實施例中，兩個相鄰28天週期為連續的。 In some embodiments, two adjacent 28 day periods may be separated by a rest period. Such rest periods may be one day, two days, three days, four days, five days, six days, seven days or more, during which no one of Compound 1 and lenalidomide is administered to the patient or Both. In a preferred embodiment, two adjacent 28 day periods are continuous.

在一些實施例中，所提供之方法包含向有需要之患者投與化合物1與來那度胺之組合，其中該患者已失敗至少一個先前療法。 In some embodiments, a method is provided comprising administering to a patient in need thereof a combination of Compound 1 and lenalidomide, wherein the patient has failed at least one prior therapy.

在一些實施例中，本發明提供一種用於治療、穩定或減輕一或多種與BTK相關之疾病或病狀之嚴重程度的系統，該系統包含化合物1及來那度胺。在一些實施例中，該系統為套組。在一些該等實施例中，該套組包含：包含化合物1之醫藥組合物及包含來那度胺之醫藥組合物。在一些實施例中，該套組包含一或多個單位劑量之化合物1與一或多個單位劑量之來那度胺之組合。在一些實施例中，該套組包含：包含化合物1之醫藥組合物、包含來那度胺之醫藥組合物及包含利妥昔單抗之醫藥組合物。在一些實施例中，該套組包含一或多個單位劑量之化合物1、一或多個單位劑量之來那度胺及一或多個單位劑量之利妥昔單抗。 In some embodiments, the invention provides a system for treating, stabilizing or attenuating the severity of one or more diseases or conditions associated with BTK, the system comprising Compound 1 and lenalidomide. In some embodiments, the system is a kit. In some such embodiments, the kit comprises: a pharmaceutical composition comprising Compound 1 and a pharmaceutical composition comprising lenalidomide. In some embodiments, the kit comprises one or more unit doses of Compound 1 in combination with one or more unit doses of lenalidomide. In some embodiments, the kit comprising: a pharmaceutical composition comprising a compound of 1, lenalidomide comprising the pharmaceutical composition comprises rituximab and pharmaceutical compositions of infliximab. In some embodiments, the kit comprises one or more unit doses of Compound 1 , one or more unit doses of lenalidomide, and one or more unit doses of rituximab.

在一些實施例中，該套組包含兩次125mg劑量之化合物1及一次2.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次125mg劑量之化合物1及一次5mg劑量之來那度胺。在一些實施例中，該套組包含兩次125mg劑量之化合物1及一次7.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次125mg劑量之化合物1及一次10mg劑量之來那度胺。在一些實施例中，該套組包含兩次125mg劑量之化合物1及一次15mg劑量之來那度胺。 In some embodiments, the kit comprises two 125 mg doses of Compound 1 and a 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 125 mg doses of Compound 1 and a 5 mg dose of lenalidomide. In some embodiments, the kit comprises two 125 mg doses of Compound 1 and a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 125 mg doses of Compound 1 and one 10 mg dose of lenalidomide. In some embodiments, the kit comprises two 125 mg doses of Compound 1 and a 15 mg dose of lenalidomide.

在一些實施例中，該套組包含兩次250mg劑量之化合物1及一次2.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次250mg劑量之化合物1及一次5mg劑量之來那度胺。在一些實施例中，該套組包含兩次250mg劑量之化合物1及一次7.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次250mg劑量之化合物1及一次10mg劑量之來那度胺。在一些實施例中，該套組包含兩次250mg劑量之化合物1及一次15mg劑量之來那度胺。 In some embodiments, the kit comprises two 250 mg doses of Compound 1 and a 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 250 mg doses of Compound 1 and a 5 mg dose of lenalidomide. In some embodiments, the kit comprises two 250 mg doses of Compound 1 and a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 250 mg doses of Compound 1 and a single 10 mg dose of lenalidomide. In some embodiments, the kit comprises two 250 mg doses of Compound 1 and a 15 mg dose of lenalidomide.

在一些實施例中，該套組包含兩次375mg劑量之化合物1及一次2.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次375mg劑量之化合物1及一次5mg劑量之來那度胺。在一些實施例中，該套組包含兩次375mg劑量之化合物1及一次7.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次375mg劑量之化合物1及一次10mg劑量之來那度胺。在一些實施例中，該套組包含兩次375mg劑量之化合物1及一次15mg劑量之來那度胺。 In some embodiments, the kit comprises a dose of 375mg twice a 2.5mg dose of compound 1 and of lenalidomide. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and a single 5 mg dose of lenalidomide. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and a single 10 mg dose of lenalidomide. In some embodiments, the kit comprises two 375 mg doses of Compound 1 and a 15 mg dose of lenalidomide.

在一些實施例中，該套組包含兩次500mg劑量之化合物1及一次2.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次500mg劑量之化合物1及一次5mg劑量之來那度胺。在一些實施例中，該套組包含兩次500mg劑量之化合物1及一次7.5mg劑量之來那度胺。在一些實施例中，該套組包含兩次500mg劑量之化合物1及一次10mg劑量之來那度胺。在一些實施例中，該套組包含兩次500mg劑量之化合物1及一次15mg劑量之來那度胺。 In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one 5 mg dose of lenalidomide. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and one 10 mg dose of lenalidomide. In some embodiments, the kit comprises two 500 mg doses of Compound 1 and a 15 mg dose of lenalidomide.

在一些實施例中，套組包含七(7)次日劑量之化合物1及來那度胺。在一些該等實施例中，套組包含十四(14)次125mg劑量之化合物1及七(7)次2.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次125mg劑量之化合物1及七(7)次5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次125mg劑量之化合物1及七 (7)次7.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次125mg劑量之化合物1及七(7)次10mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次125mg劑量之化合物1及七(7)次15mg劑量之來那度胺。 In some embodiments, the kit comprises seven (7) daily doses of Compound 1 and lenalidomide. In some of these embodiments, the kit comprises fourteen (14) doses of 125 mg of Compound 1 and seven (7) doses of 2.5 mg of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) doses of 125 mg of Compound 1 and seven (7) doses of 5 mg of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) doses of 125 mg of Compound 1 and seven (7) doses of 7.5 mg of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) doses of 125 mg of Compound 1 and seven (7) doses of 10 mg of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) doses of 125 mg of Compound 1 and seven (7) doses of 15 mg of lenalidomide.

在一些該等實施例中，套組包含十四(14)次250mg劑量之化合物1及七(7)次2.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次250mg劑量之化合物1及七(7)次5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次250mg劑量之化合物1及七(7)次7.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次250mg劑量之化合物1及七(7)次10mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次250mg劑量之化合物1及七(7)次15mg劑量之來那度胺。 In some of these embodiments, the kit comprises fourteen (14) 250 mg doses of Compound 1 and seven (7) 2.5 mg doses of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 250 mg doses of Compound 1 and seven (7) 5 mg doses of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 250 mg doses of Compound 1 and seven (7) 7.5 mg doses of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 250 mg doses of Compound 1 and seven (7) doses of 10 mg dose of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 250 mg doses of Compound 1 and seven (7) 15 mg doses of lenalidomide.

在一些該等實施例中，套組包含十四(14)次375mg劑量之化合物1及七(7)次2.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次375mg劑量之化合物1及七(7)次5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次375mg劑量之化合物1及七(7)次7.5mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次375mg劑量之化合物1及七(7)次10mg劑量之來那度胺。在一些該等實施例中，套組包含十四(14)次375mg劑量之化合物1及七(7)次15mg劑量之來那度胺。 In some of these embodiments, the kit comprises fourteen (14) 375 mg doses of Compound 1 and seven (7) 2.5 mg doses of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 375 mg doses of Compound 1 and seven (7) 5 mg doses of lenalidomide. In some of these embodiments, the kit comprises fourteen (14) 375 mg doses of Compound 1 and seven (7) 7.5 mg doses of lenalidomide. In some such embodiments, the kit comprises fourteen (14) times a 375 mg dose of Compound 1 and seven (7) times a 10 mg dose of lenalidomide. In some such embodiments, the kit comprises fourteen (14) 375 mg doses of Compound 1 and seven (7) 15 mg doses of lenalidomide.

在一些實施例中，套組包含十四(14)次500mg劑量之化合物1及七(7)次2.5mg劑量之來那度胺。在一些實施例中，套組包含十四(14)次500mg劑量之化合物1及七(7)次5mg劑量之來那度胺。在一些實施例中，套組包含十四(14)次500mg劑量之化合物1及七(7)次7.5mg劑量之來那度胺。在一些實施例中，套組包含十四(14)次500mg劑量之化合物1及七(7)次10mg劑量之來那度胺。在一些實施例中，套組包 含十四(14)次500mg劑量之化合物1及七(7)次15mg劑量之來那度胺。 In some embodiments, the kit comprises fourteen (14) times a 500 mg dose of Compound 1 and seven (7) times a 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises fourteen (14) times a 500 mg dose of Compound 1 and seven (7) times a 5 mg dose of lenalidomide. In some embodiments, the kit comprises fourteen (14) times a 500 mg dose of Compound 1 and seven (7) times a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises fourteen (14) times a 500 mg dose of Compound 1 and seven (7) times a 10 mg dose of lenalidomide. In some embodiments, the kit comprises fourteen (14) times a 500 mg dose of Compound 1 and seven (7) times a 15 mg dose of lenalidomide.

在一些實施例中，套組包含28次日劑量之化合物1及來那度胺。在一些實施例中，套組包含五十六(56)次125mg劑量之化合物1及二十八(28)次2.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次125mg劑量之化合物1及二十八(28)次5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次125mg劑量之化合物1及二十八(28)次7.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次125mg劑量之化合物1及二十八(28)次10mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次125mg劑量之化合物1及二十八(28)次15mg劑量之來那度胺。在一些實施例中，該套組另外包含一個100mg/10mL小瓶之利妥昔單抗。在一些實施例中，該套組另外包含一個500mg/50mL小瓶之利妥昔單抗。 In some embodiments, the kit comprises 28 daily doses of Compound 1 and lenalidomide. In some embodiments, the kit comprises fifty-six (56) doses of 125 mg of Compound 1 and twenty-eight (28) doses of 2.5 mg of lenalidomide. In some embodiments, the kit comprises fifty-six (56) doses of 125 mg of Compound 1 and twenty-eight (28) doses of 5 mg of lenalidomide. In some embodiments, the kit comprises fifty-six (56) doses of 125 mg of Compound 1 and twenty-eight (28) doses of 7.5 mg of lenalidomide. In some embodiments, the kit comprises fifty-six (56) doses of 125 mg of Compound 1 and twenty-eight (28) doses of 10 mg of lenalidomide. In some embodiments, the kit comprises fifty-six (56) doses of 125 mg of Compound 1 and twenty-eight (28) doses of 15 mg of lenalidomide. In some embodiments, the kit additionally comprises a 100 mg/10 mL vial of rituximab. In some embodiments, the kit additionally comprises a 500 mg/50 mL vial of rituximab.

在一些實施例中，套組包含五十六(56)次250mg劑量之化合物1及二十八(28)次2.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次250mg劑量之化合物1及二十八(28)次5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次250mg劑量之化合物1及二十八(28)次7.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次250mg劑量之化合物1及二十八(28)次10mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次250mg劑量之化合物1及二十八(28)次15mg劑量之來那度胺。在一些實施例中，該套組另外包含一個100mg/10mL小瓶之利妥昔單抗。在一些實施例中，該套組另外包含一個500mg/50mL小瓶之利妥昔單抗。 In some embodiments, the kit comprises fifty-six (56) 250 mg doses of Compound 1 and twenty-eight (28) doses of 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 250 mg doses of Compound 1 and twenty-eight (28) doses of 5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 250 mg doses of Compound 1 and twenty-eight (28) doses of 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 250 mg doses of Compound 1 and twenty-eight (28) doses of 10 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 250 mg doses of Compound 1 and twenty-eight (28) doses of 15 mg dose of lenalidomide. In some embodiments, the kit additionally comprises a 100 mg/10 mL vial of rituximab. In some embodiments, the kit additionally comprises a 500 mg/50 mL vial of rituximab.

在一些實施例中，套組包含五十六(56)次375mg劑量之化合物1及二十八(28)次2.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次375mg劑量之化合物1及二十八(28)次5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次375mg劑量之化合物1 及二十八(28)次7.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次375mg劑量之化合物1及二十八(28)次10mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次375mg劑量之化合物1及二十八(28)次15mg劑量之來那度胺。在一些實施例中，該套組另外包含一個100mg/10mL小瓶之利妥昔單抗。在一些實施例中，該套組另外包含一個500mg/50mL小瓶之利妥昔單抗。 In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and twenty-eight (28) doses of 2.5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) times a 375 mg dose of Compound 1 and twenty-eight (28) doses of a 5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and twenty-eight (28) 7.5 mg doses of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and twenty-eight (28) doses of 10 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 375 mg doses of Compound 1 and twenty-eight (28) doses of 15 mg dose of lenalidomide. In some embodiments, the kit additionally comprises a 100 mg/10 mL vial of rituximab. In some embodiments, the kit additionally comprises a 500 mg/50 mL vial of rituximab.

在一些實施例中，套組包含五十六(56)次500mg劑量之化合物1及二十八(28)次2.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次500mg劑量之化合物1及二十八(28)次5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次500mg劑量之化合物1及二十八(28)次7.5mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次500mg劑量之化合物1及二十八(28)次10mg劑量之來那度胺。在一些實施例中，套組包含五十六(56)次500mg劑量之化合物1及二十八(28)次15mg劑量之來那度胺。在一些實施例中，該套組另外包含一個100mg/10mL小瓶之利妥昔單抗。在一些實施例中，該套組另外包含一個500mg/50mL小瓶之利妥昔單抗。 In some embodiments, the kit comprises fifty-six (56) doses of 500 mg of Compound 1 and twenty-eight (28) doses of 2.5 mg of lenalidomide. In some embodiments, the kit comprises fifty-six (56) times a 500 mg dose of Compound 1 and twenty-eight (28) doses of a 5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) times a 500 mg dose of Compound 1 and twenty-eight (28) doses of a 7.5 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) times a 500 mg dose of Compound 1 and twenty-eight (28) doses of a 10 mg dose of lenalidomide. In some embodiments, the kit comprises fifty-six (56) 500 mg doses of Compound 1 and twenty-eight (28) doses of 15 mg dose of lenalidomide. In some embodiments, the kit additionally comprises a 100 mg/10 mL vial of rituximab. In some embodiments, the kit additionally comprises a 500 mg/50 mL vial of rituximab.

IV.包含化合物1之調配物IV. Formulation comprising Compound 1

如上所述，所提供之方法包含向有需要之患者投與包含化合物1之醫藥學上可接受之組合物，其中該醫藥學上可接受之組合物為口服劑型。在一些實施例中，將該醫藥學上可接受之組合物調配成膠囊。 As indicated above, the method provided comprises administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1 , wherein the pharmaceutically acceptable composition is an oral dosage form. In some embodiments, the pharmaceutically acceptable composition is formulated into a capsule.

在某些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，該組合物包含化合物1及一或多種醫藥學上可接受之賦形劑，諸如黏合劑、薄膜衣、稀釋劑、崩解劑、界面活性劑(濕潤劑)、潤滑劑及滑動劑(吸附劑)或其組合。熟習此項技術者應易於瞭解，列舉特定組分之類目並不意欲為限制性的；在一些情況下，一特定組分可適當地適合一個以上類目。同樣，應瞭解，在特定調配 物之情況下，例如視成分之量及/或其他成分及/或活性化合物之存在而定，相同組分有時可執行不同功能，或可執行一種以上功能。在一些實施例中，該醫藥學上可接受之組合物為摻合粉末。 In certain embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising Compound 1 and one or more pharmaceutically acceptable excipients, such as a binder. Agents, film coats, diluents, disintegrants, surfactants (wetting agents), lubricants and slip agents (adsorbents) or combinations thereof. It will be readily understood by those skilled in the art that the enumeration of specific components is not intended to be limiting; in some cases, a particular component may suitably be adapted to more than one category. Likewise, it is to be understood that in the case of a particular formulation, such as depending on the amount of ingredient and/or the presence of other ingredients and/or active compound, the same component may sometimes perform different functions or perform more than one function. In some embodiments, the pharmaceutically acceptable composition is a blended powder.

i.黏合劑及稀釋劑i. Adhesives and thinners

本發明所用之醫藥組合物可包含一或多種黏合劑。黏合劑用於固體口服劑型之調配，以保持活性醫藥成分與非活性成分黏著混合在一起。在一些實施例中，本發明之醫藥組合物包含約5%至約50%(w/w)之一或多種黏合劑及/或稀釋劑。在一些實施例中，本發明之醫藥組合物包含約20%(w/w)之一或多種黏合劑及/或稀釋劑。適合之黏合劑及/或稀釋劑(亦稱為「填充劑」)為此項技術中已知。代表性黏合劑及/或稀釋劑包括(但不限於)澱粉，諸如纖維素(低分子量HPC(羥丙基纖維素)、微晶纖維素(例如Avicel®)、低分子量HPMC(羥丙基甲基纖維素)、低分子量羧甲基纖維素、乙基纖維素)；糖，諸如乳糖(亦即單水合乳糖)、蔗糖、右旋糖、果糖、麥芽糖、葡萄糖；及多元醇，諸如山梨糖醇、甘露糖醇、乳糖醇、麥芽糖醇及木糖醇，或其組合。在一些實施例中，所提供之組合物包含微晶纖維素及/或單水合乳糖之黏合劑。 The pharmaceutical compositions used in the present invention may comprise one or more binders. Binders are used in the formulation of solid oral dosage forms to keep the active pharmaceutical ingredients in combination with the inactive ingredients. In some embodiments, the pharmaceutical compositions of the present invention comprise from about 5% to about 50% (w/w) of one or more binders and/or diluents. In some embodiments, the pharmaceutical compositions of the present invention comprise about 20% (w/w) one or more binders and/or diluents. Suitable binders and/or diluents (also known as "fillers") are known in the art. Representative binders and/or diluents include, but are not limited to, starches such as cellulose (low molecular weight HPC (hydroxypropyl cellulose), microcrystalline cellulose (eg Avicel ® ), low molecular weight HPMC (hydroxylpropyl) Cellulose), low molecular weight carboxymethylcellulose, ethylcellulose); sugars such as lactose (ie, lactose monohydrate), sucrose, dextrose, fructose, maltose, glucose; and polyols such as sorbose Alcohol, mannitol, lactitol, maltitol, and xylitol, or a combination thereof. In some embodiments, the provided compositions comprise a binder of microcrystalline cellulose and/or monohydrated lactose.

ii.崩解劑Ii. disintegrant

本發明所用之醫藥組合物可另外包含一或多種崩解劑。適合之崩解劑為此項技術中已知且包括(但不限於)瓊脂、碳酸鈣、碳酸鈉、碳酸氫鈉、交聯羧甲基纖維素鈉(cross-linked sodium carboxymethyl cellulose)(交聯羧甲基纖維素鈉(croscarmellose sodium))、羧甲基澱粉鈉(羥基乙酸澱粉鈉)、微晶纖維素或其組合。在一些實施例中，以調配物之總重量計，所提供之調配物包含約1%至約25%之崩解劑。 The pharmaceutical composition used in the present invention may additionally comprise one or more disintegrants. Suitable disintegrants are known in the art and include, but are not limited to, agar, calcium carbonate, sodium carbonate, sodium bicarbonate, cross-linked sodium carboxymethyl cellulose (crosslinking) Sodium carboxymethylcellulose (croscarmellose sodium), sodium carboxymethyl starch (sodium starch glycolate), microcrystalline cellulose or a combination thereof. In some embodiments, the formulation provided comprises from about 1% to about 25% of a disintegrant, based on the total weight of the formulation.

iii.界面活性劑Iii. Surfactant

界面活性劑(亦稱為生物利用度增強劑)為此項技術中所熟知且通 常藉由增強難溶藥物之溶解度來促進藥物釋放及吸收。代表性界面活性劑包括(但不限於)泊洛沙姆(poloxamer)、聚氧乙烯醚、聚氧乙烯脂肪酸酯、聚乙二醇脂肪酸酯、聚氧乙烯氫化蓖麻油、聚氧乙烯烷基醚、聚山梨醇酯及其組合。在某些實施例中，界面活性劑為泊洛沙姆。在一些該等實施例中，泊洛沙姆為泊洛沙姆407。在一些實施例中，以摻合粉末之總重量計，本發明所用之組合物包含約1重量%至約30重量%之界面活性劑。 Surfactants (also known as bioavailability enhancers) are well known in the art and are Drug release and absorption are often promoted by enhancing the solubility of poorly soluble drugs. Representative surfactants include, but are not limited to, poloxamers, polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkylenes. Ether ethers, polysorbates, and combinations thereof. In certain embodiments, the surfactant is a poloxamer. In some of these embodiments, the poloxamer is poloxamer 407. In some embodiments, the compositions used in the present invention comprise from about 1% to about 30% by weight, based on the total weight of the blended powder, of a surfactant.

iv.潤滑劑Iv. Lubricant

本發明之醫藥組合物可另外包含一或多種潤滑劑。潤滑劑為以少量添加至調配物中以改良某些加工特性之藥劑。潤滑劑防止調配混合物黏著於壓縮機械且藉由減少顆粒間摩擦增強產品流。代表性潤滑劑包括(但不限於)硬脂酸鎂、蘿酸甘油酯、硬脂醯反丁烯二酸鈉及脂肪酸(亦即棕櫚酸及硬脂酸)。在某些實施例中，潤滑劑為硬脂酸鎂。在一些實施例中，以給定調配物之總重量計，所提供之調配物包含約0.2%至約3%潤滑劑。 The pharmaceutical compositions of the present invention may additionally comprise one or more lubricants. Lubricants are agents that are added in small amounts to the formulation to improve certain processing characteristics. The lubricant prevents the compounding mixture from sticking to the compression machine and enhances product flow by reducing interparticle friction. Representative lubricants include, but are not limited to, magnesium stearate, glyceride, sodium stearyl fumarate, and fatty acids (i.e., palmitic acid and stearic acid). In certain embodiments, the lubricant is magnesium stearate. In some embodiments, the provided formulation comprises from about 0.2% to about 3% lubricant, based on the total weight of the given formulation.

v.滑動劑Slip agent

本發明之醫藥組合物可另外包含一或多種滑動劑。代表性滑動劑包括(但不限於)二氧化矽(亦即煙霧狀二氧化矽)、微晶纖維素、澱粉(亦即玉米澱粉)及碳酸鹽(亦即碳酸鈣及碳酸鎂)。在一些實施例中，以給定調配物之總重量計，所提供之調配物包含約0.2%至約3%滑動劑。 The pharmaceutical compositions of the present invention may additionally comprise one or more slip agents. Representative slip agents include, but are not limited to, ceria (i.e., fumed ceria), microcrystalline cellulose, starch (i.e., corn starch), and carbonates (i.e., calcium carbonate and magnesium carbonate). In some embodiments, the provided formulation comprises from about 0.2% to about 3% slipper, based on the total weight of the given formulation.

vi.N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽Vi. N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate

如上所述，本發明提供一種治療選自慢性淋巴球性白血病及小淋巴球性淋巴瘤之疾病或失調的方法，該方法包含向有需要之患者投與化合物1與來那度胺之組合。化合物1之苯磺酸鹽N-(3-(5-氟-2-(4-(2- 甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽近來已經過鑑定且目前在臨床試驗中作為單一療法用於患有復發性或難治性B細胞非霍奇金氏淋巴瘤(B-NHL)、慢性淋巴球性白血病(CLL)及瓦爾登斯特倫巨球蛋白血症(WM)之個體。因此，在一些實施例中，所提供之方法包含向有需要之患者投與化合物1之苯磺酸鹽。 As described above, the present invention provides a method of treating a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering a combination of Compound 1 and lenalidomide to a patient in need thereof. Benzenesulfonate compound 1 of N - (3- (5-fluoro-2- (4- (2-methoxyethoxy) phenylamino) pyrimidin-4-ylamino) phenyl) acrylamide benzene Sulfonates have recently been identified and are currently used as monotherapy in clinical trials for patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL), chronic lymphocytic leukemia (CLL) and Val Individuals of Dengstrom's macroglobulinemia (WM). Thus, in some embodiments, the method comprises providing to a patient in need of administration of a compound besylate.

在一些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，以調配物之總重量計，該組合物包含約5%至約60%之化合物1之苯磺酸鹽。在一些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，以該組合物之總重量計，該組合物包含約5%至約15%、或約7%至約15%、或約7%至約10%、或約9%至約12%之化合物1之苯磺酸鹽。在一些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，以調配物之總重量計，該組合物包含約25%至約75%、或約30%至約60%、或約40%至約50%、或約40%至約45%之化合物1之苯磺酸鹽。 在某些實施例中，所提供之方法包含向有需要之患者投與醫藥學上可接受之組合物，以給定組合物或調配物之總重量計，該組合物包含約8%、約9%、約10%、約11%、約12%、約13%、約20%、約30%、約40%、約41%、約42%、約43%、約44%、約45%、約50%、約60%、約70%或約75%之化合物1之苯磺酸鹽。 In some embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 5% to about 60% of Compound 1 based on the total weight of the formulation. Benzene sulfonate. In some embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 5% to about 15%, or about the total weight of the composition. From 7% to about 15%, or from about 7% to about 10%, or from about 9% to about 12% of the besylate salt of Compound 1 . In some embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising from about 25% to about 75%, or about 30, based on the total weight of the formulation. % to about 60%, or from about 40% to about 50%, or from about 40% to about 45% of the besylate salt of Compound 1 . In certain embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutically acceptable composition comprising about 8%, based on the total weight of the given composition or formulation. 9%, about 10%, about 11%, about 12%, about 13%, about 20%, about 30%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45% About 50%, about 60%, about 70% or about 75% of the besylate salt of Compound 1 .

在一些該等實施例中，所提供之方法包含向有需要之患者投與包含單位劑量之化合物1之醫藥組合物，其中化合物1呈苯磺酸鹽形式。在一些該等實施例中，單位劑量為足以提供約25mg、約50mg、約75mg、約100mg、約125mg、約150mg、約175mg、約200mg、約225mg或約250mg之化合物1之游離鹼的量。在一些實施例中，包含化合物1之苯磺酸鹽之醫藥組合物為固體口服劑型。 In some such embodiments, the methods provided comprise administering to a patient in need thereof a pharmaceutical composition comprising a unit dose of Compound 1 , wherein Compound 1 is in the form of a besylate salt. In some such embodiments, the unit dosage is an amount of the free base sufficient to provide about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg of Compound 1 . . In some embodiments, the pharmaceutical composition comprising the besylate salt of Compound 1 is a solid oral dosage form.

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢 性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與化合物1與來那度胺之組合，其中化合物1以苯磺酸鹽形式投與。在一些該等實施例中，化合物1之苯磺酸鹽以包含一或多種醫藥學上可接受之賦形劑之組合物形式投與，該一或多種醫藥學上可接受之賦形劑選自黏合劑、薄膜衣、稀釋劑、崩解劑、界面活性劑、潤滑劑及滑動劑。在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與化合物1、來那度胺及利妥昔單抗中之每一者，其中化合物1以苯磺酸鹽形式投與。在一些該等實施例中，化合物1之苯磺酸鹽以包含一或多種醫藥學上可接受之賦形劑之組合物形式投與，該一或多種醫藥學上可接受之賦形劑選自黏合劑、薄膜衣、稀釋劑、崩解劑、界面活性劑、潤滑劑及滑動劑。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered a combination of Compound 1 and lenalidomide, wherein Compound 1 is administered as a besylate salt. In some such embodiments, the besylate salt of Compound 1 is administered as a composition comprising one or more pharmaceutically acceptable excipients, one or more pharmaceutically acceptable excipients selected Self-adhesives, film coats, diluents, disintegrants, surfactants, lubricants and slip agents. In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising The patient is administered each of Compound 1 , lenalidomide and rituximab, wherein Compound 1 is administered as a besylate salt. In some such embodiments, the besylate salt of Compound 1 is administered as a composition comprising one or more pharmaceutically acceptable excipients, one or more pharmaceutically acceptable excipients selected Self-adhesives, film coats, diluents, disintegrants, surfactants, lubricants and slip agents.

在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與包含化合物1之苯磺酸鹽與來那度胺組合之醫藥組合物，其中化合物1之苯磺酸鹽之量足以傳遞約125mg、約250mg、約325mg、約375mg、約400mg、約500mg、約625mg、約750mg、約1000mg或約1250mg之化合物1之游離鹼。在一些該等實施例中，該醫藥組合物另外包含一或多種選自黏合劑、薄膜衣、稀釋劑、崩解劑、界面活性劑、潤滑劑及滑動劑之醫藥學上可接受之賦形劑。在一些該等實施例中，該醫藥組合物包含一或多種選自微晶纖維素、單水合乳糖、澱粉鈉、泊洛沙姆407、煙霧狀二氧化矽及硬脂酸鎂之醫藥學上可接受之賦形劑。在一些實施例中，本發明提供一種治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展 的方法，該方法包含向有需要之患者投與包含化合物1之苯磺酸鹽(亦即化合物1苯磺酸鹽)、來那度胺及利妥昔單抗中之每一者的醫藥組合物，其中化合物1之苯磺酸鹽之量足以傳遞約125mg、約250mg、約325mg、約375mg、約400mg、約500mg、約625mg、約750mg、約1000mg或約1250mg之化合物1之游離鹼。 In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising comprising administering to the patient a compound of the besylate salt of a pharmaceutical composition and to a combination of lenalidomide, wherein the amount of a compound of a besylate sufficient to transfer about 125mg, about 250mg, about 325 mg, about 375 mg of, about 400mg, About 500 mg, about 625 mg, about 750 mg, about 1000 mg, or about 1250 mg of the free base of Compound 1 . In some such embodiments, the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable shapes selected from the group consisting of binders, film coats, diluents, disintegrants, surfactants, lubricants, and slip agents. Agent. In some such embodiments, the pharmaceutical composition comprises one or more medicinal materials selected from the group consisting of microcrystalline cellulose, lactose monohydrate, sodium starch, poloxamer 407, aerosolized cerium oxide, and magnesium stearate. Acceptable excipients. In some embodiments, the invention provides a method of treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising comprising administering to the patient a compound of the benzenesulfonate of 1 (i.e., compound 1 besylate), lenalidomide and each of rituximab in the pharmaceutical composition of 1 wherein the acid compound The amount of salt is sufficient to deliver about 125 mg, about 250 mg, about 325 mg, about 375 mg, about 400 mg, about 500 mg, about 625 mg, about 750 mg, about 1000 mg, or about 1250 mg of the free base of Compound 1 .

V.用於製備包含化合物1之醫藥組合物的製程V. Process for preparing a pharmaceutical composition comprising Compound 1 乾摻合製程：Dry blending process:

稱重經研磨之N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽、經研磨之微晶纖維素、經研磨之羥基乙酸澱粉鈉、經研磨之單水合乳糖、經研磨之泊洛沙姆407及經篩選之煙霧狀二氧化矽且機械摻合。將經篩選之硬脂酸鎂的粒內部分(2.0%，根據下表1)添加至摻合機且摻合調配物。接著輥壓此摻合調配物，研磨且隨後摻合。再輥壓該摻合調配物，研磨且隨後摻合。添加硬脂酸鎂之其餘部分或粒外部分(0.5%，根據下表1)且摻合最終調配物。經由泛洪填充法機械填充或手動填充膠囊。 Weighed N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylaminobenzenesulfonic acid Salt, ground microcrystalline cellulose, ground sodium starch glycolate, ground monohydrate lactose, ground poloxamer 407 and selected aerosolized cerium oxide and mechanically blended. The intragranular portion of the screened magnesium stearate (2.0%, according to Table 1 below) was added to the blender and the blend was blended. The blended formulation is then rolled, ground and subsequently blended. The blended formulation is rolled again, ground and subsequently blended. The remainder or extragranular portion of magnesium stearate (0.5% according to Table 1 below) was added and the final formulation was blended. The capsule is mechanically filled or manually filled via a flood filling method.

本發明各態樣之所有特徵在加以必要變更下適用於所有其他態樣。本文中所提及之參考文獻(包括(但不限於)專利、專利申請案及雜誌文章)各自以引入的方式併入本文中，仿佛全部加以充分陳述一般。 All of the features of the various aspects of the invention apply to all other aspects with the necessary modifications. The references (including but not limited to) patents, patent applications, and journal articles referred to herein are hereby incorporated by reference in their entirety as if they are fully incorporated.

為了能較全面地理解本文所描述之發明，闡述下列實例。應瞭解，此等實例僅用於說明性目的，而不應理解為以任何方式限制本發明。 In order to more fully understand the invention described herein, the following examples are set forth. It is understood that the examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

例證illustration 實例1Example 1 劑量遞增研究Dose escalation study

N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙 烯醯胺苯磺酸鹽為以苯磺酸鹽形式開發之化學合成小分子經取代之嘧啶，且為白色至灰白色結晶性粉末。N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽為Btk之口服、有效(IC50<0.5nM)及選擇性小分子抑制劑。N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽顯示出在水中約0.16mg/mL之溶解度及在約pH 3.0下0.40mg/mL之最大水溶性。N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽於乙醇中之溶解度為約10mg/mL。N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽未顯示出需要專門處理之環境不穩定性(亦即熱、酸、鹼)。 N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)propenylamine benzenesulfonate is benzenesulfonate The acid form is developed by chemically synthesizing small molecules of substituted pyrimidines and is a white to off-white crystalline powder. N - (3- (5- fluoro-2- (4- (2-methoxyethoxy) phenylamino) pyrimidin-4-ylamino) phenyl) acrylamide benzenesulfonate of oral Btk Effective (IC 50 <0.5 nM) and selective small molecule inhibitors. N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine besylate is shown in water A solubility of about 0.16 mg/mL and a maximum water solubility of 0.40 mg/mL at about pH 3.0. N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine benzenesulfonate in ethanol The solubility is about 10 mg/mL. N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate did not show the need Specially treated for environmental instability (ie heat, acid, alkali).

將N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽調配成含有表1中列舉之組分及數量的膠囊以獲得研究藥物。將在劑量遞增及擴充組研究期間投與表1中列舉之膠囊。 Formulating N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate to contain The components and amounts of capsules listed in Table 1 were used to obtain the study drug. The capsules listed in Table 1 will be administered during the dose escalation and expansion group study.

2.0%(8.30mg)粒內；0.5%(2.08mg)粒外。 2.0% (8.30 mg) intragranular; 0.5% (2.08 mg) extragranular.

來那度胺亦稱為3-(4-胺基-1-側氧基-1,3-二氫-2H-異吲哚-2-基)哌啶-2,6-二酮，具有以下結構： Lenalidomide is also known as 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and has the following structure:

來那度胺為灰白色至淺黃色固體粉末且以2.5mg、5mg、10mg、15mg及25mg膠囊形式購自Celgene Corporation。各來那度胺膠囊含有無水乳糖、微晶纖維素、交聯羧甲基纖維素鈉及硬脂酸鎂。 Lenalidomide was an off-white to pale yellow solid powder and was purchased from Celgene Corporation in the form of 2.5 mg, 5 mg, 10 mg, 15 mg, and 25 mg capsules. Each lenalidomide capsule contains anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

將來那度胺調配成含有表2中列舉之組分及數量的膠囊以獲得研究藥物。將在劑量遞增及擴充組研究期間，根據所需劑量投與表2中列舉之膠囊，且代表臨床供應形式。因為亦可使用市售形式產品，所以在表3中列舉市售形式產品之組分及數量。 In the future, lenalidomide will be formulated into capsules containing the components and amounts listed in Table 2 to obtain the study drug. The capsules listed in Table 2 will be administered according to the required dose during the dose escalation and expansion group study and represent the clinical supply form. Since commercially available products can also be used, the components and amounts of commercially available products are listed in Table 3.

a針對分析及水含量來調節來那度胺之重量。 a Adjust the weight of lenalidomide for analysis and water content.

b調節無水乳糖、NF/EP之重量以達到批次之目標總摻合重量。 b Adjust the weight of anhydrous lactose, NF/EP to achieve the target total blend weight of the batch.

a針對分析及水含量調節來那度胺之重量。 a Adjust the weight of lenalidomide for analysis and water content.

b調節無水乳糖、NF/EP之重量以達到批次之目標總摻合重量。 b Adjust the weight of anhydrous lactose, NF/EP to achieve the target total blend weight of the batch.

c膠囊殼由Capsugel供應。 c capsule shells are supplied by Capsugel.

研究設計Research design

在「3+3」劑量遞增及擴充研究中登記失敗至少一個先前治療方案之患有復發性或難治性CLL或SLL之個體以便測定化合物1與來那度胺之組合的非耐受劑量(NTD)、最佳生物效應劑量(OBE)及最大耐受劑量(MTD)。在該研究中將登記約42名患者。 Non-tolerable doses (NTD) for individuals with relapsed or refractory CLL or SLL who have failed at least one prior treatment regimen in a "3+3" dose escalation and expansion study to determine the combination of Compound 1 and lenalidomide ), optimal biological effect dose (OBE) and maximum tolerated dose (MTD). Approximately 42 patients will be enrolled in the study.

三(3)次劑量及三次建議劑量如表4中所概述般定義。 Three (3) doses and three recommended doses are defined as outlined in Table 4.

*建議額外劑量。 * Suggest additional doses.

在28天週期中以規定劑量如期投與研究治療劑，直至疾病進展、毒性不可接受或出於任何其他原因中斷為止。個體將繼續起始劑量直至確定初步推薦2期劑量(RP2D)，此時其可轉變成初步RP2D。 The study therapeutic is administered as scheduled at the prescribed dose over a 28 day period until the disease progresses, the toxicity is unacceptable, or is interrupted for any other reason. The individual will continue to start the dose until a preliminary recommended phase 2 dose (RP2D) is determined, at which point it can be converted to a preliminary RP2D.

在各組內，個體在最初28天治療週期內用N-(3-(5-氟-2-(4-(2-甲 氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽與來那度胺之組合PO(口服)BID(每日兩次)治療，且評估安全性、耐受性及DLT，以及藥物動力學(「PK」)、藥效學(「PD」)及疾病反應。在某些情況下，醫師調查者可在研究期間選擇使患者休息，在此期間患者不接受治療。舉例而言，醫師調查者可因不良事件之出現或再現而選擇使患者休息。出於明瞭之目的，已休息之患者仍登記在研究中，直至醫師調查者確定該患者不應繼續治療為止，此時該等患者中斷進一步治療。在此上下文中，治療持續時間係指患者登記在研究中之時間，包括所有休息期，直至治療中斷為止。 Within each group, the individual used N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino) during the first 28 days of treatment) Combination of phenyl) acrylamide sulfonate and lenalidomide PO (oral) BID (twice daily) and assessment of safety, tolerability and DLT, and pharmacokinetics ("PK") , pharmacodynamics ("PD") and disease response. In some cases, a physician investigator may choose to rest the patient during the study, during which time the patient does not receive treatment. For example, a physician investigator may choose to rest the patient due to the occurrence or recurrence of an adverse event. For the sake of clarity, the rested patient is still enrolled in the study until the physician investigator determines that the patient should not continue treatment, at which point the patient discontinues further treatment. In this context, duration of treatment refers to the time the patient is enrolled in the study, including all rest periods, until the treatment is interrupted.

在所定義之組內，調查者可選擇減少N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽及來那度胺中之任一者或兩者之劑量。在各種情況下，調查者可選擇如下逐步降低N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽之劑量。組1中之患者可自375mg BID逐步降低至250mg BID，且隨後再次自250mg BID逐步降低至125mg BID N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。組1a中之患者可自375mg BID逐步降低至250mg BID，且隨後再次自250mg BID逐步降低至125mg BID N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。組2中之患者可自500mg BID逐步降低至375mg BID，且隨後再次自375mg BID逐步降低至250mg BID N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。組2a中之患者可自500mg BID逐步降低至375mg BID，且隨後再次自375mg BID逐步降低至250mg BID N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。組3a中之患者可自500mg BID逐步降低至375mg BID，且隨後再次自375mg BID逐步降低至250mg BID N-(3-(5-氟-2-(4-(2- 甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。組3中之患者可自500mg BID逐步降低至375mg BID，且隨後再次自375mg BID逐步降低至250mg BID N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。 Within the defined group, investigators may choose to reduce N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl a dose of either or both of acrylamide sulfonate and lenalidomide. In each case, the investigator may choose to gradually reduce the N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl group as follows. The dose of acrylamide benzene sulfonate. Patients in Group 1 were gradually reduced from 375 mg BID to 250 mg BID, and then gradually reduced from 250 mg BID to 125 mg BID N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate. Patients in group 1a can be gradually reduced from 375 mg BID to 250 mg BID, and then gradually reduced from 250 mg BID to 125 mg BID N -(3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate. Patients in Group 2 can be gradually reduced from 500 mg BID to 375 mg BID, and then gradually reduced from 375 mg BID to 250 mg BID N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate. Patients in group 2a can be gradually reduced from 500 mg BID to 375 mg BID, and then gradually reduced from 375 mg BID to 250 mg BID N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate. Patients in group 3a can be gradually reduced from 500 mg BID to 375 mg BID, and then gradually reduced from 375 mg BID to 250 mg BID N -(3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate. Patients in Group 3 can be gradually reduced from 500 mg BID to 375 mg BID, and then gradually reduced from 375 mg BID to 250 mg BID N -(3-(5-fluoro-2-(4-(2-methoxyethoxy)) Anilinopyrimidin-4-ylamino)phenyl)acrylamidobenzenesulfonate.

調查者可選擇逐步降低來那度胺之劑量。到2013年8月6日為止，該等劑量減少步驟定義於表5中： Investigators can choose to gradually reduce the dose of lenalidomide. As of August 6, 2013, the dose reduction steps are defined in Table 5:

在一些情況下，調查者可選擇根據表6逐步降低來那度胺之劑量： In some cases, investigators may choose to gradually reduce the dose of lenalidomide according to Table 6:

應瞭解，劑量減少為不需要的且僅作為緩和或緩解一或多個視為與研究藥物相關之不良事件的方式而提供。任何該劑量減少不改變患者登記；因此已具有一或多個劑量減少之任何患者仍登記在其最初分派之組中。 It will be appreciated that dose reduction is not required and is provided only as a means of mitigating or alleviating one or more adverse events considered to be related to the study drug. Any such dose reduction does not alter patient registration; therefore any patient who has one or more dose reductions is still enrolled in the group to which they were originally assigned.

患者登記之劑量應基於在登記時開設之組。僅對於第一週期而言，將在第1天至第28天投與來那度胺且將在28天週期之第8-28天投與N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。此後，將在給定28天週期之每天根據表4投與來那度胺及N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙 烯醯胺苯磺酸鹽。 The patient registration dose should be based on the group that was opened at the time of registration. For the first cycle only, lenalidomide will be administered from day 1 to day 28 and N- (3-(5-fluoro-2-() will be administered on days 8-28 of the 28-day cycle. 4-(2-Methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine besylate. Thereafter, lenalidomide and N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidine will be administered according to Table 4 on a daily basis for a given 28-day period. 4-aminoamino)phenyl)propenylamine besylate.

若三(3)名給藥個體中的零(0)名遭受DLT，則劑量視為可耐受的。僅當在任何組中登記之前三(3)名個體中無人(0)遭受劑量限制毒性(DLT)時才允許經由登記在下一個較高劑量中而使劑量遞增。若任何組中前三(3)名給藥個體中之一(1)名在第1週期遭受DLT，則另三(3)名個體應登記在該劑量組。當該組中六(6)名DLT可評估個體中之兩(2)名遭受DLT時，劑量應視為NTD。當至少六(6)名個體已登記且在該劑量下安全結束第1週期時，宣告MTD。MTD定義為低於NTD之最後劑量，其中零(0)或一(1)名DLT可評估個體在第一個28天週期內遭受DLT。 If zero (0) in three (3) administered individuals suffers from DLT, the dose is considered tolerable. Dosing is allowed to be dosed by registration in the next higher dose only if no one (3) of the three (3) individuals before the registration in any group suffers from dose limiting toxicity (DLT). If one (1) of the first three (3) administered individuals in any group suffers from DLT during the first cycle, the other three (3) individuals should be enrolled in the dose group. When two (2) of the six (6) DLT evaluable individuals in the group are exposed to DLT, the dose should be considered NTD. The MTD is declared when at least six (6) individuals have registered and safely ended the first cycle at that dose. The MTD is defined as the last dose below the NTD, where zero (0) or one (1) DLT can assess that the individual is suffering from DLT during the first 28 day period.

在劑量遞增期內，登記下一個較高劑量組之決定應基於安全性及DLT可評估患者之審閱。OBE劑量定義如下：˙在任何劑量下，在六(6)名個體中之五(5)名中的90%目標佔有率；及/或˙隨著劑量增加未另外增加暴露；及/或˙在前三個28天週期(第1-3週期)內，在六(6)名個體中之四(4)名中引起絕對淋巴細胞計數增加25%，未評估為進行性疾病(PD)；及/或˙在任何劑量或安排含量下，在至少50%之個體中引起總淋巴結面積減少50%。 During the dose escalation period, the decision to register the next higher dose group should be based on safety and review of the DLT evaluable patient. The OBE dose is defined as follows: 90 90% target occupancy rate in five (5) of six (6) individuals at any dose; and/or ̇ no additional exposure with dose increase; and/or ̇ Increased absolute lymphocyte count in four (4) of six (6) individuals during the first three 28-day cycles (lanes 1-3) 25%, not assessed as progressive disease (PD); and/or ̇ caused a reduction in total lymph node area in at least 50% of individuals at any dose or schedule 50%.

仍對個體保持研究，直至個體因疾病進展、不可接受之毒性、撤回同意或任何其他原因由醫師決定中斷為止。將評估功效之初步證據。 Research is still maintained for the individual until the individual is interrupted by the physician's decision due to disease progression, unacceptable toxicity, withdrawal consent, or any other reason. Preliminary evidence of efficacy will be assessed.

結果.「完全反應」(CR)為根據IWCLL準則，2008(無LN>1.5cm，無肝腫大、脾腫大，ALC<4000/μL，正常細胞骨髓<30%淋巴細胞，ANC>1500，血小板計數>100,000且Hgb>11.0g/dL)加以定義。「部分 反應」(PR)為經由IWCLL指南(以下準則中之至少2項：淋巴結(LN)減小50%；肝腫大減小50%；脾腫大減小50%；ALC減小50%；及以下至少1項：血小板計數>100,000；ANC>1500/μL或Hgb>11.0g/dL)加以評估。「結點反應」定義為總淋巴結面積減小至少50%。PR狀態為調查者基於淋巴結、脾臟及肝臟之物理檢驗評定及血細胞計數之實驗室值之評估。確認的PR亦包括藉由CT掃描使腫瘤病變成像。穩定疾病為根據未確認的CR臨床反應藉由重複CT掃描來確定。 Results . "Complete response" (CR) according to IWCLL guidelines, 2008 (no LN > 1.5 cm, no hepatomegaly, splenomegaly, ALC < 4000 / μL, normal cell bone marrow <30% lymphocytes, ANC > 1500, platelets Counting >100,000 and Hgb > 11.0 g/dL) is defined. "Partial response" (PR) is via the IWCLL guidelines (at least 2 of the following guidelines: lymph node (LN) reduction) 50%; hepatomegaly is reduced 50%; splenomegaly is reduced 50%; ALC reduction 50%; and at least one of the following: platelet count >100,000; ANC > 1500 / μL or Hgb > 11.0 g / dL) was evaluated. "Node response" is defined as a reduction in total lymph node area of at least 50%. The PR status is an assessment of the laboratory values of the investigator based on physical examination of lymph nodes, spleen and liver and blood cell counts. Confirmed PR also includes imaging of tumor lesions by CT scan. Stable disease was determined by repeated CT scans based on unconfirmed CR clinical response.

組1.三名個體登記在組1且用N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽BID與來那度胺QD之組合治療。在最初登記在組1之三名個體中，一名個體遭受DLT(3級幻覺)。因為研究設計不允許劑量遞增(經由登記在下一個較高劑量下)，除非在當前劑量下3名個體中之0個或6名個體中僅1個在第一個28天週期內遭受DLT，所以另外三名個體登記在組1中。 Group 1. Three individuals were registered in Group 1 and N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl Combination treatment of acrylamide besylate sulfonate BID with lenalidomide QD. Of the three individuals initially enrolled in Group 1, one individual suffered from DLT (Level 3 Illusion). Because the study design does not allow for dose escalation (via registration at the next higher dose), unless only 1 of the 3 individuals or 6 individuals in the 3 doses suffered DLT during the first 28-day period at the current dose, The other three individuals were registered in group 1.

圖13概述到2013年10月16日為止組1中之患者的疾病狀態。根據CLL診斷及治療之IWCLL指南(Hallek,2008)評估疾病狀態。在組1中所登記之六名個體中，個體A在第1週期內展現進行性疾病且中斷治療。在第6週期中，個體B展現藉由CT掃描及骨髓生檢確認之完全反應。經由骨髓之流動式細胞測量術確認MRD陰性。個體C及F在第4週期中展現部分反應。個體D及E在第4週期中展現穩定疾病。 Figure 13 summarizes the disease status of patients in Group 1 up to October 16, 2013. Disease status was assessed according to the IWCLL guidelines for CLL diagnosis and treatment (Hallek, 2008). Among the six individuals enrolled in Group 1, Individual A exhibited progressive disease and discontinued treatment during the first cycle. In cycle 6, individual B exhibited a complete response confirmed by CT scan and bone marrow biopsy. MRD was confirmed to be negative by flow cytometry of bone marrow. Individuals C and F exhibited partial responses during the fourth cycle. Individuals D and E exhibited stable disease during the fourth cycle.

到2013年10月16日為止，個體B處於第10週期中，目前兩種藥物因AE腹瀉而暫停。個體C處於第8週期中且目前接受375mg BID化合物1苯磺酸鹽。個體D在整個第5週期中接受375mg BID化合物1苯磺酸鹽。個體D撤回同意該研究。個體E處於第7週期中且目前接受組1劑量(375mg BID化合物1苯磺酸鹽及10mg QD來那度胺)。個體F處於第6週期中且接受375mg BID劑量之化合物1苯磺酸鹽。來那度胺因持續存在之嗜中性球減少症而暫停。 As of October 16, 2013, individual B was in cycle 10 and the two drugs were currently suspended due to AE diarrhea. Individual C was in cycle 8 and currently receives 375 mg of BID Compound 1 besylate. Individual D received 375 mg of BID Compound 1 benzenesulfonate throughout Cycle 5. Individual D withdrew to consent to the study. Individual E was in cycle 7 and currently receives group 1 dose (375 mg BID Compound 1 besylate and 10 mg QD lenalidomide). Individual F was in cycle 6 and received a 375 mg BID dose of Compound 1 besylate. Lenalidomide is suspended due to persistent neutropenia.

組2.三名個體登記在組2且用N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽BID與來那度胺QD之組合治療。在最初登記在組2之三名個體中，一名個體在第一個週期內遭受DLT(3級疲勞及3級皮疹)且一名個體不可評估DLT且需要替換。另外四名個體隨後登記在組2中且開始治療。 Group 2. Three individuals were registered in Group 2 and N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl Combination treatment of acrylamide besylate sulfonate BID with lenalidomide QD. Of the three individuals initially enrolled in Group 2, one subject suffered DLT (Grade 3 and Level 3 rash) during the first cycle and one individual was unable to assess DLT and needed to be replaced. The other four individuals were subsequently enrolled in Group 2 and treatment started.

圖14概述到2013年10月16日為止組2中之個體的疾病狀態。根據CLL診斷及治療之IWCLL指南(Hallek,2008)評估疾病狀態。在登記在組2之七名個體中，可獲得4名個體之反應資料。個體A及B到第3週期為止展現部分反應。個體C及D到第2週期為止展現結點反應。個體C及D因持續存在之淋巴球增多症而尚未符合部分反應準則。無法獲得登記在組2中之其餘患者的功效資料。 Figure 14 summarizes the disease status of individuals in Group 2 up to October 16, 2013. Disease status was assessed according to the IWCLL guidelines for CLL diagnosis and treatment (Hallek, 2008). Among the seven individuals enrolled in group 2, reaction data of 4 individuals was obtained. Individuals A and B exhibited partial responses until the third cycle. Individuals C and D exhibited node responses until the second cycle. Individuals C and D have not met partial response criteria due to persistent lymphocytosis. Efficacy data for the remaining patients enrolled in Group 2 could not be obtained.

到2013年10月16日為止，兩名個體已在第5週期中因疾病進展而中斷。一名個體處於第4週期中且因持續存在於基線之血小板減少症而接受500mg BID化合物1苯磺酸鹽及減少劑量之來那度胺(5mgQD)。一名個體處於第3週期中且接受減少劑量之375mg BID化合物1苯磺酸鹽；來那度胺因不良事件疲勞而暫停。一名個體處於第3週期中且接受500mg BID化合物1苯磺酸鹽；來那度胺因不良事件嗜中性球減少症而暫停。登記在組2中之另外一名個體在第2週期內因疾病進展而中斷。 As of October 16, 2013, two individuals had been interrupted by disease progression during the fifth cycle. One individual was in cycle 4 and received 500 mg of BID Compound 1 besylate and a reduced dose of lenalidomide (5 mg QD) due to thrombocytopenia persisting at baseline. One individual was in cycle 3 and received a reduced dose of 375 mg of BID Compound 1 besylate; lenalidomide was suspended due to adverse event fatigue. One individual was in cycle 3 and received 500 mg of BID Compound 1 besylate; lenalidomide was suspended due to adverse event neutropenia. Another individual registered in Group 2 was interrupted by disease progression during the second cycle.

組2a.到2013年11月7日為止，一個患者登記在組2a中且目前處於治療第1週期中。 Group 2a. As of November 7, 2013, one patient was enrolled in Group 2a and is currently in the first cycle of treatment.

擴充組.在劑量遞增研究中完成DLT觀測後，將評估累積之安全性、PK及PD資料以便選擇初步RP2D。將在24名個體之擴充組中評估初步RP2D或較完整之安全概況且進一步初步評估功效。若24名個體中之不到9名遭受DLT，則將宣告此劑量為待用於進一步研究之RP2D。若24名個體中之大於或等於9名遭受DLT，則此劑量將視為已 超過MTD且將在24名個體中評估該研究之劑量遞增組中所發現的先前最高耐受劑量。劑量將繼續以逐步漸進方式減小，直至24名個體中之不到9名遭受DLT。 Expansion group . After DLT observations are completed in the dose escalation study, cumulative safety, PK, and PD data will be assessed to select initial RP2D. Preliminary RP2D or a more complete safety profile will be assessed in an expanded group of 24 individuals and further assessed for efficacy. If less than 9 of the 24 individuals are suffering from DLT, then this dose will be declared as RP2D to be used for further study. If greater than or equal to 9 of the 24 individuals are suffering from DLT, then this dose will be considered to have exceeded the MTD and the previous highest tolerated dose found in the dose escalation group of the study will be assessed in 24 individuals. The dose will continue to decrease in a gradual, progressive manner until less than 9 of the 24 individuals suffer from DLT.

在某些情況下，醫師調查者可在研究期間選擇使患者休息，在此期間患者不接受治療。舉例而言，醫師調查者可因不良事件之出現或再現而選擇使患者休息。出於明瞭之目的，已休息之患者仍登記在研究中，直至醫師調查者確定該患者不應繼續治療為止，此時該等患者中斷進一步治療。在此上下文中，治療持續時間係指患者登記在研究中之時間，包括所有休息期，直至治療中斷為止。 In some cases, a physician investigator may choose to rest the patient during the study, during which time the patient does not receive treatment. For example, a physician investigator may choose to rest the patient due to the occurrence or recurrence of an adverse event. For the sake of clarity, the rested patient is still enrolled in the study until the physician investigator determines that the patient should not continue treatment, at which point the patient discontinues further treatment. In this context, duration of treatment refers to the time the patient is enrolled in the study, including all rest periods, until the treatment is interrupted.

不良事件.對於所有組，劑量限制毒性(DLT)定義為在第一個28天週期內觀測到且視為與治療有關之指定不良事件(AE)。血液學DLT包括根據CTCAE(4.03版)或IWCLL準則之4級貧血或血小板減少症，任何一個均引起血液閾值下降；超過5天之4級嗜中性球減少症，縱使有粒細胞群落刺激因子(G-CSF)支撐；及3級或3級以上發熱性嗜中性球減少症。非血液學DLT包括在第1週期內任意持續時間之4級或4級以上非血液學AE；3級總膽紅素升高，無論有症狀或無症狀；及在醫學療法後持續不到24小時之除噁心、嘔吐及腹瀉以外之任何3級非血液學毒性；未發展成4級且在7天以內用醫學管理消除之腫瘤溶解症候群；及短暫的、無症狀且迅速可逆(在7天內回到基線或1級)之3級非血液學實驗室異常。 Adverse events . For all groups, dose-limiting toxicity (DLT) was defined as the specified adverse event (AE) observed during the first 28-day period and considered to be treatment-related. Hematology DLT includes grade 4 anemia or thrombocytopenia according to CTCAE (version 4.03) or IWCLL guidelines, any of which causes a drop in blood threshold; grade 4 neutropenia over 5 days, even with granulocyte community stimulating factors (G-CSF) support; and grade 3 or higher febrile neutrophilia. Non-hematologic DLT includes non-hematologic AEs of grade 4 or higher at any duration within the first cycle; elevated levels of total bilirubin at grade 3, whether symptomatic or asymptomatic; and less than 24 after medical therapy Any grade 3 non-hematologic toxicity other than nausea, vomiting, and diarrhea; tumor lysis syndrome that has not progressed to grade 4 and is medically eliminated within 7 days; and transient, asymptomatic and rapidly reversible (in 7 days) Return to baseline or Level 1) Level 3 non-hematology laboratory abnormalities.

在第一個28天治療週期結束時無疾病進展之個體適合繼續接受N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽及來那度胺，再持續28天週期，直至(i)患者遭受不可接受之毒性、(ii)潛在惡性腫瘤進展、(iii)患者撤回同意、或(iv)治療醫師調查者以其他方式確定患者不應繼續治療為止。 Individuals who have no disease progression at the end of the first 28-day treatment period are eligible to continue receiving N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidine-4- Amino)phenyl)propenylamine sulfonate and lenalidomide for a further 28-day period until (i) the patient suffers from unacceptable toxicity, (ii) potential malignancy progression, and (iii) patient withdrawal Agree, or (iv) the treating physician investigator otherwise determines that the patient should not continue treatment.

到2013年10月16日為止，組1中之個體報導出現幻覺(1名患者； 第1週期)，需要擴充組1；敗血症(1名患者；第4週期)；發燒(1名患者；第5週期)及嗜中性球減少症(1名患者；第3週期)。 As of October 16, 2013, individuals in Group 1 reported hallucinations (1 patient; In the first cycle), group 1 was required; sepsis (1 patient; cycle 4); fever (1 patient; cycle 5) and neutropenia (1 patient; cycle 3).

到2013年10月16日為止，組2中之個體報導出現敗血症(1名患者；第2週期)、血小板減少症(1名患者；第1週期，存在於基線)、發熱性嗜中性球減少症(1名患者；第2週期)及嗜中性球減少症(1名患者；第1週期)。一名個體報導出現疲勞及皮疹(第1週期)，需要擴充組2。 As of October 16, 2013, individuals in Group 2 reported sepsis (1 patient; Cycle 2), thrombocytopenia (1 patient; 1st cycle, present at baseline), febrile neutrophil Reduction (1 patient; cycle 2) and neutropenia (1 patient; cycle 1). One individual reported fatigue and rash (Phase 1) and group 2 was needed.

在組1及2中所登記之前十三名個體(組1中6名及組2中7名)中，三名報導輕度腫瘤加劇(tumor flare)，其在所有患者第二週治療結束前消除。 Of the top 13 individuals (6 of group 1 and 7 of group 2) enrolled in groups 1 and 2, three reported mild tumor flare, which was before the end of the second week of treatment in all patients. eliminate.

Btk佔有率. N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽之共價作用機制允許開發共價探針來偵測來源於組織培養物、動物組織或臨床樣品之溶解物中之游離、不受抑制之Btk。PBMC溶解物在給藥前30分鐘、給藥後4小時或24小時自全血樣品分離且與生物素標記之共價探針一起培育。不受抑制之Btk由共價探針捕捉且藉由ELISA定量。相對於未經處理之對照樣品進行校正，從而測定%Btk佔有率。 Btk occupancy. N -(3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenyl benzene sulfonate The covalent mechanism of action allows the development of covalent probes to detect free, uninhibited Btk in lysates derived from tissue culture, animal tissue or clinical samples. PBMC lysates were isolated from whole blood samples 30 minutes prior to dosing, 4 hours or 24 hours after dosing and incubated with biotinylated covalent probes. Uninhibited Btk was captured by covalent probes and quantified by ELISA. The %Btk occupancy was determined by calibration relative to the untreated control sample.

Btk目標位點佔有率ELISA：細胞溶解物或脾臟勻漿與含1μM N1-(3-(3-(4-(3-丙烯醯胺基苯基胺基)-5-甲基嘧啶-2-基胺基)苯氧基)丙基)-N5-(15-側氧基-19-((3aS,4S,6aR)-2-側氧基六氫-1H-噻吩并[3,4-d]咪唑-4-基)-4,7,10-三氧雜-14-氮雜十九基)戊二醯胺(2)之PBS、0.05% Tween-20、1% BSA溶液一起在室溫下培育1小時。化合物2具有以下結構： Btk target site occupancy ELISA: cell lysate or spleen homogenate with 1 μM N 1 -(3-(3-(4-(3-acrylamidophenylamino)-5-methylpyrimidine-2) -aminoamino)phenoxy)propyl)-N 5 -(15-sided oxy-19-((3aS,4S,6aR)-2-yloxyhexahydro-1 H -thieno[3, 4-d]imidazol-4-yl)-4,7,10-trioxa-14-aza-n-pentyl)pentaneamine ( 2 ) in PBS, 0.05% Tween-20, 1% BSA solution together Incubate for 1 hour at room temperature. Compound 2 has the following structure:

將標準物及樣品轉移至塗佈有抗生蛋白鏈菌素之96孔ELISA板且在震盪時在室溫下混合1小時。α-Btk抗體(BD 611116，1：1000稀釋於PBS+0.05% Tween-20+0.5% BSA中)接著在室溫下培育1小時。在洗滌後，添加山羊α-小鼠-HRP(1：5000稀釋於PBS+0.05% Tween-20+0.5% BSA中)且在室溫下培育1小時。ELISA藉由添加四甲基聯苯胺(TMB)接著添加停止溶液而顯影且在OD 450nm下讀取。使用人類全長重組Btk蛋白質生成標準曲線(11.7-3000pg/μL)且使用Gen5軟體中之4參數曲線擬合繪圖。自樣品偵測到之不受抑制之Btk校正為μg蛋白質總量，如由BCA蛋白質分析所測定(Pierce目錄號23225)。 Standards and samples were transferred to 96-well ELISA plates coated with streptavidin and mixed for 1 hour at room temperature on shaking. The α-Btk antibody (BD 611116, 1:1000 diluted in PBS + 0.05% Tween-20 + 0.5% BSA) was then incubated for 1 hour at room temperature. After washing, goat alpha-mouse-HRP (1:5000 diluted in PBS + 0.05% Tween-20 + 0.5% BSA) was added and incubated for 1 hour at room temperature. The ELISA was developed by the addition of tetramethylbenzidine (TMB) followed by the addition of a stop solution and read at OD 450 nm. A standard curve (11.7-3000 pg/μL) was generated using human full-length recombinant Btk protein and the mapping was fitted using a 4-parameter curve in the Gen5 software. Btk, which was undetected from the sample, was corrected to the total amount of μg of protein as determined by BCA protein analysis (Pierce Cat. No. 23225).

實例2 Example 2 Cell Titer Glo組合分析Cell Titer Glo combination analysis

在四個模型B細胞癌細胞株中分析N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽(化合物1苯磺酸鹽)及來那度胺之組合，以確定該組合是否展現任何協同效應。 Analysis of N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl) in four model B cell carcinoma cell lines A combination of acrylamide sulfonate (compound 1 besylate) and lenalidomide to determine if the combination exhibits any synergistic effect.

DLBCL細胞株OCI-LY-10、WSU-DLCL2、Riva及TMD-8生長於RMPI+10% FBS培養基中且以10000個細胞/孔塗佈於96孔板中。各細胞株以90微升/孔塗佈於多個96孔板。 DLBCL cell lines OCI-LY-10, WSU-DLCL2, Riva and TMD-8 were grown in RMPI + 10% FBS medium and plated in 96-well plates at 10,000 cells/well. Each cell strain was applied to a plurality of 96-well plates at 90 μl/well.

基於各細胞株之初始化合物生存率分析，確定用於各細胞株之 化合物濃度範圍以便在均勻展開細胞生存率的情況下達到最大及最小細胞生存率。製備10mM之化合物1苯磺酸鹽於DMSO中之儲備溶液。將10mM儲備溶液稀釋3×-10×至3333與1000nM之間且在DMSO中以10點稀釋系列進一步稀釋3倍。稀釋系列在RMPI+10% FBS培養基中稀釋50×且添加5μL化合物1苯磺酸鹽至95μL細胞培養物中，產生1：1000稀釋物。 Based on the initial compound survival analysis of each cell line, the concentration range of the compound used for each cell strain was determined to achieve maximum and minimum cell survival rates in the case of uniform cell survival. A stock solution of 10 mM Compound 1 besylate in DMSO was prepared. The 10 mM stock solution was diluted between 3 x - 10 x to 3333 and 1000 nM and further diluted 3 fold in DMSO in a 10 point dilution series. The dilution series was diluted 50× in RMPI + 10% FBS medium and 5 μL of Compound 1 besylate was added to 95 μL of cell culture to yield a 1:1000 dilution.

來那度胺在DMSO中製備成10mM儲備溶液且在DMSO中稀釋1000×至所需最終濃度。稀釋系列在RMPI+10% FBS培養基中稀釋200×且添加5μL來那度胺至95μL細胞培養物中，產生1：1000稀釋物。來那度胺之最終濃度範圍介於41-10000nM之間。 Lenalidomide was prepared as a 10 mM stock solution in DMSO and diluted 1000 x in DMSO to the desired final concentration. The dilution series was diluted 200 x in RMPI + 10% FBS medium and 5 [mu]L of lenalidomide was added to 95 [mu]L of cell culture to yield a 1:1000 dilution. The final concentration of lenalidomide ranges from 41 to 10000 nM.

對於組合分析，添加一種濃度之來那度胺至化合物1苯磺酸鹽之一式三份稀釋系列中。分析至少三種且至多五種不同濃度之來那度胺與化合物1苯磺酸鹽之一式三份稀釋系列之組合。在塗佈後第二天將化合物1苯磺酸鹽及來那度胺相伴隨地應用於細胞。 For combinatorial analysis, a concentration of lenalidomide to a one-part dilution series of compound 1 besylate was added. A combination of at least three and up to five different concentrations of lenalidomide and one of the three dilutions of Compound 1 besylate is analyzed. Compound 1 besylate and lenalidomide were applied to the cells on the second day after coating.

在藥物投與後72小時，根據製造商說明書使用CellTiter-Glo測定活細胞的數目。簡言之，使細胞及CellTiter-Glo平衡至室溫。將CellTiter-Glo以1：1(v/v)添加至細胞且進行分析。在Molecular Devices spectramax L發光偵測器上讀取結果。 The number of viable cells was determined using CellTiter-Glo 72 hours after drug administration according to the manufacturer's instructions. Briefly, cells and CellTiter-Glo were allowed to equilibrate to room temperature. CellTiter-Glo was added to the cells at 1:1 (v/v) and analyzed. The results were read on a Molecular Devices spectramax L luminescence detector.

將發光讀數校正為平均對照(DMSO處理)發光讀數之百分比。使用下式計算預期組合生存率：(化合物1苯磺酸鹽%存活分率)×(來那度胺%存活分率)/100 The luminescence readings were corrected to the percentage of the average control (DMSO treated) luminescence reading. The expected combination survival rate was calculated using the following formula: (Compound 1 benzenesulfonate % survival fraction) × (Lenalidomide % survival fraction) / 100

使用具有XLfit插件之Microsoft Excel繪製生存率曲線。藉由繪製在觀測到及預期之組合治療值之間的差異產生協同作用(「火山」)圖。結果呈現於圖1-12中。除非另外指明，否則圖式中描繪之圖形為例示性的。 The survival rate curve was drawn using Microsoft Excel with the XLfit plugin. A synergistic ("volcano") map is generated by plotting the difference between the observed and expected combination of treatment values. The results are presented in Figures 1-12 . The figures depicted in the drawings are illustrative unless otherwise indicated.

圖1、3、5、7、9及11中之劑量反應曲線描繪化合物1苯磺酸鹽與 來那度胺之組合在細胞株OCI-LY-10(圖1)、WSU-DLCL2(圖3)、Riva(圖5、7及9)及TMD-8(圖11)中之結果。細胞對濃度增加之化合物1苯磺酸鹽的反應由●指示。細胞對測試濃度之來那度胺的反應由□指示。該組合之預期(或計算)活性由△指示。該組合之觀測到之活性由◇指示。當該組合之預期或計算活性等於觀測到之活性時(亦即當由△及◇表示之線重疊時)，該組合為累加的。 The dose response curves in Figures 1, 3, 5, 7, 9 and 11 depict the combination of Compound 1 besylate and lenalidomide in the cell line OCI-LY-10 (Figure 1), WSU-DLCL2 (Figure 3 ), Riva (Figures 5, 7 and 9) and TMD-8 (Figure 11). The response of the cells to the concentration of Compound 1 besylate is indicated by ●. The response of the cells to the test concentration of lenalidomide is indicated by □. The expected (or calculated) activity of the combination is indicated by Δ. The observed activity of this combination is indicated by ◇. When the expected or calculated activity of the combination is equal to the observed activity (i.e., when the lines represented by Δ and ◇ overlap), the combination is additive.

圖1呈現使用化合物1苯磺酸鹽及一種特定濃度之來那度胺(3000nM)在OCI-LY-10細胞株中所觀測到之劑量反應曲線。圖1中所呈現之結果似乎展示累加效應，且藉由額外實驗確認(資料未展示)。圖1因此可視為代表在OCI-LY-10細胞株中關於化合物1苯磺酸鹽與來那度胺之組合所獲得的資料。圖2呈現化合物1苯磺酸鹽及來那度胺在OCI-LY-10細胞株中之「火山」圖。圖2中展示之火山圖為使用在不同濃度來那度胺下進行之實驗的資料生成，且代表在OCI-LY-10細胞株中之額外實驗。藉由額外實驗確認結果(資料未展示)。化合物1苯磺酸鹽及來那度胺因此在OCI-LY-10細胞株中似乎為累加的。 Figure 1 presents dose response curves observed with compound 1 besylate and a specific concentration of lenalidomide (3000 nM) in OCI-LY-10 cell lines. The results presented in Figure 1 appear to show an additive effect and are confirmed by additional experiments (data not shown). Figure 1 can thus be considered to represent data obtained in the OCI-LY-10 cell line for the combination of Compound 1 besylate and lenalidomide. Figure 2 presents a "volcano" plot of Compound 1 besylate and lenalidomide in the OCI-LY-10 cell line. The volcano map shown in Figure 2 is generated using data from experiments conducted at different concentrations of lenalidomide and represents an additional experiment in the OCI-LY-10 cell line. Confirm the results by additional experiments (data not shown). Compound 1 besylate and lenalidomide therefore appeared to be additive in the OCI-LY-10 cell line.

圖3描繪WSU-DLCL2細胞株中化合物1苯磺酸鹽及一種特定濃度之來那度胺(3333nM)的特定劑量反應曲線。藉由額外實驗確認圖3中描繪之結果(資料未展示)。圖3因此可視為代表在WSU-DLCL2細胞株中關於化合物1苯磺酸鹽與來那度胺之組合所獲得的資料。圖3中呈現之結果似乎展示累加效應。圖4呈現化合物1苯磺酸鹽及來那度胺在WSU-DLCL2細胞株中之「火山」圖。亦測試來那度胺與37nM、111nM、370nM及1111nM之化合物1苯磺酸鹽之組合。在此實驗中，在此等濃度下無明顯協同作用(資料未展示)。化合物1苯磺酸鹽及來那度胺因此在WSU-DLCL2細胞株中似乎為累加的。 Figure 3 depicts a specific dose response curve for Compound 1 besylate and a specific concentration of lenalidomide (3333 nM) in the WSU-DLCL2 cell line. The results depicted in Figure 3 were confirmed by additional experiments (data not shown). Figure 3 thus can be considered to represent data obtained in the WSU-DLCL2 cell line for the combination of Compound 1 besylate and lenalidomide. The results presented in Figure 3 appear to show an additive effect. Figure 4 presents a "volcano" plot of Compound 1 besylate and lenalidomide in a WSU-DLCL2 cell line. The combination of lenalidomide with 37 nM, 111 nM, 370 nM and 1111 nM of Compound 1 besylate was also tested. In this experiment, there was no significant synergy at these concentrations (data not shown). Compound 1 besylate and lenalidomide therefore appeared to be additive in the WSU-DLCL2 cell line.

圖5描繪Riva細胞株中化合物1苯磺酸鹽及來那度胺(3333nM)之特定劑量反應曲線。在此濃度下，化合物1苯磺酸鹽及來那度胺似乎 為協同的(由箭頭指示)。圖6呈現在41nM、1111nM及3333nM之來那度胺濃度下，化合物1苯磺酸鹽及來那度胺在Riva細胞株中之「火山」圖。在某些濃度下，化合物1苯磺酸鹽及來那度胺似乎為協同的(由箭頭指示)。 Figure 5 depicts a specific dose response curve for Compound 1 besylate and lenalidomide (3333 nM) in Riva cell lines. At this concentration, Compound 1 besylate and lenalidomide appeared to be synergistic (indicated by arrows). Figure 6 presents a "volcano" plot of Compound 1 besylate and lenalidomide in Riva cell lines at concentrations of lenalidomide at 41 nM, 1111 nM and 3333 nM. At certain concentrations, Compound 1 besylate and lenalidomide appeared to be synergistic (indicated by arrows).

圖7呈現Riva細胞株中化合物1苯磺酸鹽及來那度胺(333nM)之特定劑量反應曲線。化合物1苯磺酸鹽及來那度胺在此圖中似乎為協同的(由箭頭指示)。圖8呈現在41nM、123nM及370nM之來那度胺濃度下，使用化合物1苯磺酸鹽及來那度胺在Riva細胞株中之特定實驗的「火山」圖。化合物1苯磺酸鹽及來那度胺在此圖中似乎為協同的(由箭頭指示)。 Figure 7 presents a specific dose response curve for Compound 1 besylate and lenalidomide (333 nM) in the Riva cell line. Compound 1 besylate and lenalidomide appear synergistic in this figure (indicated by arrows). Figure 8 presents a "volcano" plot of a specific experiment using Compound 1 besylate and lenalidomide in Riva cell lines at lenalidomide concentrations of 41 nM, 123 nM and 370 nM. Compound 1 and benzenesulfonate lenalidomide appears to be synergistic (indicated by arrows) in this figure.

圖9呈現Riva細胞株中化合物1苯磺酸鹽及來那度胺(333nM)之另一劑量反應曲線。化合物1苯磺酸鹽及來那度胺在此圖中似乎為累加的。圖10呈現在41nM、123nM及370nM之來那度胺濃度下，化合物1苯磺酸鹽及來那度胺在Riva細胞株中之另一實驗的「火山」圖。化合物1苯磺酸鹽及來那度胺在圖10中似乎為累加的。圖7-10中之資料似乎展示化合物1苯磺酸鹽與來那度胺之組合並不拮抗，且可為協同的。 Figure 9 presents another dose response curve for Compound 1 besylate and lenalidomide (333 nM) in the Riva cell line. Compound 1 besylate and lenalidomide appear to be additive in this figure. Figure 10 presents a "volcano" plot of another experiment of Compound 1 besylate and lenalidomide in Riva cell lines at concentrations of lenalidomide at 41 nM, 123 nM and 370 nM. Compound 1 besylate and lenalidomide appeared to be additive in Figure 10 . The data in Figures 7-10 appear to show that the combination of Compound 1 besylate and lenalidomide is not antagonistic and may be synergistic.

圖11呈現TMD-8細胞株中化合物1苯磺酸鹽及來那度胺(3000nM)之特定劑量反應曲線。化合物1苯磺酸鹽及來那度胺似乎為協同的(由箭頭指示)。圖12呈現在300nM、1000nM及3000nM之來那度胺濃度下，使用化合物1苯磺酸鹽及來那度胺在TMD-8細胞株中之特定實驗的「火山」圖。化合物1苯磺酸鹽及來那度胺在此圖中似乎為協同的(由箭頭指示)。亦測試來那度胺與100nM、300nM及1000nM濃度之化合物1苯磺酸鹽之組合，且確認明顯協同作用(資料未展示)。 Figure 11 presents a specific dose response curve for Compound 1 besylate and lenalidomide (3000 nM) in the TMD-8 cell line. Compound 1 besylate and lenalidomide appeared to be synergistic (indicated by arrows). Figure 12 presents a "volcano" plot of a specific experiment using Compound 1 besylate and lenalidomide in a TMD-8 cell line at concentrations of lenalidomide at 300 nM, 1000 nM, and 3000 nM. Compound 1 besylate and lenalidomide appear synergistic in this figure (indicated by arrows). The combination of lenalidomide with Compound 1 besylate at concentrations of 100 nM, 300 nM and 1000 nM was also tested and significant synergy was confirmed (data not shown).

化合物1苯磺酸鹽及來那度胺在OCI-LY-10(圖1及圖2)及WSU-DLCL2(圖3及圖4)細胞株中似乎為累加的。 Compound 1 besylate and lenalidomide appeared to be additive in OCI-LY-10 ( Figures 1 and 2 ) and WSU-DLCL2 ( Figures 3 and 4 ) cell lines.

在圖5及圖6中，在3333nM濃度之來那度胺下，化合物1苯磺酸鹽及來那度胺在Riva細胞株中似乎為協同的。化合物1苯磺酸鹽及來那度胺在圖5及6中似乎為協同的(由箭頭指示)。在圖7及8中，在333nM濃度之來那度胺下，化合物1苯磺酸鹽及來那度胺展示一些明顯的協同作用。在圖9及10中，在333nM濃度之來那度胺下，化合物1苯磺酸鹽及來那度胺似乎為累加的。在圖11及圖12中，確認化合物1苯磺酸鹽及來那度胺在TMD-8細胞株中為協同的。因此，在至少TMD-8細胞株中，化合物1苯磺酸鹽及來那度胺似乎展示協同效應。亦似乎在Riva細胞株中觀測到協同作用的一些證據。 In Figures 5 and 6 , Compound 1 besylate and lenalidomide appeared to be synergistic in the Riva cell line at 3333 nM concentration of lenalidomide. Compound 1 besylate and lenalidomide appeared synergistic in Figures 5 and 6 (indicated by arrows). In Figures 7 and 8 , Compound 1 besylate and lenalidomide exhibited some significant synergy at 333 nM concentration of lenalidomide. In Figures 9 and 10 , Compound 1 besylate and lenalidomide appeared to be additive at 333 nM concentration of lenalidomide. In Fig. 11 and Fig. 12 , it was confirmed that the compound 1 besylate and lenalidomide were synergistic in the TMD-8 cell line. Thus, Compound 1 besylate and lenalidomide appear to exhibit a synergistic effect in at least the TMD-8 cell line. It also appears that some evidence of synergy has been observed in Riva cell lines.

實例3Example 3

針對342種激酶篩選一種特定的不可逆BTK抑制劑化合物2，以確定激酶活性及/或選擇性： Screen for a specific irreversible BTK inhibitor Compound 2 against 342 kinases to determine kinase activity and/or selectivity:

用於瞭解激酶活性概況之結合分析系統基於HotSpot技術(Reaction Biology Corp.；Malvern,PA,USA)且使用基於放射性同位素之P81過濾。將化合物2溶解於純DMSO中以製得10mM儲備溶液，且進行連續稀釋至最終3μM測試濃度。每日在反應緩衝液中新鮮製備針對化合物2測試之各種激酶的受質(受質信息可在Reaction Biology Corp.網站上獲得)。接著添加任何所需輔因子至受質溶液。各種激酶之適當輔因子的鑑定及選擇在熟習此項技術者之能力內。參見例如Handbook of Assay Development in Drug Discovery,Lisa K.編Minor, 2006：CRC出版社，Boca Raton,Florida；Gao等人，「A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery」,Biochem J.2013,451(2)：313-28；及Eglen等人，「Drug discovery and the human kinome： Recent trends」,Pharmacology & Therapeutics 2011,130(2)：144-156。接著添加激酶至受質溶液且平緩地混合。化合物2(5nL)接著藉由音波式液滴噴射而添加至激酶反應混合物且在室溫下預培育30分鐘。將33P-ATP(100μM)傳遞至反應混合物中以引發反應。此後在室溫下培育2小時。終止反應且使用0.1%磷酸洗去任何未反應之磷酸鹽，隨後利用專有技術偵測。一式兩份地進行研究且使用星形孢菌素(staurosporine，一種非選擇性、ATP競爭性激酶抑制劑)作為具有起始於1μM、50μM或100μM之3倍連續稀釋液的10次劑量IC50模式中之陽性對照。DMSO用作陰性對照。 The binding assay system for understanding the activity profile of the kinase was based on the HotSpot technique (Reaction Biology Corp.; Malvern, PA, USA) and was filtered using a radioisotope based P81. Compound 2 was dissolved in pure DMSO to make a 10 mM stock solution and serial dilutions were made to a final 3 [mu]M test concentration. The substrate for each of the kinases tested for Compound 2 was prepared daily in reaction buffer (substance information is available on the Reaction Biology Corp. website). Any desired cofactor is then added to the substrate solution. Identification and selection of appropriate cofactors for various kinases is within the skill of those skilled in the art. See, for example, Handbook of Assay Development in Drug Discovery , Lisa K. ed. Minor, 2006: CRC Press, Boca Raton, Florida; Gao et al., "A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery" , Biochem J. 2013, 451(2): 313-28; and Eglen et al., "Drug discovery and the human kinome: Recent trends", Pharmacology & Therapeutics 2011, 130(2): 144-156. The kinase is then added to the substrate and gently mixed. Compound 2 (5 nL) was then added to the kinase reaction mixture by sonic droplet ejection and pre-incubated for 30 minutes at room temperature. 33 P-ATP (100 μM) was delivered to the reaction mixture to initiate the reaction. Thereafter, it was incubated at room temperature for 2 hours. The reaction was terminated and any unreacted phosphate was washed away with 0.1% phosphoric acid and subsequently detected using proprietary techniques. Studies were performed in duplicate and staurosporine (a non-selective, ATP-competitive kinase inhibitor) was used as a 10-dose IC50 model with 3 fold serial dilutions starting at 1 μM, 50 μM or 100 μM. A positive control in the middle. DMSO was used as a negative control.

抑制百分比之測定 .根據下式確定測試化合物(例如化合物2)對激酶之抑制百分比：抑制百分比=[(陰性對照之激酶活性)-(在例如化合物2之測試化合物存在下的激酶活性)/(陰性對照之激酶活性)]×100。抑制百分比表示為在進行不止一次(例如一式兩份)分析之情況下的平均值。 Determination of percentage of inhibition. Percent inhibition of kinase by test compound (eg Compound 2 ) is determined according to the following formula: percent inhibition = [(kinase activity of negative control) - (kinase activity in the presence of, for example, test compound of compound 2 ) / ( Kinase activity of the negative control)] × 100. Percent inhibition is expressed as the average value in the case of more than one (eg, duplicate) analysis.

表7闡述化合物2針對各種激酶之平均抑制百分比： Table 7 illustrates the average percent inhibition of Compound 2 against various kinases:

實例4Example 4 利妥昔單抗之劑量遞增研究Dose escalation study of rituximab

此研究所用之包含N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽之膠囊對應於實例1中之表1。 N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)propenyl benzene sulfonic acid is used in this study. The capsule of salt corresponds to Table 1 in Example 1.

來那度胺膠囊對應於實例1之表2及3中所列舉之來那度胺膠囊。 The lenalidomide capsules correspond to the lenalidomide capsules listed in Tables 2 and 3 of Example 1.

利妥昔單抗以10mg/mL小瓶(包含100mg/10mL或500mg/50mL)提供於醫師/調查者。在投與前，用5%右旋糖水溶液或0.9%氯化鈉稀釋利妥昔單抗至1mg/mL、2mg/mL、3mg/mL或4mg/mL之劑量。此後根據下表8中陳述之劑量，以1mg/mL至4mg/mL輸注形式投與利妥昔單抗。 Rituximab is provided to the physician/investigator in a 10 mg/mL vial containing 100 mg/10 mL or 500 mg/50 mL. Rituximab was diluted to a dose of 1 mg/mL, 2 mg/mL, 3 mg/mL or 4 mg/mL with 5% dextrose in water or 0.9% sodium chloride prior to administration. Thereafter, rituximab was administered as an infusion as described in Table 8, below, at a dose of 1 mg/mL to 4 mg/mL.

研究設計Research design

在「3+3」劑量遞增及擴充研究中登記具有至少一個先前治療方案之患有復發性或難治性CLL或SLL之個體以便測定化合物1、來那度胺及利妥昔單抗之非耐受劑量(NTD)、最佳生物效應劑量(OBE)及最大耐受劑量(MTD)。預期在該研究中登記約30-42名患者。 Individuals with recurrent or refractory CLL or SLL with at least one prior treatment regimen were enrolled in the "3+3" dose escalation and expansion study to determine the resistance of Compound 1 , lenalidomide and rituximab Subjected dose (NTD), optimal biological effect dose (OBE) and maximum tolerated dose (MTD). Approximately 30-42 patients are expected to be enrolled in the study.

在28天週期中以規定劑量如期投與研究治療，直至疾病進展、毒性不可接受或出於任何其他原因中斷為止。個體將以起始劑量繼續直至確定初步推薦2期劑量(RP2D)，此時其可轉變成初步RP2D。 Study treatment is administered as scheduled at the prescribed dose over a 28 day period until disease progression, toxicity is unacceptable, or is interrupted for any other reason. The individual will continue with the starting dose until a preliminary recommended phase 2 dose (RP2D) is determined, at which point it can be converted to a preliminary RP2D.

將根據表8中列舉之組投與N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽(化合物1苯磺酸鹽)、來那度胺及利妥昔單抗： N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilinyl)pyrimidin-4-ylamino)phenyl)propene will be administered according to the groups listed in Table 8. Indole benzene sulfonate (compound 1 besylate), lenalidomide and rituximab:

在各組內，個體將根據表8中之組進行治療且評估安全性、耐受性及DLT，以及藥物動力學(「PK」)、藥效學(「PD」)及疾病反應。 Within each group, individuals will be treated according to the group in Table 8 and assessed for safety, tolerability, and DLT, as well as pharmacokinetics ("PK"), pharmacodynamics ("PD"), and disease response.

根據表8投與(PO)化合物1苯磺酸鹽及來那度胺。 (PO) Compound 1 besylate and lenalidomide were administered according to Table 8.

利妥昔單抗以單次靜脈內(IV)輸注形式投與。在第1週期內之初始輸注將以375mg/m2投與；在第2週期至第6週期內之後續輸注將以500mg/m2投與。利妥昔單抗之投與將發生在各28天週期之第1天。在第6週期輸注後，將中斷利妥昔單抗。若適當，個體可繼續用化合物1苯磺酸鹽及/或來那度胺治療。利妥昔單抗之首次輸注將在50mg/h之速率下。在不存在輸注毒性之情況下，輸注速率將以每30分鐘50mg/h遞增量增加，達到最大400mg/h。各後續輸注將以100mg/h開始。在不存在輸注毒性之情況下，輸注速率將以30分鐘時間間隔100mg/h遞增量增加，達到最大400mg/h。 Rituximab is administered as a single intravenous (IV) infusion. The initial infusion in the first cycle will be administered at 375 mg/m 2 ; the subsequent infusion in the second to sixth cycles will be administered at 500 mg/m 2 . The administration of rituximab will occur on the first day of each 28-day cycle. After the infusion of the sixth cycle, rituximab will be discontinued. If appropriate, the individual can continue to be treated with Compound 1 besylate and/or lenalidomide. The first infusion of rituximab will be at a rate of 50 mg/h. In the absence of infusion toxicity, the infusion rate will increase by 50 mg/h every 30 minutes, reaching a maximum of 400 mg/h. Each subsequent infusion will start at 100 mg/h. In the absence of infusion toxicity, the infusion rate will increase by 100 mg/h in 30 minute intervals to a maximum of 400 mg/h.

若來那度胺在5mg下之2個週期後(亦即總共至少3個28天週期結束後)未達成耐受及/或所需反應，則來那度胺之劑量可遞增至10mgQD。 If lenalidomide does not achieve tolerance and/or desired response after 2 cycles at 5 mg (i.e., after a total of at least 3 28-day cycles have ended), the dose of lenalidomide can be increased to 10 mg QD.

Claims (28)

一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與化合物1(N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺)： 或其醫藥學上可接受之鹽，及來那度胺(lenalidomide)。 A method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering Compound 1 ( N- (3-(5-fluoro-2-(4)) to a patient in need thereof) -(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine): Or a pharmaceutically acceptable salt thereof, and lenalidomide. 如請求項1之方法，其中該與BTK相關之疾病或病狀為慢性淋巴球性白血病。 The method of claim 1, wherein the disease or condition associated with BTK is chronic lymphocytic leukemia. 如請求項1之方法，其中該與BTK相關之疾病或病狀為小淋巴球性淋巴瘤。 The method of claim 1, wherein the disease or condition associated with BTK is a small lymphocytic lymphoma. 如請求項2或3之方法，其中化合物1一天投與兩次。 The method of claim 2 or 3, wherein Compound 1 is administered twice a day. 如請求項4之方法，其中化合物1呈苯磺酸鹽形式。 The method of claim 4, wherein the compound 1 is in the form of a besylate salt. 如請求項5之方法，其中來那度胺一天投與一次。 The method of claim 5, wherein the lenalidomide is administered once a day. 如請求項6之方法，其中化合物1及來那度胺各自以口服劑型投與。 The method of claim 6, wherein the compound 1 and lenalidomide are each administered in an oral dosage form. 如請求項7之方法，其中化合物1及來那度胺各自投與至少一個28天週期。 The method of claim 7, wherein Compound 1 and lenalidomide are each administered for at least one 28 day period. 如請求項2或3之方法，其中該患者已失敗至少一個先前療法。 The method of claim 2 or 3, wherein the patient has failed at least one prior therapy. 如請求項5之方法，其中化合物1以包含約10%至約50% N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽之組合物形式投與。 The method of claim 5, wherein the compound 1 comprises from about 10% to about 50% of N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidine-4 The composition of the composition of the group -aminoamino)phenyl)propenylamine besylate is administered. 如請求項10之方法，其中該組合物包含約42% N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺苯磺酸鹽。 The method of claim 10, wherein the composition comprises about 42% N- (3-(5-fluoro-2-(4-(2-methoxyethoxy)anilino)pyrimidin-4-ylamino) Phenyl) acrylamide benzene sulfonate. 如請求項1之方法，另外包含投與抗CD20抗體。 The method of claim 1, additionally comprising administering an anti-CD20 antibody. 一種預防、治療、穩定或減輕選自由慢性淋巴球性白血病及小淋巴球性淋巴瘤組成之群之疾病或失調之嚴重程度或進展的方法，該方法包含向有需要之患者投與治療有效量之化合物1或其醫藥學上可接受之鹽及治療有效量之來那度胺，其中化合物1之該治療有效量為每日約750mg至約1000mg。 A method of preventing, treating, stabilizing or ameliorating the severity or progression of a disease or disorder selected from the group consisting of chronic lymphocytic leukemia and small lymphocytic lymphoma, the method comprising administering a therapeutically effective amount to a patient in need thereof Compound 1 or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of lenalidomide, wherein the therapeutically effective amount of Compound 1 is from about 750 mg to about 1000 mg per day. 如請求項13之方法，其中化合物1之該治療有效量為約375mg BID。 The method of claim 13, wherein the therapeutically effective amount of Compound 1 is about 375 mg BID. 如請求項13之方法，其中化合物1之該治療有效量為約500mg BID。 The method of claim 13, wherein the therapeutically effective amount of Compound 1 is about 500 mg BID. 如請求項14或15之方法，其中來那度胺之該治療有效量為約10mg。 The method of claim 14 or 15, wherein the therapeutically effective amount of lenalidomide is about 10 mg. 如請求項14或15之方法，其中來那度胺之該治療有效量為約5mg。 The method of claim 14 or 15, wherein the therapeutically effective amount of lenalidomide is about 5 mg. 如請求項16或17之方法，其中來那度胺一天投與一次(QD)。 The method of claim 16 or 17, wherein the lenalidomide is administered once a day (QD). 如請求項13之方法，另外包含投與抗CD20抗體。 The method of claim 13, additionally comprising administering an anti-CD20 antibody. 一種用於治療、穩定或減輕一或多種與BTK相關之疾病或病狀之嚴重程度的系統，該系統包含化合物1或其醫藥學上可接受之鹽及來那度胺。 A system for treating, stabilizing or ameliorating the severity of one or more diseases or conditions associated with BTK, the system comprising Compound 1, or a pharmaceutically acceptable salt thereof, and lenalidomide. 如請求項20之方法，其中該系統另外包含抗CD20抗體。 The method of claim 20, wherein the system further comprises an anti-CD20 antibody. 一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與不可逆BTK抑制劑及來那度胺，其中該不可逆BTK抑制劑具有選自以下各物之激酶 之不超過約50%抑制：c-Kit、PDGFRa、RIPK2、HCK、EPHA6、LYN、CSK、LCK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、BRAF、RIPK3、ARAF及SRMS，或其組合。 A method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions comprising administering to a patient in need thereof an irreversible BTK inhibitor and lenalidomide, wherein the irreversible BTK inhibitor has a kinase selected from the following Not more than about 50% inhibition: c-Kit, PDGFRa, RIPK2, HCK, EPHA6, LYN, CSK, LCK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, BRAF, RIPK3, ARAF and SRMS, or a combination thereof . 如請求項22之方法，其中另外投與該有需要之患者抗CD20抗體。 The method of claim 22, wherein the patient anti-CD20 antibody is additionally administered. 如請求項22之方法，其中該不可逆BTK抑制劑具有選自以下各物之激酶之不超過約30%抑制：c-Kit、RIPK2、HCK、EPHA6、LYN、CSK、ZAK/MLTK、LYN B、FRK/PTK5、FYN、BRAF、RIPK3、ARAF及SRMS，或其組合。 The method of claim 22, wherein the irreversible BTK inhibitor has no more than about 30% inhibition of a kinase selected from the group consisting of c-Kit, RIPK2, HCK, EPHA6, LYN, CSK, ZAK/MLTK, LYN B, FRK/PTK5, FYN, BRAF, RIPK3, ARAF and SRMS, or a combination thereof. 如請求項22之方法，其中該不可逆BTK抑制劑具有選自以下各物之激酶之不超過約10%抑制：EPHA6、LYN B、FRK/PTK5、BRAF、RIPK3、ARAF及SRMS，或其組合。 The method of claim 22, wherein the irreversible BTK inhibitor has no more than about 10% inhibition of a kinase selected from the group consisting of: EPHA6, LYN B, FRK/PTK5, BRAF, RIPK3, ARAF, and SRMS, or a combination thereof. 如請求項22之方法，其中該不可逆BTK抑制劑具有不超過約20-30%之LYN之抑制百分比。 The method of claim 22, wherein the irreversible BTK inhibitor has a percent inhibition of LYN of no more than about 20-30%. 如請求項22之方法，另外包含投與抗CD20抗體。 The method of claim 22, additionally comprising administering an anti-CD20 antibody. 一種治療、穩定或減輕一或多種與BTK相關之疾病及病狀之嚴重程度或進展的方法，包含向有需要之患者投與化合物1(N-(3-(5-氟-2-(4-(2-甲氧基乙氧基)苯胺基)嘧啶-4-基胺基)苯基)丙烯醯胺)： 或其醫藥學上可接受之鹽、來那度胺及抗CD20抗體。 A method of treating, stabilizing or ameliorating the severity or progression of one or more BTK-related diseases and conditions, comprising administering Compound 1 ( N- (3-(5-fluoro-2-(4)) to a patient in need thereof) -(2-methoxyethoxy)anilino)pyrimidin-4-ylamino)phenyl)propenylamine): Or a pharmaceutically acceptable salt thereof, lenalidomide and an anti-CD20 antibody.
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