TW202140470A - Methods of cancer treatment using bcl-2 inhibitor - Google Patents
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本文揭露了用Bcl-2抑制劑、特別是化合物1或其藥學上可接受的鹽治療癌症之方法。This article discloses a method of treating cancer with a Bcl-2 inhibitor, particularly Compound 1 or a pharmaceutically acceptable salt thereof.
細胞凋亡功能受損對腫瘤發展、腫瘤維持和治療抗性具有重要影響。可經由以下兩條主要途徑觸發細胞凋亡：外源性或死亡受體媒介途徑，以及內源性或粒線體途徑（Czabotar等人，2014）。在淋巴惡性瘤中，更常影響內源性途徑。藉由這個途徑媒介的細胞死亡，由B細胞淋巴瘤-2(Bcl-2)相關蛋白家族成員調控，此家族目前包括三個亞家族。促存活亞組（Bcl-2、Bcl-xL、Bcl-W、Mcl-1、A1/Bfl-1，及可能包括Bcl-B）藉由抑制其促凋亡相關蛋白來增進細胞存活。促凋亡BAX/BAK樣蛋白（包括BOK）為細胞凋亡的重要效應子，且單一BH3區段蛋白(BH3-only protein)（BIM、PUMA、BID、NOXA、BMF、BIK和HRK）為細胞凋亡的起始子（Anderson等人，2014）。在健康細胞中，促存活Bcl-2蛋白結合並抑制BAX和BAK（在其受到部分激活後），從而降低BAX/BAK寡聚體化並形成孔洞以引發粒線體外膜通透的能力。單一BH3區段蛋白在不同的壓力下轉錄或轉錄後引發，並藉由結合促存活Bcl-2蛋白從而釋放BAX/BAK，或藉由直接活化這些細胞凋亡的效應子，以啟動細胞凋亡。各種Bcl-2家族蛋白彼此間具有不同的結合專一性，形成掌握細胞命運的複雜、有規律的交互作用網路（Roberts，2016）。Impaired cell apoptosis has an important impact on tumor development, tumor maintenance, and treatment resistance. Apoptosis can be triggered through two main pathways: the exogenous or death receptor mediator pathway, and the endogenous or mitochondrial pathway (Czabotar et al., 2014). In lymphoid malignancies, the endogenous pathway is more often affected. Cell death mediated by this pathway is regulated by members of the B-cell lymphoma-2 (Bcl-2)-related protein family, which currently includes three subfamilies. The pro-survival subgroups (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1/Bfl-1, and possibly Bcl-B) promote cell survival by inhibiting their pro-apoptotic related proteins. Pro-apoptotic BAX/BAK-like proteins (including BOK) are important effectors of cell apoptosis, and single BH3-only protein (BIM, PUMA, BID, NOXA, BMF, BIK and HRK) is the cell The initiator of apoptosis (Anderson et al., 2014). In healthy cells, the pro-survival Bcl-2 protein binds to and inhibits BAX and BAK (after partial activation), thereby reducing the ability of BAX/BAK to oligomerize and form holes to trigger the permeation of the outer mitochondrial membrane. A single BH3 segment protein is transcribed or triggered after transcription under different pressures, and binds to the pro-survival Bcl-2 protein to release BAX/BAK, or directly activates these apoptotic effectors to initiate apoptosis . Various Bcl-2 family proteins have different binding specificities with each other, forming a complex and regular interaction network that controls cell fate (Roberts, 2016).
Bcl-2為80年代第一個發現的抗凋亡蛋白，其為t (14;18) 染色體易位的結果，並且是FL的標記。BCL-2的基因存在於染色體18q21.33。Bcl-2蛋白具有239個胺基酸，分子量為26 kDA的（Schenk等人，2017）。Bcl-2在發育過程中廣泛表現，並且在許多組織發育完成後受到限制（Kondo等人，2008）。缺乏Bcl-2的小鼠在生命初期死於多囊性腎病變，這是由於Bcl-2對胚胎發育期間腎上皮先驅細胞的存活至關重要（Veis等人，1993）。此外，Bcl-2缺陷小鼠中成熟的未活化B和T淋巴細胞數量異常減少，並且由於黑色素細胞的異常死亡而過早老化（Veis等人，1993；Yamamura等人，1996）。雖然Bcl-2最初認為是典型的生長驅動致癌基因，但後來證明，Bcl-2反而會藉由減弱細胞凋亡來促進惡性細胞存活。具有可生成各種血球Bcl-2表現的基因轉殖小鼠（VavP-BCL-2 ）優先發生濾泡型淋巴瘤，在此之前為急性生發中心增生（Egle等人，2004）。同時表現BCL-2和MYC轉殖基因的小鼠，比僅表現任一轉殖基因的同窩小鼠明顯更快發生淋巴瘤，這點證實了BCL-2為致癌基因（Adams和Cory，2007）。Bcl-2 is the first anti-apoptotic protein discovered in the 1980s. It is the result of t (14;18) chromosomal translocation and a marker of FL. The gene for BCL-2 is found on chromosome 18q21.33. The Bcl-2 protein has 239 amino acids and a molecular weight of 26 kDA (Schenk et al., 2017). Bcl-2 is widely expressed during development and is restricted after the development of many tissues (Kondo et al., 2008). Mice lacking Bcl-2 die of polycystic nephropathy early in life, because Bcl-2 is essential for the survival of renal epithelial precursor cells during embryonic development (Veis et al., 1993). In addition, the number of mature unactivated B and T lymphocytes in Bcl-2 deficient mice is abnormally reduced, and premature aging due to abnormal death of melanocytes (Veis et al., 1993; Yamamura et al., 1996). Although Bcl-2 was originally thought to be a typical growth-driven oncogene, it was later proved that Bcl-2 can promote the survival of malignant cells by reducing apoptosis. Transgenic mice (VavP-BCL-2 ) with the expression of Bcl-2 that can produce various blood cells preferentially develop follicular lymphoma, which was previously an acute germinal center hyperplasia (Egle et al., 2004). Mice expressing both BCL-2 and MYC transgenic genes developed lymphoma significantly faster than littermate mice expressing either of the transgenic genes, which confirms that BCL-2 is an oncogene (Adams and Cory, 2007 ).
Bcl-2高度表現在CLL、FL、MCL及華氏巨球蛋白血症(WM)中幾乎普遍存在；相較之下，Bcl-2表現程度在多發性骨髓瘤(MM)中差異略為顯著，並且在DLBCL和B細胞急性淋巴性白血病中差異非常大（Roberts和Huang 2017）。當Bcl-2過度表現時，會影響促凋亡和抗凋亡Bcl-2家族成員的比例，並可防止細胞因凋亡而死亡。此外，Bcl-2蛋白與血液腫瘤的化學抗性息息相關。由於Bcl-2媒介對內源性細胞凋亡的抗性，一般認為是重要病因，以Bcl-2做為目標可增進細胞凋亡，並解決Bcl-2對癌症療法的抗藥性。因此，Bcl-2已成為癌症治療策略中引人注目的目標。The high level of Bcl-2 is almost universal in CLL, FL, MCL and Waldenstrom's macroglobulinemia (WM); in contrast, the degree of Bcl-2 is slightly different in multiple myeloma (MM), and The difference between DLBCL and B-cell acute lymphoblastic leukemia is very large (Roberts and Huang 2017). When Bcl-2 is overexpressed, it will affect the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family members, and can prevent cell death due to apoptosis. In addition, Bcl-2 protein is closely related to the chemoresistance of hematological tumors. Due to the resistance of Bcl-2 mediator to endogenous cell apoptosis, it is generally considered to be an important cause. Targeting Bcl-2 can promote cell apoptosis and solve the resistance of Bcl-2 to cancer therapy. Therefore, Bcl-2 has become an attractive target in cancer treatment strategies.
維奈托克（venetoclax）（ABT-199）被批准用於治療患有慢性淋巴性白血病（CLL）和急性成急性骨髓性白血病（AML）的患者。然而，儘管具有這樣高的臨床活性和良好的安全特徵，但隨著時間的推移，患者在持續治療下仍會對維奈托克產生獲得性抗性。Blombery等人證明瞭BCL-2 中的Gly101Val突變（G101V突變）藉由降低維奈托克的結合親和力且不破壞促凋亡蛋白與Bcl-2的結合來賦予獲得性難治性。15名患者中有7名在進展中鑒定出在Bcl-2 中的新穎Gly101Val突變。這種突變主要發現於長期暴露於維奈托克單一療法的患者中（Tausch等人2019）。Venetoclax (ABT-199) is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). However, despite such high clinical activity and good safety characteristics, patients will still develop acquired resistance to Venetog under continuous treatment over time. Blombery et al. demonstrated that the Gly101Val mutation (G101V mutation) in BCL-2 confers acquired refractory properties by reducing the binding affinity of Venetog without disrupting the binding of pro-apoptotic proteins to Bcl-2. Seven of the 15 patients identified novel Gly101Val mutations in Bcl-2 in progression. This mutation is mainly found in patients who have been exposed to Venetoque monotherapy for a long time (Tausch et al. 2019).
WO 2019/210828 A揭露了具有以下式 (III-B)、(III-C)、(III-D) 或 (III-E) 的一系列化合物、或其立體異構物、或其藥學上可接受的鹽作為Bcl-2抑制劑，
在WO 2019/210828 A中揭露的化合物係有效的且具有選擇性的Bcl-2蛋白抑制劑。The compound disclosed in WO 2019/210828 A is an effective and selective Bcl-2 protein inhibitor.
本揭露的發明人已經發現，具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl2抑制劑、特別是化合物 1 （COMPOUND 1 ）（化合物 1 （Compound 1 ））或其藥學上可接受的鹽表現出針對多種淋巴瘤和白血病細胞系的有效細胞殺傷活性，該等淋巴瘤和白血病細胞系包括MV4-11（急性骨髓性白血病，AML）、OCI-LY10（B細胞非何杰金氏淋巴瘤，B-NHL）、Toledo（彌漫性大型B細胞淋巴瘤，DLBCL）、DOHH2（濾泡型淋巴瘤，FL）、DHL-4（生發中心B細胞樣彌漫性大型B細胞淋巴瘤，GCB-DLBCL）和MAVER-1（被套細胞淋巴瘤，MCL）。此外，發現IC50 值在從0.6 nM至13 nM的範圍內。The inventors of the present disclosure have discovered that Bcl2 inhibitors having the formula (III-B), (III-C), (III-D) or (III-E), especially the compound 1 ( COMPOUND 1 ) ( Compound 1 ( Compound 1 )) or its pharmaceutically acceptable salts show effective cell killing activity against a variety of lymphoma and leukemia cell lines, including MV4-11 (acute myelogenous leukemia, AML), OCI -LY10 (B-cell non-Hodgkin's lymphoma, B-NHL), Toledo (diffuse large B-cell lymphoma, DLBCL), DOHH2 (follicular lymphoma, FL), DHL-4 (germinal center B cell Diffuse large B-cell lymphoma, GCB-DLBCL) and MAVER-1 (mantle cell lymphoma, MCL). In addition, the IC 50 value was found to be in the range from 0.6 nM to 13 nM.
本揭露的發明人已經發現，具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl2抑制劑、特別是化合物 1
或其藥學上可接受的鹽表現出以高安全性顯著抑制癌症中腫瘤生長，該等癌症包括選自急性淋巴母性白血病（ALL）、被套細胞淋巴瘤（MCL）和彌漫性大型B細胞淋巴瘤（DLBCL）的B細胞惡性腫瘤。諸位發明人已經發現所述B細胞惡性腫瘤具有Bcl-2表現和/或Bcl-2 G101V突變表現。The inventors of the present disclosure have discovered that a Bcl2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E), especially
在第一方面，本文揭露了一種用Bcl-2抑制劑治療癌症之方法，其中該Bcl-2抑制劑係由下式 (III-B)、(III-C)、(III-D) 或 (III-E) 表示的化合物，
在第二方面，本文揭露了具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl-2抑制劑、或其立體異構物、或其藥學上可接受的鹽，用於在治療癌症中使用。In the second aspect, this document discloses a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmacological agent thereof An acceptable salt for use in the treatment of cancer.
在第三方面，本文揭露了治療受試者的癌症之方法，所述方法包括向該受試者施用治療有效量的具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl-2抑制劑、或其立體異構物、或其藥學上可接受的鹽。In a third aspect, this document discloses a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of formula (III-B), (III-C), (III-D) Or (III-E) Bcl-2 inhibitor, or its stereoisomer, or its pharmaceutically acceptable salt.
在第四方面，本文揭露了藥物組成物在製造用於治療癌症的藥物中的用途，所述藥物組合包含具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl-2抑制劑、或其立體異構物、或其藥學上可接受的鹽。In the fourth aspect, this article discloses the use of the pharmaceutical composition in the manufacture of drugs for the treatment of cancer, the pharmaceutical combination comprising formula (III-B), (III-C), (III-D) or (III-B), (III-C), (III-D) or (III-D). -E) The Bcl-2 inhibitor, or its stereoisomer, or its pharmaceutically acceptable salt.
在上述方面中每一個的實施方式中，該Bcl-2抑制劑係化合物 1 （化合物 1 ）或其藥學上可接受的鹽。In an embodiment of each of the above aspects, the Bcl-2 inhibitor is Compound 1 ( Compound 1 ) or a pharmaceutically acceptable salt thereof.
在上述方面中每一個的實施方式中，該癌症係B細胞惡性腫瘤。In an embodiment of each of the above aspects, the cancer is a B cell malignancy.
在上述方面中每一個的實施方式中，該癌症係淋巴瘤或白血病。In an embodiment of each of the above aspects, the cancer is lymphoma or leukemia.
在上述方面中每一個的一個實施方式中，該癌症選自由以下組成之群組：急性骨髓性白血病（AML）、B細胞非何杰金氏淋巴瘤（B-NHL）、惰性B細胞非何杰金氏淋巴瘤（NHL）、彌漫性大型B細胞淋巴瘤（DLBCL）、生發中心B細胞樣彌漫性大型B細胞淋巴瘤（GCB-DLBCL）、濾泡型淋巴瘤（FL）、被套細胞淋巴瘤（MCL）、急性淋巴母性白血病（ALL）、慢性淋巴性白血病/小淋巴球性淋巴瘤（CLL/SLL）和邊緣區淋巴瘤（MZL）。In one embodiment of each of the above aspects, the cancer is selected from the group consisting of: acute myeloid leukemia (AML), B-cell non-Hodgkin’s lymphoma (B-NHL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) Jakin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), follicular lymphoma (FL), mantle cell lymphoma Neoplasms (MCL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL).
在上述方面中每一個的一個實施方式中，該癌症係復發性/難治性、或轉化性的。In one embodiment of each of the above aspects, the cancer is relapsed/refractory, or transformative.
在上述方面中每一個的一個實施方式中，以20 mg/天至700 mg/天的劑量口服施用該Bcl-2抑制劑。In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally at a dose of 20 mg/day to 700 mg/day.
在上述方面中每一個的一個實施方式中，該癌症具有Bcl-2表現。In one embodiment of each of the above aspects, the cancer has Bcl-2 manifestations.
在上述方面中每一個的一個實施方式中，該癌症具有Bcl-2 Gly101Val突變表現。In one embodiment of each of the above aspects, the cancer has Bcl-2 Gly101Val mutation manifestations.
定義definition
除非在本文檔其他地方具體定義，否則本文使用的所有其他技術和科學術語具有熟悉該項技術者通常理解之含義。Unless specifically defined elsewhere in this document, all other technical and scientific terms used in this article have the meanings commonly understood by those familiar with the technology.
如本文所用，包括所附請求項，除非上下文另外明確說明，否則例如「一個 」、「一種 」和「該 」的單數形式包括它們相應複數指代。As used herein, including the appended claims, unless the context clearly dictates otherwise , singular forms such as "a ", " an " and " the " include their corresponding plural references.
除非上下文另外明確說明，否則術語「或 」意指術語「和/或」並且可與術語「和/或」互換使用。Unless the context clearly dictates otherwise, the term " or " means the term "and/or" and is used interchangeably with the term "and/or".
如本文所用的術語「抗癌劑 」係指可用於治療細胞增殖性障礙（如癌症）的任何藥劑，包括但不限於細胞毒性劑、化學治療劑、放射療法和放射治療劑、靶向性抗癌劑、和免疫治療劑。The term " anti-cancer agent " as used herein refers to any agent that can be used to treat cell proliferative disorders (such as cancer), including but not limited to cytotoxic agents, chemotherapeutics, radiotherapy and radiotherapeutics, targeted anti- Cancer agent, and immunotherapeutic agent.
本文中的術語「施用（ administration/administering ） 」和「治療（ treating/treatment ） 」，當應用於動物、人、實驗受試者、細胞、組織、器官或生物流體時，意指外源性藥物、治療劑、診斷劑或組成物與該動物、人、受試者、細胞、組織、器官或生物流體接觸。細胞的處理涵蓋試劑與細胞的接觸以及試劑與流體的接觸，其中該流體與細胞接觸。術語「施用」和「治療」還意指例如藉由試劑、診斷劑、結合化合物或另一種細胞進行的細胞的體外和離體處理。本文中的術語「受試者」包括任何生物，較佳的是動物，更較佳的是哺乳動物（例如，大鼠、小鼠、狗、貓、兔），最較佳的是人。在一個方面，治療任何疾病或障礙係指改善該疾病或障礙（即，減緩或阻止或減少疾病或其至少一種臨床症狀的發展）。在另一個方面，「治療（treat/treating/treatment）」係指緩解或改善至少一個身體參數，包括患者可能無法辨別的那些。在又另一個方面，「治療（treat/treating/treatment）」係指在身體上（例如，可辨別症狀的穩定化）、在生理上（例如，身體參數的穩定化）或兩者上調節疾病或障礙。在又另一個方面，「治療（treat/treating/treatment）」係指預防或延遲疾病或障礙的發作或發展或進展。The term "administration (administration / administering)" herein and "treatment (treating / treatment)", when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means exogenous drugs , The therapeutic agent, diagnostic agent or composition is in contact with the animal, human, subject, cell, tissue, organ or biological fluid. The treatment of cells encompasses the contact of the reagent with the cell and the contact of the reagent with the fluid, where the fluid is in contact with the cell. The terms "administration" and "treatment" also mean the in vitro and ex vivo treatment of cells, for example, by reagents, diagnostic agents, binding compounds, or another kind of cells. The term "subject" as used herein includes any organism, preferably animals, more preferably mammals (for example, rats, mice, dogs, cats, rabbits), and most preferably humans. In one aspect, treating any disease or disorder refers to ameliorating the disease or disorder (ie, slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In another aspect, "treat/treating/treatment" refers to alleviation or improvement of at least one physical parameter, including those that the patient may not be able to distinguish. In yet another aspect, "treat/treating/treatment" refers to the regulation of disease physically (for example, stabilization of discernible symptoms), physiologically (for example, stabilization of physical parameters), or both Or obstacles. In yet another aspect, "treat/treating/treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.
在本揭露的上下文中，術語「受試者 」係哺乳動物，例如，靈長類動物，較佳的是高等靈長類動物，例如人（例如，患有本文所述之障礙或處於患有本文所述之障礙的風險的患者）。在一些實施方式中，該受試者係人或患者。In the context of the present disclosure, the term " subject " refers to a mammal, for example, a primate, preferably a higher primate, such as a human (for example, suffering from the disorders described herein or suffering from Patients at risk of the disorders described in this article). In some embodiments, the subject is a human or patient.
本文中的術語「癌症 」或「腫瘤 」具有如本領域理解的最廣泛的含義，並且是指哺乳動物中典型地以不受調控的細胞生長為特徵的生理病症。在本揭露的上下文中，癌症不限於某個類型或位置。The term " cancer " or " tumor " herein has the broadest meaning as understood in the art, and refers to a physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of this disclosure, cancer is not limited to a certain type or location.
如本文所用的術語「治療有效量 」係指當施用於受試者以治療疾病、或疾病或障礙的至少一種臨床症狀時，足以影響該疾病、障礙或症狀的治療的Bcl-2抑制劑的量。「治療有效量 」可以隨藥劑，疾病，障礙，和/或疾病或障礙的症狀，疾病、障礙、和/或疾病或障礙的症狀的嚴重程度，待治療的受試者的年齡，和/或待治療的受試者的體重而變化。在任何給定情況下的合適量對於熟悉該項技術者而言係顯而易見的，或者可以藉由常規實驗確定。在組合療法的情況下，「治療有效量 」係指用於有效治療疾病、障礙或病症的組成物件的總量。實施方式 The term " therapeutically effective amount " as used herein refers to the amount of a Bcl-2 inhibitor that is sufficient to affect the treatment of the disease, disorder, or symptom when administered to a subject to treat at least one clinical symptom of the disease, disorder, or disorder quantity. The " therapeutically effective amount " may vary depending on the medicament, disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or The weight of the subject to be treated varies. The appropriate amount in any given situation is obvious to those skilled in the art, or can be determined by routine experimentation. In the case of combination therapy, the " therapeutically effective amount " refers to the total amount of constituents used to effectively treat a disease, disorder, or condition. Implementation
本揭露提供了一種用Bcl-2抑制劑、特別是化合物1（化合物1）或其藥學上可接受的鹽治療受試者的癌症之方法。Bcl-2 抑制劑 The present disclosure provides a method for treating cancer in a subject with a Bcl-2 inhibitor, particularly Compound 1 (Compound 1) or a pharmaceutically acceptable salt thereof. Bcl-2 inhibitor
本揭露的Bcl-2抑制劑係藉由下式 (III-B)、(III-C)、(III-D) 或 (III-E) 表示的化合物，
在一些實施方式中，R2 係氫。In some embodiments, R 2 is hydrogen.
在一些實施方式中，當在環B（包括氮丙啶-1-基、氮雜環丁烷-1-基、吡咯啶-1-基、吡咯啶-2-基、哌啶-1-基、氮雜環庚烷-1-基、或氮雜環辛-1-基，較佳的是吡咯啶-1-基基團）的位置2處的苯基基團上取代時，R1d
獨立地是鹵素、-C1-8
烷基、-C2-8
烯基、-C2-8
炔基、環烷基、雜環基、芳基、雜芳基、-CN、-ORBa
、-SO2
RBa
、-CONRBa
RBb
、-NO2
、-NRBa
RBb
、-NRBa
CORBb
、或-NRBa
SO2
RBb
；其中所述-C1-8
烷基、-C2-8
烯基、-C2-8
炔基、環烷基、雜環基、芳基或雜芳基各自獨立地視需要被1至4個取代基RBd
（如用式 (III-B)、(III-C)、(III-D) 或 (III-E) 定義）取代，較佳的是被1個或2個取代基RBd
（如用式 (III-B)、(III-C)、(III-D) 或 (III-E) 定義）取代。在另一個方面，一個R1d
在環B的位置2處的苯基環的位置2處。In some embodiments, when in ring B (including aziridin-1-yl, azetidine-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl , Azepan-1-yl, or azepan-1-yl, preferably a pyrrolidin-1-yl group) when substituted on the phenyl group at
在一些實施方式中，R1d 係甲基、乙基、異丙基、丙基或甲氧基甲基、或在苯基環位置處的兩個甲基；或丙烯基；或環丙基、環丁基、環戊基、或環己基；或乙氧基或異丙氧基；或胺基或二甲基胺基。In some embodiments, R 1d is methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyl groups at the position of the phenyl ring; or propenyl; or cyclopropyl, Cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.
在一些實施方式中，在式 (III-B)、(III-C)、(III-D) 或 (III-E) 中的2-(2-取代的苯基)吡咯啶-1-基部分選自由以下組成之群組：
在一些實施方式中，m係1；並且L5 係直接鍵、-(CRa Rb )t -或-NRa -，其中t係1至7中的一個數，並且-(CRa Rb )t -中的一個或兩個CRa Rb 部分未被替換或被選自O和NRa 的一個或多個部分替換，其中Ra 和Rb 用式 (III-B)、(III-C)、(III-D) 或 (III-E) 定義。In some embodiments, m is 1; and L 5 is a direct bond, -(CR a R b ) t -or -NR a -, where t is a number from 1 to 7, and -(CR a R b ) t - one or two CR a R b or more portions of a replacement part is not replaced or selected from O and NR a, wherein R a and R b are represented by the formula (III-B), (III- C), (III-D) or (III-E) definition.
在一些實施方式中，L5 係直接鍵、-(CRa Rb )1-4 -、-O-(CRa Rb )1-3 -、-NH-(CRa Rb )1-3 、或-NH-，其中Ra 和Rb 如用式 (III-B)、(III-C)、(III-D) 或 (III-E) 定義，因此-L5 -CyC部分分別是CyC、-(CRa Rb )1-4 -CyC、-O-(CRa Rb )1-3 -CyC、-NH-(CRa Rb )1-3 -CyC、或-NH-CyC。更較佳的是，L5 係直接鍵、-(CH2 )1-4 -、-O-(CH2 )1-3 -、-NH-(CRa Rb )-(CH2 )2 -、或-NH-，其中Ra 係氫，並且Rb 係視需要被苯基-S-取代的C1-8 烷基，因此-L5 -CyC部分分別是CyC、-(CH2 )1-4 -CyC、-O-(CH2 )1-3 -CyC、-NH-(CRa Rb )-(CH2 )2 -CyC、或-NH-CyC。更較佳的是，L5 係直接鍵、-CH2 -、-O-CH2 -、-NH-CH2 -、或-NH-，因此-L5 -CyC部分分別是CyC、-CH2 -CyC、-O-CH2 -CyC、-NH-CH2 -CyC、或-NH-CyC。In some embodiments, L 5 is a direct bond, -(CR a R b ) 1-4 -, -O-(CR a R b ) 1-3 -, -NH-(CR a R b ) 1-3 , or -NH-, wherein, (III-C), ( III-D) or (III-E) R a and R b are defined as with formula (III-B), and therefore are part -L 5 -CyC CyC , -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b ) 1-3 -CyC, or -NH-CyC. More preferably, L 5 is a direct bond, -(CH 2 ) 1-4 -, -O-(CH 2 ) 1-3 -, -NH-(CR a R b )-(CH 2 ) 2- , or -NH-, wherein R a hydrogen-based, and R b based -S- optionally substituted phenyl C 1-8 alkyl group, thus are part -L 5 -CyC CyC, - (CH 2) 1 -4 -CyC, -O-(CH 2 ) 1-3 -CyC, -NH-(CR a R b )-(CH 2 ) 2 -CyC, or -NH-CyC. More preferably, L 5 is a direct bond, -CH 2 -, -O-CH 2 -, -NH-CH 2 -, or -NH-, so the -L 5 -CyC part is CyC, -CH 2 respectively -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC, or -NH-CyC.
在一些實施方式中，CyC係環烷基或雜環基，它們中的每一個視需要被一個或兩個取代基R5a 取代； R5a 獨立地選自氫、鹵素、氰基、側氧基、-OR5b 、-NR5b R5c 、-COR5b 、-SO2 R5b 、-C1-8 烷基、-C2-8 炔基、-環烷基、或雜環基，所述-C1-8 烷基和雜環基中的每一個視需要被一個或兩個取代基R5e 取代，該取代基選自：氫、鹵素、氰基、-OR5f 、-C1-8 烷基、-環烷基、或雜環基； 其中R5b 和R5c 各自獨立地是氫、-C1-8 烷基或雜環基，所述-C1-8 烷基視需要被一個或兩個取代基R5e 取代，該取代基係氫、-NR5f R5g 或-環烷基； R5f 和R5g 各自獨立地是氫或-C1-8 烷基； 或在苯基環上的兩個相鄰R5 與苯基環一起形成苯并環，所述環視需要被雜芳基取代。In some embodiments, CyC is a cycloalkyl or heterocyclic group, each of which is optionally substituted by one or two substituents R 5a ; R 5a is independently selected from hydrogen, halogen, cyano, pendant oxy , -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 alkyl, -C 2-8 alkynyl, -cycloalkyl, or heterocyclic group, the- Each of the C 1-8 alkyl group and the heterocyclic group is optionally substituted with one or two substituents R 5e selected from the group consisting of hydrogen, halogen, cyano, -OR 5f , -C 1-8 alkane Group, -cycloalkyl, or heterocyclyl; wherein R 5b and R 5c are each independently hydrogen, -C 1-8 alkyl or heterocyclyl, and the -C 1-8 alkyl group is optionally substituted by one or Two substituents R 5e are substituted. The substituents are hydrogen, -NR 5f R 5g or -cycloalkyl; R 5f and R 5g are each independently hydrogen or -C 1-8 alkyl; or on the phenyl ring Two adjacent R 5 of and together with the phenyl ring form a benzo ring, and the ring is optionally substituted with a heteroaryl group.
在一些實施方式中，CyC係選自單環C3-8
環烷基或橋聯環烷基（
在一些實施方式中，CyC係選自以下的雜環基： a) 單環4員至9員雜環基基團，其含有一個氮或氧或硫雜原子作為環成員； b) 單環4員至9員雜環基基團，其含有選自氧、硫和氮的兩個雜原子作為環成員；和 c) 5員至20員螺雜環基，其包含選自氮、硫和氧的一個或兩個雜原子作為環成員， 它們中的每一個視需要被一個或兩個R5a 取代。In some embodiments, CyC is a heterocyclic group selected from the following: a) a monocyclic 4-membered to 9-membered heterocyclic group containing a nitrogen or oxygen or sulfur heteroatom as a ring member; b) a monocyclic ring 4 A to 9-membered heterocyclic group containing two heteroatoms selected from oxygen, sulfur and nitrogen as ring members; and c) a 5- to 20-membered spiro heterocyclic group containing a group selected from nitrogen, sulfur and oxygen One or two heteroatoms of as ring members, and each of them is substituted by one or two R 5a as necessary.
在一些實施方式中，CyC係單環4員至6員雜環基基團，其含有一個氮或氧或硫雜原子作為環成員。更較佳的是，Cyc選自氧雜環丁烷基、四氫呋喃基、四氫哌喃基、氮雜環丁烷基、吡咯啶基和哌啶基。甚至更較佳的是，CyC選自氧雜環丁烷-2-基、氧雜環丁烷-3-基、四氫呋喃-4-基、四氫呋喃-2-基、四氫呋喃-3-基、四氫哌喃-2-基、四氫哌喃-3-基、四氫哌喃-4-基、氮雜環丁烷-3-基、氮雜環丁烷-2-基、吡咯啶-2-基、吡咯啶-3-基、哌啶-4-基、哌啶-2-基、和哌啶-3-基。In some embodiments, CyC is a monocyclic 4-membered to 6-membered heterocyclic group, which contains a nitrogen or oxygen or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, azetidinyl, pyrrolidinyl and piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl Piperan-2-yl, tetrahydropiperan-3-yl, tetrahydropiperan-4-yl, azetidine-3-yl, azetidine-2-yl, pyrrolidine-2- Yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.
在一些實施方式中，CyC係單環6員雜環基基團，其含有選自氧和氮的兩個雜原子作為環成員。更較佳的是，CyC係二㗁基、啉代、啉基、或哌基。甚至更較佳的是1,3-二㗁-2-基、1,3-二㗁-4-基、1,4-二㗁-2-基、啉-1-基、啉-2-基、或啉-3-基。In some embodiments, CyC is a monocyclic 6-membered heterocyclic group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is a diethyl group, a lino group, a linyl group, or a piperyl group. Even more preferred are 1,3-di-e-2-yl, 1,3-di-e-4-yl, 1,4-di-e-2-yl, lin-1-yl, lin-2-yl , Or lin-3-yl.
在一些實施方式中，R5a 獨立地選自氫、鹵素、氰基、側氧基、-OR5b 、-NR5b R5c 、-COR5b 、-SO2 R5b 、-C1-8 烷基、-C2-8 炔基、單環C3-8 環烷基、或單環4員至9員雜環基基團（含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員），所述-C1-8 烷基和單環4員至9員雜環基基團中的每一個視需要被一個或兩個取代基R5e 取代；較佳的是，作為R5a 的環烷基係C3-6 環烷基；更較佳的是環丙基；較佳的是，作為R5a 的雜環基係4員至6員雜環基基團，其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員；更較佳的是，作為R5a 的雜環基係氧雜環丁烷基、四氫呋喃基、四氫哌喃基、哌基、或啉基；甚至更較佳的是，作為R5a 的雜環基係氧雜環丁烷-3-基、四氫呋喃-3-基、四氫-2H-哌喃-4-基、或嗎啡-4-基。In some embodiments, R 5a is independently selected from hydrogen, halogen, cyano, pendant oxy, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 alkyl , -C 2-8 alkynyl, monocyclic C 3-8 cycloalkyl, or monocyclic 4 to 9 member heterocyclic group (containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms As a ring member), each of the -C 1-8 alkyl group and the monocyclic 4- to 9-membered heterocyclic group is optionally substituted with one or two substituents R 5e ; preferably, as The cycloalkyl group of R 5a is a C 3-6 cycloalkyl group; more preferably a cyclopropyl group; preferably, the heterocyclic group of R 5a is a 4- to 6-membered heterocyclic group, which contains One or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms are used as ring members; more preferably, the heterocyclic group of R 5a is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, Piperyl, or linyl; even more preferably, the heterocyclic group of R 5a is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-piperan-4-yl, Or morphine-4-yl.
在一些實施方式中，作為R5e 的雜環基係單環4員至9員雜環基基團，其含有選自氮或氧或硫雜原子的一個或兩個雜原子作為環成員。In some embodiments, the heterocyclic group as R 5e is a monocyclic 4-membered to 9-membered heterocyclic group, which contains one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members.
在一些實施方式中，作為R5e 的雜環基係四氫-哌喃-4-基。In some embodiments, the heterocyclic group as R 5e is tetrahydro-piperan-4-yl.
在一些實施方式中，R5a 係-NR5b R5c ，其中R5b 係氫，並且R5c 係雜環基。In some embodiments, R 5a is -NR 5b R 5c , wherein R 5b is hydrogen, and R 5c is a heterocyclic group.
在一些實施方式中，R5a 係-NR5b R5c ，其中R5b 係氫，並且R5c 係四氫-哌喃-4-基。In some embodiments, R 5a is -NR 5b R 5c , where R 5b is hydrogen, and R 5c is tetrahydro-piperan-4-yl.
在一些實施方式中，R5a 係-NR5b R5c ，其中R5b 和R5c 各自獨立地是氫或被環烷基取代的-C1-6 烷基，較佳的是被單環C3-8 環烷基取代的-C1-6 烷基。In some embodiments, R 5a is -NR 5b R 5c , wherein R 5b and R 5c are each independently hydrogen or -C 1-6 alkyl substituted by cycloalkyl, preferably a monocyclic C 3- 8 -C 1-6 alkyl substituted with cycloalkyl.
在一些實施方式中，R5a 係-OR5b 或-SO2 R5b ，其中R5b 係氫或C1-8 烷基，較佳的是甲基。In some embodiments, R 5a is -OR 5b or -SO 2 R 5b , wherein R 5b is hydrogen or C 1-8 alkyl, preferably methyl.
在一些實施方式中，R5a 係-COR5b ，其中R5b 係氫或視需要被-NR5f R5g 取代的C1-8 烷基，其中R5f 和R5g 各自獨立地是氫或C1-8 烷基，較佳的是甲基。In some embodiments, R 5a is -COR 5b , wherein R 5b is hydrogen or a C 1-8 alkyl group optionally substituted by -NR 5f R 5g , wherein R 5f and R 5g are each independently hydrogen or C 1 -8 alkyl, preferably methyl.
在一些實施方式中，在苯基環上的兩個相鄰R5 與苯基環一起形成被四氫哌喃基取代的吲唑基。In some embodiments, two adjacent R 5 on the phenyl ring together with the phenyl ring form an indazolyl group substituted with a tetrahydropiperanyl group.
在一些實施方式中，m係1，並且R5
係選自由以下組成之群組的-L5
-CyC：
在一些實施方式中，m係1，並且R5
係
在一些實施方式中，本揭露的Bcl-2抑制劑選自由以下組成之群組： 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((R)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(7-(2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.5]壬烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(7-(2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.5]壬烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(9-(2-(2-環丙基苯基)吡咯啶-1-基)-3-氮雜螺[5.5]十一烷-3-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(9-(2-(2-環丙基苯基)吡咯啶-1-基)-3-氮雜螺[5.5]十一烷-3-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-(2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯-2-(二甲基胺基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； N-((4-((((R)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-8-氮雜螺[4.5]癸烷-8-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R) 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-8-氮雜螺[4.5]癸烷-8-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； N-((4-((((R)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(8-(2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[4.5]癸烷-2-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺；化合物 1 ； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((4-氟四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； N-((4-((((R)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s,4s)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s,4s)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((R)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丁基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丁基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)-4-(2-(2-(鄰甲苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-氯苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-溴苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-氯苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(4-氯苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-乙氧基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-(二甲基胺基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-(二甲基胺基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-(雙(甲基-d3)胺基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)-4-(2-(2-(2-(吡咯啶-1-基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-(1-甲基-1,2,3,6-四氫吡啶-4-基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-(1-甲基哌啶-4-基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-甲氧基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙氧基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-(甲氧基甲基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-(羥基甲基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯-2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯-2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(5-氯-2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯-2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； (S或R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-氯-2-乙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2,4-二環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2,5-二環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(3-(2-氯苯基)噻吩-2-基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-甲基吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(4-環丙基-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-苯基-2,5-二氫-1H-吡咯-1-基)-7-氮雜螺[3.5]壬烷-7-基) -N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4,4-二甲基吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4,4-二氟吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-(三氟甲基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-(二甲基胺基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-4-(2-(二甲基胺基)乙氧基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)-3,3-二甲基吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((((1s,4s) 或 (1r,4r))-4-((二甲基(側氧基)-l6-氫硫基亞基)胺基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-(甲基(3-硝基-4-(((四氫-2H-哌喃-4-基)甲基)胺基)苯基)(側氧基)-l6-氫硫基亞基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((-3-氧雜二環[3.1.0]己烷-6-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((4-羥基-4-(三氟甲基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-(三氟甲基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1s,4s)-4-羥基-4-(三氟甲基)環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((1r,4r)-4-甲氧基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((S)-4-甲基環己-3-烯-1-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-(丙-1-烯-2-基)苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺； N-((4-((((R)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(6-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-異丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-乙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； N-((4-((((S)-1,4-二㗁-2-基)甲基)胺基)-3-硝基苯基)磺醯基)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-乙基苯基)吡咯啶-1-基)-2-氮雜螺[3.3]庚烷-2-基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(四氫-2H-哌喃-4-基)乙基)胺基)苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((2-啉代乙基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-((2-(3-側氧基啉代)乙基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-(((3-氧雜二環[3.1.0]己烷-6-基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((2,6-二甲基四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((3-硝基-4-(((2,2,6,6-四甲基四氫-2H-哌喃-4-基)甲基)胺基)苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-6-氮雜螺[3.4]辛烷-6-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(6-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[3.4]辛烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-((7R或7S)-7-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[4.4]壬烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-((7S或7R)-7-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-2-氮雜螺[4.4]壬烷-2-基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(((2,2-二甲基四氫-2H-哌喃-4-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； (S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-(3-甲基-3-((四氫-2H-哌喃-4-基)甲基)脲基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-N-((4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯基)磺醯基)-4-(2-((S)-2-苯基吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((順式或反式)-4-羥基四氫呋喃-2-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-((S)-2-(2-環丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)-N-((4-((((反式或順式)-4-羥基四氫呋喃-2-基)甲基)胺基)-3-硝基苯基)磺醯基)苯甲醯胺； 或其藥學上可接受的鹽、或其立體異構物。In some embodiments, the Bcl-2 inhibitor of the present disclosure is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-( 2-((S)-2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(( ((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H -Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-7-yl)-N-((4-(((4-Fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfon (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) -4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro- 4-(((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -Yl)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide ; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4- (((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3- b]Pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7- Base)-N-((4-(((4-Fluorotetrahydro-2H- Piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl )Oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)- N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; ( S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidine-1- Yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino )Phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2- (2-Cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro- 2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N- ((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-aza Spiro[5.5]undecane-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl Yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4 -Yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)- 4-(6-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro- 4-(((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b] Pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]Nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4- ((((S)-1,4-Diethyl)-2-yl)methyl)amino) -3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2- (2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; N-((4-((((R)- 1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl )Oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzene Formamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decane-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4 -Yl)methyl)amino)phenyl)sulfonyl)benzamide; (R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4 -(2-((S)-2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decane-8-yl)-N-((3- Nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S) -1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzene Formamide; N-((4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-( (1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4 -(8-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.5]decane-2-yl)-N-((3-nitro-4 -(((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; compound 1 ; N-((4-((((S)- 1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl )Oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-( 2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((四Hydrogen-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) -4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; N-(( 4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]Nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s, 4s)-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropyl Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl )-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide ; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methyl ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2- (2-(2-Cyclobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)- N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) (Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2 -(3-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro -2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)-4-( 2-(2-(O-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl )-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino) (Phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-( 2-Chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piper (Pyr-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro -4-(((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2 ,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7 -Yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S )-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl )Sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N -((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-( (1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)benzene Yl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2 -(Dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)- 4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzene Yl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl )Oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-7 -Azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl) Sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-( 1-Methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-( ((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b ]Pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl )-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-( 2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl )Oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)- N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H- Pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl ) Benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2- Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piper (Pyr-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N- ((3-Nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo [2,3-b]Pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl ) Benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2- Ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan -4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl) Oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N- ((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl Yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylbenzene Yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4- (L)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2- (2-(2,5-Dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4- (((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidine- 1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl) 2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(( (Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro [3.5] Nonane-7-yl) -N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl) Benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4, 4-Dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan -4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (2-(2-(2-Cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-(( 3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonamide Yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)- 4-(Trifluoromethyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy -4-Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(dimethylamino)pyrrolidin-1-yl)-7-azaspiro[3.5]non Alk-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide ; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2-( Dimethylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro -2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl )-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(side oxy )-l6-Hydroxysulfanyl)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5 ]Nonane-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)(Pendant oxy )-l6-Hydroxythiol)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((- 3-oxabicyclo[3.1.0]hexane-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-( 2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2 ,3-b)pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl) )Methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N -((4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4- (2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-( (1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl) ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2- ((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((( 1r,4r)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[ 2,3-b)pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitro Phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r )-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(propyl- 1-En-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2, 3-b)pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitro Phenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7- Yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methyl (Cyclohexyl) methyl) amino)-3-nitrophenyl) sulfonyl) benzyl Amide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(( 1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 2-Azaspiro[3.3]heptan-2-yl)benzamide; N-((4-((((R)-1,4-diethyl-2-yl)methyl)amino) -3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2- (2-Cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3- b)Pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzene Yl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl ) Benzamide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidine-1- Yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-(( ((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((( (S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2- Yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-piperan -4-yl)ethyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy )-4-(2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-( (2-Pholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2- ((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7- Azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((2-(3-oxolineo)ethyl)amino)phenyl)sulfonyl ) Benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0 ]Hexane-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) -4-(2-((S)-2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-(( 4-(((2,6-Dimethyltetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S) -2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl) -7-Azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-piperan- 4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-( 2-((S)-2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octane-6-yl)-N-((4-(( ((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[ 2,3-b)pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro [3.4]octane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl )Sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S) -2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r) -4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b] Pyridin-5-yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro [4.4]Nonane-2-yl)-N-((4-((((1r,4 r)-4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3- b]Pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non Alk-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfon (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-piper Pyran-4-yl)methyl)ureido)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl) Oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4 -(2-((S)-2-Phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[ 2,3-b)pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-7-yl)-N-((4-((((cis or trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl )Sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2- Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((trans or cis)-4-hydroxy Tetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt or stereoisomer thereof.
在一些實施方式中，本揭露的Bcl-2抑制劑係化合物 1 （化合物 1 ）或其藥學上可接受的鹽。Bcl-2 抑制劑的製備 In some embodiments, the Bcl-2 inhibitor of the present disclosure is Compound 1 ( Compound 1 ) or a pharmaceutically acceptable salt thereof. Preparation of Bcl-2 inhibitor
包括化合物 1
（化合物 1
）的所有具有式 (III-B)、(III-C)、(III-D) 或 (III-E) 的Bcl-2抑制劑可藉由在國際公開WO 2019/210828 A1中揭露之方法製備。化合物 1 的製備 Including compound 1 ( compound 1 ), all Bcl-2 inhibitors of formula (III-B), (III-C), (III-D) or (III-E) can be disclosed in International Publication WO 2019/210828 Prepared by the method disclosed in A1. Preparation of
步驟1：2,2-二甲氧基-7-氮雜螺[3.5]壬烷鹽酸鹽Step 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane hydrochloride
在室溫下，向三級丁基2-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸酯（500 g，2.09 mol）在MeOH（750 mL）和EA（750 mL）中的溶液中添加濃HCl（350 mL，4.18 mol）並且攪拌4小時。在真空中濃縮後，將MeOH（750 mL）添加至殘餘物中，然後將所得混合物在真空中濃縮（重複此處理兩次）。將棕色殘餘物懸浮於EA（1250 mL）中，並且攪拌1小時。將固體沈澱過濾並且在真空中乾燥，以得到呈灰白色粉末的標題產物（350 g，產率：76.0%）。1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 3.03 (s, 6 H), 2.96-2.89 (m, 4 H), 1.93 (s, 4 H), 1.74-1.67 (m, 4 H)。MS (ESI, m/e) [M+1]+ 186.0。At room temperature, add tertiary butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 g, 2.09 mol) in MeOH (750 mL) and EA (750 mL) Add concentrated HCl (350 mL, 4.18 mol) to the solution in) and stir for 4 hours. After concentration in vacuo, MeOH (750 mL) was added to the residue, and then the resulting mixture was concentrated in vacuo (this process was repeated twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 hour. The solid precipitate was filtered and dried in vacuum to obtain the title product (350 g, yield: 76.0%) as an off-white powder. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 3.03 (s, 6 H), 2.96-2.89 (m, 4 H), 1.93 (s, 4 H), 1.74-1.67 (m, 4 H) . MS (ESI, m/e) [M+1] + 186.0.
步驟2：甲基2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2,2-二甲氧基-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5] Nonane-7-yl) benzoate
在85°C下，將甲基2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-氟苯甲酸酯（100 g）、2,2-二甲氧基-7-氮雜螺[3.5]壬烷鹽酸鹽（116 g，1.5當量）和DBU（160 g，3.0當量）在NMP（500 mL）中的混合物攪拌16小時。反應完成後，將混合物冷卻至50°C ± 5°C，並且在攪拌下將檸檬酸水溶液（2%，5 L）逐滴添加至系統中。過濾後，收集濾餅並將其用DCM（1.5 L）溶解。將粗產物的溶液用檸檬酸水溶液（2%，1.5 L）、NaHCO3 飽和水溶液（1.5 L）和15% NaCl水溶液（1.5 L）洗滌，然後經無水Na2 SO4 乾燥。在攪拌下，將矽膠（100 g）添加至粗產物的溶液中，然後過濾。將濾液濃縮至300 mL。將MTBE（500 mL）倒入系統中。攪拌2小時後，過濾後收集濾餅並將其在真空中乾燥，以給出灰白色固體（192 g，產率：72.1%）。1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.63 (s, 1H), 8.00 (d,J = 2.4 Hz, 1H), 7.76 (d,J = 9.2 Hz, 1H), 7.47 (t,J = 3.2 Hz, 1H), 7.42 (d,J = 2.4 Hz, 1H), 6.79 (dd,J = 2.4 Hz,J = 9.2 Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H)。MS (ESI, m/e) [M+1]+ 451.9。At 85°C, the methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (100 g), 2,2- A mixture of dimethoxy-7-azaspiro[3.5]nonane hydrochloride (116 g, 1.5 equivalents) and DBU (160 g, 3.0 equivalents) in NMP (500 mL) was stirred for 16 hours. After the reaction was completed, the mixture was cooled to 50°C ± 5°C, and an aqueous citric acid solution (2%, 5 L) was added dropwise to the system under stirring. After filtration, the filter cake was collected and dissolved in DCM (1.5 L). The solution of the crude product was washed with aqueous citric acid (2%, 1.5 L), saturated aqueous NaHCO 3 (1.5 L), and 15% aqueous NaCl (1.5 L), and then dried over anhydrous Na 2 SO 4 . Under stirring, silicone gel (100 g) was added to the solution of the crude product, and then filtered. The filtrate was concentrated to 300 mL. Pour MTBE (500 mL) into the system. After stirring for 2 hours, the filter cake was collected after filtration and dried in vacuum to give an off-white solid (192 g, yield: 72.1%). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 11.63 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). MS (ESI, m/e) [M+1] + 451.9.
步驟3：甲基2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-側氧基-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonane- 7-yl) benzoate
向甲基2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2,2-二甲氧基-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯（176 g，0.39 mol）在DCM（2 L）中的溶液中添加稀HCl（1 M，1.5 L）並且攪拌過夜。反應完成後，將混合物冷卻至10°C，並且在攪拌下用NaOH水溶液（4 M）調節至pH = 8-9。將有機相分離並且用15% NaCl水溶液（1 L）洗滌，然後用H2 O（1 L）洗滌。將有機相濃縮至500 mL後，將MTBE（1 L）倒入溶液中，然後將系統濃縮至500 mL（重複此處理3次）。將所得系統攪拌0.5小時。過濾後，收集濾餅然後將其在真空中乾燥，以獲得呈白色固體的標題產物（152 g，產率：96.23%）。1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 11.64 (s, 1H), 8.02 (d,J = 2.4 Hz, 1H), 7.78 (d,J = 9.2 Hz, 1H), 7.47 (t,J = 3.2 Hz, 1H), 7.44 (d,J = 2.4 Hz, 1H), 6.83 (dd,J = 2.4 Hz,J = 9.2 Hz, 1H), 6.43 (d,J = 2.4 Hz, 1H), 6.38-6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H)。MS (ESI, m/e) [M+1]+ 405.9。To methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonane To a solution of -7-yl)benzoate (176 g, 0.39 mol) in DCM (2 L) was added dilute HCl (1 M, 1.5 L) and stirred overnight. After the reaction was completed, the mixture was cooled to 10°C and adjusted to pH=8-9 with aqueous NaOH (4 M) while stirring. The organic phase was separated and washed with 15% aqueous NaCl (1 L), then with H 2 O (1 L). After concentrating the organic phase to 500 mL, pour MTBE (1 L) into the solution, and then concentrate the system to 500 mL (repeat this treatment 3 times). The resulting system was stirred for 0.5 hour. After filtration, the filter cake was collected and then dried in vacuum to obtain the title product (152 g, yield: 96.23%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 11.64 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.38 -6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H). MS (ESI, m/e) [M+1] + 405.9.
步驟4：(S)-三級丁基2-(2-(丙-1-烯-2-基)苯基)吡咯啶-1-甲酸酯Step 4: (S)-Tributyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate
向(S)-三級丁基2-(2-溴苯基)吡咯啶-1-甲酸酯（50 g，153.3 mmol）和4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧雜環戊硼烷（38.6 g，229.9 mmol）在二㗁（500 mL）和H2 O（50 mL）中的混合物中添加Cs2 CO3 （100 g，305 mmol）和Pd(dppf)Cl2 （6.6 g，7.5 mmol）。將混合物在100°C下攪拌8小時。TLC顯示反應完成。將混合物在真空中濃縮。將殘餘物藉由矽膠柱層析法（洗脫液：PE/EA（v/v）= 100/1至10/1）純化以獲得(S)-三級丁基2-(2-(丙-1-烯-2-基)苯基)吡咯啶-1-甲酸酯（65 g，粗品）。將粗產物直接用於下一步驟。To (S)-tertiary butyl 2-(2-bromophenyl) pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(propane -1-En-2-yl)-1,3,2-Dioxolane (38.6 g, 229.9 mmol) was added to the mixture of dioxane (500 mL) and H 2 O (50 mL) Cs 2 CO 3 (100 g, 305 mmol) and Pd(dppf)Cl 2 (6.6 g, 7.5 mmol). The mixture was stirred at 100°C for 8 hours. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA (v/v) = 100/1 to 10/1) to obtain (S)-tertiary butyl 2-(2-(propylene) -1-En-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.
步驟5：(S)-三級丁基2-(2-異丙基苯基)吡咯啶-1-甲酸酯Step 5: (S)-Tributyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate
向(S)-三級丁基2-(2-(丙-1-烯-2-基)苯基)吡咯啶-1-甲酸酯（30 g，104.39 mmol）在MeOH（500 mL）中的溶液中添加Pd/C（10 g，10%），並且在20°C下在H2 （15 Psi）下將混合物攪拌12小時。TLC顯示反應完成。將混合物過濾，並且將濾液在真空中濃縮以給出(S)-三級丁基2-(2-異丙基苯基)吡咯啶-1-甲酸酯（60 g，粗品），將其無需進一步純化而用於下一步驟。1 H NMR (400 MHz, CDCl3 ) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H)。To (S)-tertiary butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) Pd/C (10 g, 10%) was added to the solution, and the mixture was stirred at 20°C under H 2 (15 Psi) for 12 hours. TLC showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to give (S)-tertiarybutyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude), which It was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.47 -2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H).
步驟6：(S)-2-(2-異丙基苯基)吡咯啶鹽酸鹽Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride
在室溫下，向三級丁基2-(2-異丙基苯基)吡咯啶-1-甲酸酯（55 g，190 mmol）在DCM（50 mL）中的溶液中逐滴添加在1,4-二㗁（4 M，142 mL，570 mmol）中的HCl。將混合物在室溫下攪拌過夜。將混合物在真空中濃縮。將所得殘餘物用EA（100 mL）漿化，然後過濾，在真空中乾燥以給出(S)-2-(2-異丙基苯基)吡咯啶鹽酸鹽26 g（產率：60.4%）。1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.25 (m, 1H), 2.40-2.21 (m, 1H), 2.19-1.86 (m, 3H), 1.25 (d,J = 6.7 Hz, 3H), 1.17 (d,J = 6.7 Hz, 3H)。MS (ESI, m/e) [M+1]+ 190.0。At room temperature, to a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-Di㗁 (4 M, 142 mL, 570 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was slurried with EA (100 mL), then filtered, and dried in vacuum to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4 %). 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.25 (m, 1H), 2.40-2.21 (m, 1H), 2.19-1.86 (m, 3H) , 1.25 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H). MS (ESI, m/e) [M+1] + 190.0.
步驟7：甲基(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯Step 7: Methyl(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) )Pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoate
將(S)-2-(2-異丙基苯基)吡咯啶鹽酸鹽（120 g，0.535莫耳）和甲基2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-側氧基-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯（218 g，0.509莫耳）在DCM（2.2 L）中的混合物裝入反應器中。將溫度控制在低於30°C，並且將NaBH(OAc)3 （216 g，1.018莫耳）分5-6部分添加至反應器中。然後將反應混合物在室溫下攪拌，並且藉由TLC監測。在起始材料酮完全消耗後，將混合物用稀HCl（0.5 M）調節至pH = 4至5。將分離的有機相用H2 O（600 mL × 2）洗滌，然後用NaHCO3 水溶液（600 mL × 2）、NaCl飽和水溶液（600 mL）洗滌。收集有機相，然後將其經無水Na2 SO4 乾燥，並且濃縮。獲得256 g灰白色固體作為粗產物，將其直接用於下一步驟。MS (ESI, m/e) [M+1]+ 579.0。Combine (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-4-(2-side oxy-7-azaspiro[3.5]nonane-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) The mixture is charged into the reactor. The temperature was controlled below 30°C, and NaBH(OAc) 3 (216 g, 1.018 mol) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After the starting material ketone was completely consumed, the mixture was adjusted to pH = 4 to 5 with dilute HCl (0.5 M). The separated organic phase was washed with H 2 O (600 mL × 2), and then washed with aqueous NaHCO 3 (600 mL × 2) and saturated aqueous NaCl (600 mL). The organic phase was collected, then it was dried over anhydrous Na 2 SO 4 and concentrated. 256 g of off-white solid was obtained as a crude product, which was directly used in the next step. MS (ESI, m/e) [M+1] + 579.0.
步驟8：(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸Step 8: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrole (Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoic acid
向甲基(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸酯（105 g，181.7 mmol）在THF（525 mL）和MeOH（525 mL）中的溶液中添加NaOH水溶液（3.5 M），將其在室溫下攪拌過夜。將THF和MeOH在真空中去除後，將3.5 L水添加至殘餘物中。在室溫下，伴隨攪拌，將所得混合物用3 N HCl調節至pH = 5至6。將沈澱過濾並且在真空中乾燥，以給出呈白色固體的產物（102.4 g，產率：99%）。1 H NMR (400 MHz, DMSO-d6 ) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d,J = 8.0 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.35 (s, 1H), 7.27 - 7.04 (m, 3H), 6.68 (d,J = 8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 - 3.26 (m, 1H), 3.10 - 3.04 (m, 4H), 2.35-2.30 (m, 1 H), 2.9-2.15 (m, 1 H), 1.74 -1.64 (m, 4H), 1.52-1.37 (m, 6H), 1.28 - 1.06 (m, 6H)。MS (ESI, m/e) [M+1]+ 564.9。To methyl(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrole (Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoate (105 g, 181.7 mmol) was added to a solution of THF (525 mL) and MeOH (525 mL) NaOH aqueous solution (3.5 M) was stirred at room temperature overnight. After removing THF and MeOH in vacuo, 3.5 L of water was added to the residue. At room temperature, with stirring, the resulting mixture was adjusted to pH=5 to 6 with 3 N HCl. The precipitate was filtered and dried in vacuum to give the product (102.4 g, yield: 99%) as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56- 7.40 (m, 2H), 7.35 (s, 1H), 7.27-7.04 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 -3.26 (m, 1H), 3.10-3.04 (m, 4H), 2.35-2.30 (m, 1 H), 2.9-2.15 (m, 1 H), 1.74 -1.64 (m, 4H), 1.52-1.37 ( m, 6H), 1.28-1.06 (m, 6H). MS (ESI, m/e) [M+1] + 564.9.
步驟9：化合物 1 Step 9:
在室溫下，將(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸（44 g，78 mmol）、4-((((1r,4r)-4-羥基-4-甲基環己基)甲基)胺基)-3-硝基苯磺醯胺（26.8 g，78 mmol）、TEA（15.7 g，156 mmol）、EDCI（19.4 g，101 mmol）和DMAP（19 g，156 mmol）在無水DCM（880 mL）中的混合物攪拌過夜。將反應藉由HPLC監測。起始材料(S)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧基)-4-(2-(2-(2-異丙基苯基)吡咯啶-1-基)-7-氮雜螺[3.5]壬烷-7-基)苯甲酸完全消耗後，將反應混合物加熱至約35°C，並且一次性添加N1 ,N1 -二甲基乙烷-1,2-二胺（17.2 g，195 mmol）。將反應再攪拌12小時。將混合物用10 wt% AcOH水溶液（300 mL × 2）洗滌兩次，然後用NaHCO3 飽和水溶液（300 mL× 2）洗滌。收集有機層並將其濃縮至約90 mL。添加22 g矽膠並將其攪拌2小時。過濾後，在回流下將180 mL EA添加至濾液中，並且進一步攪拌5小時。將混合物冷卻至室溫後，將沈澱過濾，然後將濕餅用EA（180 mL）洗滌兩次。在80℃-90℃下，在真空中乾燥後，獲得所希望的化合物（48 g，產率：69.5%）。1 H NMR (DMSO-d6 ) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 (d,J = 2.8 Hz, 1H), 7.74 (d,J = 8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d,J = 9.2 Hz, 1H), 6.65 (d,J = 1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.44-1.26 (m, 7H), 1.19 (d,J = 8.0 Hz, 3H), 1.14 (d,J = 8.0 Hz, 3H), 1.10 (s, 4H)。MS (ESI, m/e) [M+1]+ 889.9。治療方法 At room temperature, (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylbenzene Yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy- 4-Methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol) and DMAP ( A mixture of 19 g, 156 mmol) in dry DCM (880 mL) was stirred overnight. The reaction was monitored by HPLC. Starting material (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrole After the pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoic acid is completely consumed, the reaction mixture is heated to about 35°C, and N 1 ,N 1 -dimethyl is added all at once Ethane-1,2-diamine (17.2 g, 195 mmol). The reaction was stirred for another 12 hours. The mixture was washed twice with 10 wt% AcOH aqueous solution (300 mL × 2), and then washed with NaHCO 3 saturated aqueous solution (300 mL × 2). The organic layer was collected and concentrated to about 90 mL. Add 22 g of silicone gel and stir for 2 hours. After filtration, 180 mL of EA was added to the filtrate under reflux, and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered, and then the wet cake was washed twice with EA (180 mL). After drying in vacuum at 80°C-90°C, the desired compound (48 g, yield: 69.5%) was obtained. 1 H NMR (DMSO- d 6 ) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 (d, J = 2.8 Hz, 1H), 7.74 (d , J = 8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 1.2 Hz, 1H) , 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.44-1.26 (m, 7H), 1.19 (d, J = 8.0 Hz, 3H), 1.14 (d, J = 8.0 Hz, 3H), 1.10 (s, 4H). MS (ESI, m/e) [M+1] + 889.9. treatment method
在一個方面，本揭露提供了一種治療癌症之方法。在某些方面，該方法包括向有需要的患者施用有效量的化合物 1
。該癌症可以包括但不限於選自由以下組成之群組的B細胞惡性腫瘤、淋巴瘤或白血病：急性骨髓性白血病（AML）、B細胞非何杰金氏淋巴瘤（B-NHL）、惰性B細胞非何杰金氏淋巴瘤（NHL）、彌漫性大型B細胞淋巴瘤（DLBCL）、生發中心B細胞樣彌漫性大型B細胞淋巴瘤（GCB-DLBCL）、濾泡型淋巴瘤（FL）、被套細胞淋巴瘤（MCL）、急性淋巴母性白血病（ALL）、慢性淋巴性白血病/小淋巴球性淋巴瘤（CLL/SLL）和邊緣區淋巴瘤（MZL）。在一些實施方式中，該癌症係復發性/難治性、或轉化性的。In one aspect, the present disclosure provides a method of treating cancer. In certain aspects, the method includes administering an effective amount of
可以藉由任何合適的方式施用化合物 1
，該等方式包括口服施用、腸胃外施用、肺內施用和鼻內施用，並且如果需要局部治療，則藉由病灶內施用。可以藉由任何合適的途徑給藥。本文考慮了多種給藥方案，包括但不限於單次施用或在不同時間點的多次施用、推注施用、和脈衝輸注。
化合物 1
將以符合良好醫學實踐的方式配製、給藥和施用。關於這點要考慮的因素包括治療的特定障礙、治療的特定哺乳動物、個體患者的臨床病症、障礙的起因、藥劑的遞送位點、施用方法、施用方案、和醫療從業者已知的其他因素。化合物 1
視需要與目前用於預防或治療所研究的障礙的一種或多種藥劑一起配製。此類其他藥劑的有效量取決於配製物中化合物 1
的量、障礙或治療的類型、以及上文討論的其他因素。
為預防或治療疾病，化合物 1
的合適的劑量將取決於待治療的疾病的類型、疾病的嚴重程度和病程、施用化合物 1
係用於預防還是治療目的、先前療法、患者的臨床病史和對化合物 1
的反應、以及主治醫生的判斷。化合物 1
適當地以一次或經一系列治療施用於患者。實例 To prevent or treat the disease, the appropriate dose of
藉由說明本發明的以下實例進一步示例說明本發明，但不限於該等實例。實例 1 ： Bcl-2 抑制劑在 RS4; 11 急性淋巴性白血病 (ALL) 皮下異種移植模型中的療效研究 The present invention is further illustrated by the following examples illustrating the present invention, but is not limited to these examples. Example 1 : Efficacy study of Bcl-2 inhibitor in RS4; 11 acute lymphocytic leukemia (ALL) subcutaneous xenograft model
RS4; 11細胞源自於急性淋巴性白血病(ALL)，並且獲得自美國典型培養物保藏中心（American Type Culture Collection，ATCC CRL-1873，馬納薩斯（Manassas），維吉尼亞州（VA），哥倫比亞特區（DC），美國）。細胞在補充有10%（v/v）胎牛血清（吉博科公司（Gibco），目錄號10099-141C）和100 μg/mL的青黴素和鏈黴素（吉博科公司，目錄號15140-122）的RPMI 1640培養基（康寧公司（Corning），目錄號10-040-CVR）中生長。將RS4; 11細胞作為懸浮細胞培養物維持在37°C下、5% CO2 氣氛中。五至六週齡的雌性NCG小鼠購自資訊技術中心的集萃藥康生物科技有限公司（Gempharmatech of Information Technology Center）。將所有動物維持在無特定病原體（SPF）的「全屏障（full barrier）」條件下，並且可以自由獲取食物和水。在IVC籠子（淩雲博極（北京）科技有限公司（Lingyunboji (Beijing) Technology Co., Ltd.））中，在20°C-26°C的溫度和37%-62%的濕度下，在12小時的光照 : 黑暗循環（在08:00開燈）下將小鼠分組圈養。用經Co60放射滅菌的完整顆粒飼料（北京科奧謝利飼料有限公司（Beijing Ke Ao Xie Li Feed Co., Ltd.））飼喂小鼠。RS4; 11 cells were derived from acute lymphoblastic leukemia (ALL) and were obtained from the American Type Culture Collection (ATCC CRL-1873, Manassas, Virginia (VA) ), District of Columbia (DC), United States). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). RS4; 11 cells were maintained as a suspension cell culture at 37°C in an atmosphere of 5% CO 2. Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). Maintain all animals under "full barrier" conditions free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyunboji (Beijing) Technology Co., Ltd.), at a temperature of 20°C-26°C and a humidity of 37%-62%, at 12 Hours of light: The mice are housed in groups under a dark cycle (light on at 08:00). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.
在植入當天，收穫RS4; 11細胞，並用適當體積的冰冷的DPBS和相同體積的基質膠（Matrigel）（康寧公司，目錄號356237）重懸，以給出最終濃度為5 × 107 個細胞/mL。在接種前，將重懸的細胞置於冰上。在細胞接種前，將每隻小鼠的右前脅腹區用75%乙醇清洗。經由26號針頭，在右前脅腹處向每隻動物皮下注射在200 μL細胞懸液中的1 × 107 個細胞。植入後，使用游標尺測量腫瘤的二維初始體積。On the day of implantation, harvest RS4;11 cells and resuspend them with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 5 × 10 7 cells /mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Via a 26-gauge needle, each animal was injected subcutaneously with 1 × 10 7 cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.
根據體重和腫瘤體積（100 mm3
-200 mm3
），將動物隨機分配至10個組中，每組10隻小鼠。該等組由以下組成：媒介物組，5、15、50 mg/kg的維奈托克以QD給藥，5、15、50 mg/kg的化合物 1
以QD給藥，以及2.5、7.5、25 mg/kg的化合物 1
以BID給藥。藉由口服管飼（p.o.）以10 mL/kg體重的體積施用治療。在評估體重後立即給藥，並相應地調整劑量。According to body weight and tumor volume (100 mm 3 -200 mm 3 ), the animals were randomly assigned to 10 groups, each with 10 mice. These groups consisted of the following: vehicle group, 5, 15, 50 mg/kg of Venetog was administered in QD, 5, 15, 50 mg/kg of
每週兩次記錄個體體重，並且在研究期間每天監測小鼠的毒性臨床體征。當小鼠的腫瘤體積達到2,000 mm3 、腫瘤潰爛或體重減輕超過20%時，使用二氧化碳對小鼠進行安樂死。Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm 3 , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.
使用以下公式計算腫瘤體積：V = 0.5 (a × b2 )，其中a和b分別為腫瘤的長徑和短徑。Use the following formula to calculate the tumor volume: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively.
在NCG小鼠中皮下生長的RS4; 11 ALL異種移植物中，檢查了化合物 1
的體內功效，並將其與維奈托克進行比較。在以良好耐受的劑量口服施用後，化合物 1
有效地且劑量依賴性地抑制腫瘤生長（圖 1
和表 1
）。在5 mg/kg和15 mg/kg的相同總日劑量下，與維奈托克相比，化合物 1
表現出明顯更好的功效。在臨床上，將維奈托克以每天400 mg給藥。基於游離AUC，其在小鼠中的臨床相關劑量為大約15 mg/kg QD。2.5 mg/kg化合物 1
BID的活性比15 mg/kg維奈托克 QD高。此外，在15 mg/kg和50 mg/kg的相同總日劑量下，化合物 1
的QD與BID給藥方案顯示出等效的抗腫瘤活性。該等結果示於圖 1
中。In RS4; 11 ALL xenografts grown subcutaneously in NCG mice, the in vivo efficacy of
在整個研究中，所有治療組對動物體重均無明顯影響。
[表 1
]
MAVER-1細胞源自於被套細胞淋巴瘤（MCL），並且獲得自美國典型培養物保藏中心（ATCC CRL-3008，馬納薩斯，維吉尼亞州，哥倫比亞特區，美國）。細胞在補充有10%（v/v）胎牛血清（吉博科公司（Gibco），目錄號10099-141C）和100 μg/mL的青黴素和鏈黴素（吉博科公司，目錄號15140-122）的RPMI 1640培養基（康寧公司（Corning），目錄號10-040-CVR）中生長。將MAVER-1細胞作為懸浮細胞培養物維持在37°C下、5% CO2 氣氛中。五至六週齡的雌性NCG小鼠購自資訊技術中心的集萃藥康生物科技有限公司（Gempharmatech of Information Technology Center）。將所有動物維持在無特定病原體（SPF）的「全屏障」條件下，並且可以自由獲取食物和水。在IVC籠子（淩雲博極（北京）科技有限公司）中，在21°C-26°C的溫度和44%-61%的濕度下，在12小時的光照 : 黑暗循環（在08:00開燈）下將小鼠分組圈養。用經Co60放射滅菌的完整顆粒飼料（北京科奧謝利飼料有限公司（Beijing Ke Ao Xie Li Feed Co., Ltd.））飼喂小鼠。MAVER-1 cells were derived from mantle cell lymphoma (MCL) and were obtained from the American Type Culture Collection (ATCC CRL-3008, Manassas, Virginia, District of Columbia, USA). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). MAVER-1 cells were maintained as a suspension cell culture in a 5% CO 2 atmosphere at 37°C. Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyun Boji (Beijing) Technology Co., Ltd.), at a temperature of 21°C-26°C and a humidity of 44%-61%, 12 hours of light: dark cycle (open at 08:00 The mice are grouped and housed under the light). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.
在植入當天，收穫MAVER-1細胞，並用適當體積的冰冷的DPBS和相同體積的基質膠（Matrigel）（康寧公司，目錄號356237）重懸，以給出最終濃度為1.5 × 107 個細胞/mL。在接種前，將重懸的細胞置於冰上。在細胞接種前，將每隻小鼠的右前脅腹區用75%乙醇清洗。經由26號針頭，在右前脅腹處向每隻動物皮下注射在200 μL細胞懸液中的3 × 106 個細胞。植入後，使用游標尺測量腫瘤的二維初始體積。On the day of implantation, harvest MAVER-1 cells and resuspend them with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 1.5 × 10 7 cells /mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 3 × 10 6 cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.
根據體重和腫瘤體積（100 mm3
-200 mm3
），將動物隨機分配至7個組中，每組10隻小鼠。該等組由以下組成：媒介物組，5、15 mg/kg的維奈托克以QD給藥，5、15 mg/kg的化合物 1
以QD給藥，2.5、7.5 mg/kg的化合物 1
以BID給藥。藉由口服管飼（p.o.）以10 mL/kg體重的體積施用治療。在評估體重後立即給藥，並相應地調整劑量。According to body weight and tumor volume (100 mm 3 -200 mm 3 ), the animals were randomly assigned to 7 groups, each with 10 mice. The groups consisted of the following: vehicle group, 5 and 15 mg/kg of Venetog were administered in QD, 5, 15 mg/kg of
每週兩次記錄個體體重，並且在研究期間每天監測小鼠的毒性臨床體征。當小鼠的腫瘤體積達到2,000 mm3 、腫瘤潰爛或體重減輕超過20%時，使用二氧化碳對小鼠進行安樂死。Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm 3 , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.
使用以下公式計算腫瘤體積：V = 0.5 (a × b2
)，其中a和b分別為腫瘤的長徑和短徑。使用以下公式計算腫瘤生長抑制（TGI）：%TGI = 100 × [1 - (經治療t
- 經治療t0
)/(媒介物t
- 媒介物t0
)]（經治療t = 在時間t處的經治療的腫瘤體積，經治療t0 = 在時間0處的經治療的腫瘤體積，媒介物t = 在時間t媒介物處的腫瘤體積，以及媒介物t0 = 在時間0處的媒介物腫瘤體積）Use the following formula to calculate the tumor volume: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Use the following formula to calculate tumor growth inhibition (TGI): %TGI = 100 × [1-(treated t -treated t0 )/(vehicle t -vehicle t0 )] (treated t = treated t0 at time t Tumor volume treated, treated t0 = treated tumor volume at
還在NCG小鼠中皮下生長的MAVER-1 MCL異種移植物中，檢查了化合物1的體內功效，並將其與維奈托克進行比較。化合物1以劑量依賴性方式有效地抑制腫瘤生長。對於2.5、7.5 mg/kg BID和5、15 mg/kg QD的化合物1，在第14天的腫瘤生長抑制（TGI）分別是77%、103%以及86%、103%。5 mg/kg和15 mg/kg QD的維奈托克分別達到了38%和91%的TGI。在5 mg/kg和15 mg/kg的相同總日劑量下，與維奈托克相比，化合物1表現出更高的抗腫瘤活性。15 mg/kg QD與7.5 mg/kg BID化合物1的活性類似。該等結果示於圖2和表2中。The in vivo efficacy of
在整個研究中，所有治療組對動物體重均無明顯影響。
[表 2
]
Toledo細胞源自於彌漫性大型B細胞淋巴瘤（DLBCL），並且獲得自美國典型培養物保藏中心（ATCC CRL-2631，馬納薩斯，維吉尼亞州，哥倫比亞特區，美國）。細胞在補充有10%（v/v）胎牛血清（吉博科公司（Gibco），目錄號10099-141C）和100 μg/mL的青黴素和鏈黴素（吉博科公司，目錄號15140-122）的RPMI 1640培養基（康寧公司（Corning），目錄號10-040-CVR）中生長。將Toledo細胞作為懸浮細胞培養物維持在37°C下、5% CO2 氣氛中。五至六週齡的雌性NCG小鼠購自資訊技術中心的集萃藥康生物科技有限公司（Gempharmatech of Information Technology Center）。將所有動物維持在無特定病原體（SPF）的「全屏障」條件下，並且可以自由獲取食物和水。在IVC籠子（淩雲博極（北京）科技有限公司）中，在21°C-26°C的溫度和35%-61%的濕度下，在12小時的光照 : 黑暗循環（在08:00開燈）下將小鼠分組圈養。用經Co60放射滅菌的完整顆粒飼料（北京科奧謝利飼料有限公司（Beijing Ke Ao Xie Li Feed Co., Ltd.））飼喂小鼠。Toledo cells were derived from diffuse large B-cell lymphoma (DLBCL) and were obtained from the American Type Culture Collection (ATCC CRL-2631, Manassas, Virginia, District of Columbia, USA). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). Toledo cells were maintained as a suspension cell culture in a 5% CO 2 atmosphere at 37°C. Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyun Boji (Beijing) Technology Co., Ltd.), at a temperature of 21°C-26°C and a humidity of 35%-61%, 12 hours of light: dark cycle (open at 08:00 The mice are grouped and housed under the light). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.
在植入當天，收穫Toledo細胞，並用適當體積的冰冷的DPBS和相同體積的基質膠（Matrigel）（康寧公司，目錄號356237）重懸，以給出最終濃度為1.5 × 107 個細胞/mL。在接種前，將重懸的細胞置於冰上。在細胞接種前，將每隻小鼠的右前脅腹區用75%乙醇清洗。經由26號針頭，在右前脅腹處向每隻動物皮下注射在200 μL細胞懸液中的3 × 106 個細胞。植入後，使用游標尺測量腫瘤的二維初始體積。On the day of implantation, Toledo cells were harvested and resuspended with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 1.5 × 10 7 cells/mL . Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 3 × 10 6 cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.
根據移植順序和體重，將移植的動物在第0天隨機分至10個組中，每組10隻小鼠。該等組由以下組成：媒介物組，5、15、50 mg/kg的維奈托克以QD給藥，5、15、50 mg/kg的化合物 1
以QD給藥，以及2.5、7.5、25 mg/kg的化合物 1
以BID給藥。藉由口服管飼（p.o.）以10 mL/kg體重的體積施用治療。在評估體重後立即給藥，並相應地調整劑量。According to the transplantation order and body weight, the transplanted animals were randomly divided into 10 groups on
每週兩次記錄個體體重，並且在研究期間每天監測小鼠的毒性臨床體征。當小鼠的腫瘤體積達到2,000 mm3 、腫瘤潰爛或體重減輕超過20%時，使用二氧化碳對小鼠進行安樂死。Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm 3 , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.
使用以下公式計算腫瘤體積：V = 0.5 (a × b2
)，其中a和b分別為腫瘤的長徑和短徑。使用以下公式計算腫瘤生長抑制（TGI）：%TGI = 100 × [1 - (經治療t
- 經治療t0
)/(媒介物t
- 媒介物t0
)]（經治療t = 在時間t處的經治療的腫瘤體積，經治療t0 = 在時間0處的經治療的腫瘤體積，媒介物t = 在時間t媒介物處的腫瘤體積，以及媒介物t0 = 在時間0處的媒介物腫瘤體積）Use the following formula to calculate the tumor volume: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively. Use the following formula to calculate tumor growth inhibition (TGI): %TGI = 100 × [1-(treated t -treated t0 )/(vehicle t -vehicle t0 )] (treated t = treated t0 at time t Tumor volume treated, treated t0 = treated tumor volume at
在Toledo DLBCL皮下異種移植模型中，進一步檢查了化合物 1
的體內功效，並將其與維奈托克進行比較。在以2.5、7.5、25 mg/kg BID或5、15、50 mg/kg QD的良好耐受的劑量每日口服施用後，化合物 1
誘導了劑量依賴性抗腫瘤作用。在5 mg/kg和15 mg/kg的相同總日劑量下，與維奈托克相比，化合物 1
表現出明顯更好的功效。該等結果示於圖 3
和表 3
中。In the Toledo DLBCL subcutaneous xenograft model, the in vivo efficacy of
在整個研究中，所有治療組對動物體重均無明顯影響。
[表 3
]
RS4; 11 Bcl-2G101V KI細胞源自於急性淋巴母性白血病（ALL），並在內部進行了篩選。細胞在補充有10%（v/v）胎牛血清（吉博科公司（Gibco），目錄號10099-141C）和100 μg/mL的青黴素和鏈黴素（吉博科公司，目錄號15140-122）的RPMI 1640培養基（康寧公司（Corning），目錄號10-040-CVR）中生長。將RS4; 11 Bcl-2G101V KI細胞作為懸浮細胞培養物維持在37°C下、5% CO2 氣氛中。五至六週齡的雌性NCG小鼠由中國江蘇的集萃藥康生物科技有限公司（GemPharmatech Co., Ltd）提供。將所有動物維持在無特定病原體（SPF）的「全屏障」條件下，並且可以自由獲取食物和水。在IVC籠子（淩雲博極（北京）科技有限公司（Lingyunboji (Beijing) Technology Co., Ltd.））中，在20°C-26°C的溫度和37%-62%的濕度下，在12小時的光照 : 黑暗循環（在08:00開燈）下將小鼠分組圈養。用經Co60放射滅菌的完整顆粒飼料（北京科奧謝利飼料有限公司）飼喂小鼠。RS4; 11 Bcl-2G101V KI cells were derived from acute lymphoblastic leukemia (ALL) and were screened internally. The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). RS4; 11 Bcl-2G101V KI cells were maintained as a suspension cell culture at 37°C in a 5% CO 2 atmosphere. Five to six weeks old female NCG mice were provided by GemPharmatech Co., Ltd (GemPharmatech Co., Ltd) in Jiangsu, China. All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyunboji (Beijing) Technology Co., Ltd.), at a temperature of 20°C-26°C and a humidity of 37%-62%, at 12 Hours of light: The mice are housed in groups under a dark cycle (light on at 08:00). Mice were fed with whole pellet feed (Beijing Kooseli Feed Co., Ltd.) sterilized by Co60 radiation.
在植入當天，收穫RS4; 11 Bcl-2G101V KI細胞，並用適當體積的冰冷的DPBS和相同體積的基質膠（Matrigel）（康寧公司，目錄號356237）重懸，以給出最終濃度為5 × 107 個細胞/mL。在接種前，將重懸的細胞置於冰上。在細胞接種前，將每隻小鼠的右前脅腹區用75%乙醇清洗。經由26號針頭，在右前脅腹處向每隻動物皮下注射在200 μL細胞懸液中的1 × 107 個細胞。植入後，使用游標尺測量腫瘤的二維初始體積。On the day of implantation, RS4; 11 Bcl-2G101V KI cells were harvested and resuspended with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 5 × 10 7 cells/mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 1 × 10 7 cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.
根據體重和腫瘤體積（大約300 mm3
），將動物隨機分配至7個組中，每組8隻小鼠。該等組由以下組成：媒介物組，15、50和100 mg/kg的維奈托克以QD給藥，15、50和100 mg/kg的化合物 1
以QD給藥。藉由口服管飼（p.o.）以10 mL/kg體重的體積施用治療。在評估體重後立即給藥，並相應地調整劑量。According to body weight and tumor volume (approximately 300 mm 3 ), the animals were randomly assigned to 7 groups, each with 8 mice. The groups consisted of the following: vehicle group, 15, 50, and 100 mg/kg of Venetog were administered QD, and 15, 50, and 100 mg/kg of
每週兩次記錄個體體重，並且在研究期間每天監測小鼠的毒性臨床體征。當小鼠的腫瘤體積達到2,000 mm3 、腫瘤潰爛或體重減輕超過20%時，使用二氧化碳對小鼠進行安樂死。Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm 3 , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.
使用以下公式計算腫瘤體積：V = 0.5 (a × b2 )，其中a和b分別為腫瘤的長徑和短徑。Use the following formula to calculate the tumor volume: V = 0.5 (a × b 2 ), where a and b are the long and short diameters of the tumor, respectively.
在NCG小鼠中皮下生長的RS4; 11 Bcl-2G101V KI異種移植物中，檢查了化合物 1
的體內功效，並將其與維奈托克進行比較。維奈托克即使在較高劑量水平下也幾乎沒有顯示出功效，而化合物 1
則有效地且劑量依賴性地抑制腫瘤生長。該等結果示於圖 4
和表 4
中。化合物 1
在50 mg/kg p.o. QD與100 mg/kg p.o. QD下的曲線合併。In RS4; 11 Bcl-2G101V KI xenografts grown subcutaneously in NCG mice, the in vivo efficacy of
在整個研究中，所有治療組對動物體重均無明顯影響。
[表 4
]
前述實例和某些實施方式的描述應被視為係說明性的，而非限制由請求項所限定的本發明。如將容易理解的，在不脫離如請求項中所闡述的本發明的情況下，可以使用上述特徵的許多變化和組合。所有該等變化都旨在落入本發明的範圍之內。引用的所有參考文獻都藉由引用以其全文併入本文。The foregoing examples and descriptions of certain implementations should be regarded as illustrative rather than limiting the invention defined by the claims. As will be readily understood, many variations and combinations of the above-mentioned features can be used without departing from the invention as set forth in the claims. All these changes are intended to fall within the scope of the present invention. All references cited are incorporated by reference in their entirety.
參考文獻
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Schenk, R. L., Strasser, A., and Dewson, G. (2017) BCL-2: Long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482, 459-469.
Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Dohner, H., Mertens, D., and Stilgenbauer, S. (2019) Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434-e437.
Veis, D.J., Sorenson, C.M., Shutter, J.R. and Korsmeyer, S.J. (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75, 229-240.
Yamamura, K., Kamada, S., Ito, S., Nakagawa, K., Ichihashi, M., and Tsujimoto, Y. (1996) Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res 56, 3546-3550. References Adams, JM, and Cory, S. (2007) The Bcl-2 apoptotic switch in cancer development and therapy.
無none
圖 1 示出了Bcl-2抑制劑在RS4; 11急性淋巴母性白血病（ALL）皮下異種移植模型中的功效。 藉由單因素ANOVA（鄧尼特（Dunnett）多重比較檢驗），相對於媒介物，####p ＜ 0.0001 藉由單因素ANOVA（圖基（Tukey）多重比較檢驗），相對於維奈托克，*p ＜ 0.05，****p ＜ 0.0001。 縮寫：ANOVA，方差分析；SEM，平均值的標準差；QD，每天一次；BID，每天兩次；p.o.，口服管飼。圖 2 示出了Bcl-2抑制劑在MAVER-1被套細胞淋巴瘤（MCL）皮下異種移植模型中的功效。 藉由單因素ANOVA（鄧尼特多重比較檢驗），相對於媒介物，##p ＜ 0.01，####p ＜ 0.0001。 藉由單因素ANOVA（圖基多重比較檢驗），相對於維奈托克，****p ＜ 0.0001。 縮寫：ANOVA，方差分析；SEM，平均值的標準差；QD，每天一次；BID，每天兩次；p.o.，口服管飼。圖 3 示出了Bcl-2抑制劑在Toledo彌漫性大型B細胞淋巴瘤（DLBCL）皮下異種移植模型中的功效。 藉由單因素ANOVA（鄧尼特多重比較檢驗），相對於媒介物，###p ＜ 0.001，####p ＜ 0.0001。 藉由單因素ANOVA（圖基多重比較檢驗），相對於維奈托克，**p ＜ 0.01，****p ＜ 0.0001。 縮寫：ANOVA，方差分析；SEM，平均值的標準差；QD，每天一次；BID，每天兩次；p.o.，口服管飼。圖 4 示出了Bcl-2抑制劑在RS4; 11 Bcl-2G101V KI急性淋巴母性白血病（ALL）皮下異種移植模型中的功效。 藉由單因素ANOVA，相對於媒介物，## p ＜ 0.01，#### p ＜ 0.0001；藉由單因素ANOVA，相對於維奈托克，**** p ＜ 0.0001。 Figure 1 shows the efficacy of Bcl-2 inhibitors in the RS4; 11 acute lymphomaternal leukemia (ALL) subcutaneous xenograft model. By one-way ANOVA (Dunnett's multiple comparison test), #### p <0.0001 relative to the vehicle, and by one-way ANOVA (Tukey's multiple comparison test), relative to Veneto Grams, * p <0.05, **** p <0.0001. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 2 shows the efficacy of Bcl-2 inhibitors in the MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model. By one-way ANOVA (Dunnett's multiple comparison test), ## p <0.01, #### p <0.0001 relative to the vehicle. With one-way ANOVA (Tukey's multiple comparison test), **** p <0.0001 relative to Venetog. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 3 shows the efficacy of Bcl-2 inhibitors in a subcutaneous xenograft model of Toledo diffuse large B-cell lymphoma (DLBCL). By one-way ANOVA (Dunnett's multiple comparison test), ### p <0.001 and #### p <0.0001 relative to the vehicle. With one-way ANOVA (Tukey's multiple comparison test), ** p ＜ 0.01, **** p ＜ 0.0001 relative to Venetog. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 4 shows the efficacy of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. With one-way ANOVA, relative to the vehicle, ## p <0.01, #### p <0.0001; with one-way ANOVA, relative to Venetog, **** p <0.0001.
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