TW202114682A - Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof - Google Patents

Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof Download PDF

Info

Publication number
TW202114682A
TW202114682A TW109120291A TW109120291A TW202114682A TW 202114682 A TW202114682 A TW 202114682A TW 109120291 A TW109120291 A TW 109120291A TW 109120291 A TW109120291 A TW 109120291A TW 202114682 A TW202114682 A TW 202114682A
Authority
TW
Taiwan
Prior art keywords
alkyl
group
branched
linear
hydrogen atom
Prior art date
Application number
TW109120291A
Other languages
Chinese (zh)
Inventor
塞巴斯蒂安 班固特
阿里克斯 達雷爾
芙羅倫斯 賓利曲
戴爾 波特
安薩 哈利洛維奇
Original Assignee
法商施維雅藥廠
瑞士商諾華公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 法商施維雅藥廠, 瑞士商諾華公司 filed Critical 法商施維雅藥廠
Publication of TW202114682A publication Critical patent/TW202114682A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A combination comprising a Mcl-1 inhibitor and a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant, and compositions and uses thereof.

Description

MCL-1抑制劑與乳癌標準療法之組合，其用途及醫藥組合物Combination of MCL-1 inhibitor and standard breast cancer therapy, its use and pharmaceutical composition

本發明係關於Mcl-1抑制劑與第二抗癌劑之組合，其中第二抗癌劑係選自埃雷布林(eribulin) (細胞毒性劑)及氟維司群(fulvestrant) (激素療法)。本發明亦係關於該組合在治療癌症、具體而言乳癌且更具體而言管腔乳癌、HER2+ 乳癌及三陰性乳癌中之用途。亦提供適於投與該等組合之醫藥調配物。The present invention relates to a combination of an Mcl-1 inhibitor and a second anticancer agent, wherein the second anticancer agent is selected from the group consisting of eribulin (cytotoxic agent) and fulvestrant (hormonal therapy) ). The present invention also relates to the use of the combination in the treatment of cancer, specifically breast cancer and more specifically luminal breast cancer, HER2 + breast cancer and triple negative breast cancer. Pharmaceutical formulations suitable for administration of these combinations are also provided.

乳癌(BC)係最常被診斷的且在全世界女性中係癌症相關死亡之第二主要原因(Siegel等人CA Cancer J. Clin. 2017, 67, 7-30)。其治療之主要挑戰之一係其異質性質，其將藉由評估幾種生物標記來確定治療選擇，該等生物標記包括激素受體(HR) [雌激素受體(ER)及助孕酮受體(PR)]之存在、人類表皮生長因子受體2 (HER2)蛋白之過量含量及/或HER2 基因之額外拷貝(Hammond等人Arch. Pathol. Lab. Med. 2010, 134, e48-72；Wolff等人J. Clin. Oncol. 2013, 31, 3997-4013)。Breast cancer (BC) is the most commonly diagnosed and the second leading cause of cancer-related deaths among women worldwide (Siegel et al. CA Cancer J. Clin. 2017, 67, 7-30). One of the main challenges of its treatment is its heterogeneous nature. It will determine treatment options by evaluating several biomarkers, including hormone receptor (HR) [estrogen receptor (ER) and progesterone receptors). The presence of human body (PR)], the excess content of human epidermal growth factor receptor 2 (HER2) protein and/or the extra copy of the HER2 gene (Hammond et al. Arch. Pathol. Lab. Med. 2010, 134, e48-72; Wolff et al . J. Clin. Oncol. 2013, 31, 3997-4013).

BC被分類為四個主要分子亞型：(i) 管腔A (HR+ /HER2− )；(ii) HER2+ ；(iii) 管腔B (HR+ /HER2+ )；及(iv) 三陰性(HR− /HER2− )。該等亞型中之每一者對於發病率、治療反應、疾病進展及轉移之優先器官部位具有不同之危險因子。BC is classified into four main molecular subtypes: (i) Lumen A (HR + /HER2 − ); (ii) HER2 + ; (iii) Lumen B (HR + /HER2 + ); and (iv) Three Negative (HR − /HER2 − ). Each of these subtypes has different risk factors for morbidity, treatment response, disease progression, and preferred organ sites for metastasis.

在發達國家中，HR陽性(HR+ )之管腔BC佔BC病例之絕大多數(60-80%)(American Cancer Society. Breast Cancer Facts & Figures 2017-18. Atlanta: American Cancer Society, Inc. (2017))。對於HR+ BC，內分泌療法係主要治療手段。推薦依序投與內分泌治療，直至需要快速反應或有臨床抗性之證據，此時指示適用化學療法(Reinert等人Ther. Adv. Med. Oncol. 2015, 7, 304-320)。由於內分泌藥物藉由不同機制起作用，故其通常組合使用以獲得更佳抗癌效能。然而，已報導衝突結果(Michaud等人Oncologist 2001, 6, 538-546；Bergh等人J. Clin. Oncol. 2012, 30, 1919-1925；Mehta等人N. Eng. J. Med. 2012, 367, 435-444)。通常認為，初次內分泌療法之晚期BC患者及患有高度內分泌敏感性腫瘤之患者可自組合內分泌療法中受益最大(Johnston等人Lancet Oncol. 2013, 14, 989-998)。轉移性HR+ BC可能對標準激素療法產生抗性，此係由ER之基因體改變及/或其他信號路徑之上調介導。In developed countries, HR positive (HR + ) luminal BC accounts for the vast majority (60-80%) of BC cases (American Cancer Society. Breast Cancer Facts & Figures 2017-18. Atlanta: American Cancer Society, Inc. (2017)). For HR + BC, endocrine therapy is the main treatment. It is recommended to administer endocrine therapy sequentially until a rapid response or evidence of clinical resistance is required, at which time chemotherapy is indicated (Reinert et al . Ther. Adv. Med. Oncol. 2015, 7, 304-320). Since endocrine drugs work by different mechanisms, they are usually used in combination to obtain better anti-cancer efficacy. However, conflict results have been reported (Michaud et al. Oncologist 2001, 6, 538-546; Bergh et al . J. Clin. Oncol. 2012, 30, 1919-1925; Mehta et al . N. Eng. J. Med. 2012, 367 , 435-444). It is generally believed that patients with advanced endocrine therapy and patients with highly endocrine-sensitive tumors can benefit the most from combined endocrine therapy (Johnston et al. Lancet Oncol. 2013, 14, 989-998). Metastatic HR + BC may develop resistance to standard hormone therapy, which is mediated by genetic changes in ER and/or upregulation of other signal pathways.

三陰性乳癌(TNBC)係一種更具侵襲性之疾病。其與較差預後、局部復發之高風險以及較差無疾病存活及總體存活相關。TNBC佔BC之10-15%，且與診斷時年齡偏低、高組織學等級及較差短期預後相關(Lebert,Curr. Oncol. 2018, 25, S142-S150；Stevens等人Cancer Res. 2013, 73, 2025-2030)。對於TNBC，標準化學療法仍係主要治療手段。有趣的是，TNBC係對化學療法具有更高完全反應率(22%)之BC亞型。然而，復發及轉移率高於攜帶非TNBC腫瘤之彼等(Liedtke等人J. Clin. Oncol. 2008, 26, 1275-1281)。患有轉移性TNBC之患者利用習用細胞毒性劑之中值OS(總體存活)約為9-12個月。缺乏ER、PR及HER2表現無法在晚期TNBC中使用靶向療法，且唯一批准之全身治療選擇係化學療法(通常係紫杉烷(taxane)、蒽環及鉑藥物(Berrada等人Ann. Oncol. 2010, 21, vii30-35)，具有或無貝伐珠單抗(bevacizumab))。然而，儘管在該領域進行了深入研究，但仍需要用於TNBC之新療法。Triple negative breast cancer (TNBC) is a more aggressive disease. It is associated with poor prognosis, high risk of local recurrence, and poor disease-free survival and overall survival. TNBC accounts for 10-15% of BC and is associated with low age at diagnosis, high histological grade, and poor short-term prognosis (Lebert, Curr. Oncol. 2018, 25, S142-S150; Stevens et al. Cancer Res. 2013, 73 , 2025-2030). For TNBC, standard chemotherapy is still the main treatment. Interestingly, TNBC is a BC subtype with a higher complete response rate (22%) to chemotherapy. However, the recurrence and metastasis rates are higher than those with non-TNBC tumors (Liedtke et al . J. Clin. Oncol. 2008, 26, 1275-1281). The median OS (overall survival) of patients with metastatic TNBC using conventional cytotoxic agents is approximately 9-12 months. Lack of ER, PR and HER2 manifestations cannot be used in advanced TNBC targeted therapy, and the only approved systemic treatment option is chemotherapy (usually taxane (taxane), anthracycline and platinum drugs (Berrada et al . Ann. Oncol. 2010, 21, vii30-35), with or without bevacizumab). However, despite in-depth research in this field, new therapies for TNBC are still needed.

細胞凋亡係由各種細胞毒性刺激(包括致癌應激及化學治療劑)引發之高度調控之細胞死亡路徑。已顯示逃避細胞凋亡係癌症之標誌，且許多化學治療劑之效能取決於固有線粒體路徑之活化(Hanahan等人 Cell 2011, 144, 646-742)。Apoptosis is a highly regulated cell death pathway triggered by various cytotoxic stimuli (including carcinogenic stress and chemotherapeutics). It has been shown that evasion of apoptosis is a hallmark of cancer, and the efficacy of many chemotherapeutics depends on the activation of the intrinsic mitochondrial pathway (Hanahan et al. Cell 2011, 144, 646-742).

Bcl-2(B細胞淋巴瘤-2)家族蛋白在平衡細胞存活及細胞凋亡中起重要作用(Tsujimoto, Genes to Cells 1998, 3, 697-707) 。 Bcl-2蛋白之三個不同亞組控制固有路徑：促細胞凋亡之僅BH3蛋白(Noxa、PUMA、Bim、Bid)、促存活成員(Bcl-2、Bcl-xL、Bcl-w、Mcl-1、Bcl-2A1)及促細胞凋亡效應蛋白(Bax及Bak)(Adams等人 Current Opinion in Immunology 2007, 19, 488-496；Czabotar等人，Nature Reviews Molecular Cell Biology 2014, 15, 49-63)。已發現Bcl-2家族蛋白在血液系統惡性病中失調，但在實體腫瘤中亦失調，且在獲得性化學抗性癌細胞中經常上調(Maji等人 Advances in Cancer Research 2017, 137, 37-75)。正常乳房上皮細胞中促細胞凋亡及抗細胞凋亡信號受到嚴格調控。此平衡之失調係乳房腫瘤發生及增加對各種治療(包括靶向療法、放射療法及化學療法)之後天抗性所需的(Williams等人 Oncotarget 2014, 6, 3519-3530)。在BC中，跨腫瘤亞型之促存活蛋白之差異表現表明，在不同腫瘤亞型中可靶向此蛋白類別之不同成員(Merino等人 Sci. Transl. Med. 2017, 9, pii: eaam7049)。Bcl-2 (B-cell lymphoma-2) family proteins play an important role in balancing cell survival and apoptosis (Tsujimoto, Genes to Cells 1998, 3, 697-707) . Three different subgroups of Bcl-2 protein control the inherent pathway: only BH3 protein (Noxa, PUMA, Bim, Bid) that promotes apoptosis, and survival-promoting members (Bcl-2, Bcl-xL, Bcl-w, Mcl- 1. Bcl-2A1) and pro-apoptotic effector proteins (Bax and Bak) (Adams et al. Current Opinion in Immunology 2007, 19, 488-496; Czabotar et al., Nature Reviews Molecular Cell Biology 2014, 15, 49-63 ). It has been found that Bcl-2 family proteins are dysregulated in hematological malignancies, but are also dysregulated in solid tumors, and are often upregulated in acquired chemoresistance cancer cells (Maji et al. Advances in Cancer Research 2017, 137, 37-75 ). Pro-apoptotic and anti-apoptotic signals in normal breast epithelial cells are strictly regulated. This disorder of balance is required for breast tumors to develop and increase acquired resistance to various treatments (including targeted therapies, radiotherapy, and chemotherapy) (Williams et al. Oncotarget 2014, 6, 3519-3530). In BC, the differential expression of pro-survival proteins across tumor subtypes indicates that different members of this protein class can be targeted in different tumor subtypes (Merino et al. Sci. Transl. Med. 2017, 9, pii: eaam7049) .

Bcl-2係雌激素反應性基因，其在約85%之ER+ 陽性BC中過表現(Dawson等人 British J. Cancer 2010, 103, 668-675)。使用ER+ BC之患者源異種移植模型之臨床前數據表明，間歇投用與他莫昔芬(tamoxifen)(抗雌激素治療)協同之Bcl-2抑制劑(維尼托克萊克斯(venetoclax))藉由增加細胞凋亡改良腫瘤反應(Vaillant等人Cancer Cell 2013, 24, 120-129)。該等數據最近在Ib期臨床研究中確認，組合維尼托克萊克斯與內分泌療法具有可耐受之安全性概況，且在ER+ 及Bcl-2陽性BC中引發顯著活性(Lok等人 Cancer Discov. 2019, 9, 354-369)。Bcl-2 is an estrogen-responsive gene, which is expressed in approximately 85% of ER+ -positive BC (Dawson et al. British J. Cancer 2010, 103, 668-675). Preclinical data of a patient-derived xenograft model using ER + BC indicate that intermittent administration of Bcl-2 inhibitors (venetoclax) in conjunction with tamoxifen (anti-estrogen therapy) Improve tumor response by increasing apoptosis (Vaillant et al Cancer Cell 2013, 24, 120-129). These data have recently confirmed in a phase Ib clinical study that the combination of Veneto Clax and endocrine therapy has a tolerable safety profile and induces significant activity in ER + and Bcl-2 positive BC (Lok et al. Cancer Discov . 2019, 9, 354-369).

Mcl-1係發現之Bcl-2家族之第二個成員(Kozopas等人 Proc. Natl. Acad. Sci. USA 1993, 90, 3516-3520)。Mcl-1亦可為治療靶標，此乃因已在跨多種癌症(包括乳癌)之體細胞拷貝數變化之大規模高解析度研究中觀察到Mcl-1擴增，且Mcl-1可賦予化學療法或靶向療法抗性(Wertz等人 Nature 2011, 471, 110-114；Placzek等人 Cell Death & Disease 2010, 1, e40)。Mcl-1似乎係TNBC中上調之主要促存活蛋白(Goodwin等人 Cell Death Differ. 2015, 22, 2098-2106；Xiao等人 Mol. Cancer Ther. 2015, 14, 1837-1847)。此外，通常在前導性化學療法未能達到完全病理反應之TNBC腫瘤中觀察到Mcl-1擴增(Balko等人 Cancer Discov. 2014, 4, 232-245)。最後，發現Mcl-1表現在抗雌激素抗性細胞系中上調，且抗性細胞中Mcl-1之耗盡導致癌細胞之存活率降低(Thrane等人 Oncogene 2015, 34, 4199-4210；Dawson等人 2010)。Mcl-1 is the second member of the Bcl-2 family discovered (Kozopas et al. Proc. Natl. Acad. Sci. USA 1993, 90, 3516-3520). Mcl-1 can also be a therapeutic target, because Mcl-1 amplification has been observed in large-scale high-resolution studies of somatic cell copy number changes across a variety of cancers (including breast cancer), and Mcl-1 can confer chemical Resistance to therapy or targeted therapy (Wertz et al. Nature 2011, 471, 110-114; Placzek et al. Cell Death & Disease 2010, 1, e40). Mcl-1 seems to be the main pro-survival protein up-regulated in TNBC (Goodwin et al. Cell Death Differ. 2015, 22, 2098-2106; Xiao et al. Mol. Cancer Ther. 2015, 14, 1837-1847). In addition, Mcl-1 amplification is usually observed in TNBC tumors where a complete pathological response has not been achieved by leading chemotherapy (Balko et al. Cancer Discov. 2014, 4, 232-245). Finally, it was found that Mcl-1 was upregulated in anti-estrogen-resistant cell lines, and the depletion of Mcl-1 in resistant cells resulted in a decrease in the survival rate of cancer cells (Thrane et al. Oncogene 2015, 34, 4199-4210; Dawson Et al. 2010).

因此，顯然需要開發旨在逆轉對激素療法之抗性的新藥劑。儘管吾人對BC中之分子基礎之瞭解有所提高，但在抵抗此疾病中，防止發生抗性及為已產生抗藥性之患者鑑別適當治療靶標變得愈來愈重要。本發明提供Mcl-1抑制劑及第二抗癌劑之新穎組合，其中第二抗癌劑係埃雷布林及氟維司群。結果顯示與埃雷布林組合之Mcl-1抑制劑(表2)在TNBC及ER+ /HER2− 乳癌細胞系中展現強烈協同促細胞凋亡活性。此外，目前正進行I/II期臨床試驗(實例2)。Therefore, there is a clear need to develop new agents aimed at reversing resistance to hormone therapy. Although our understanding of the molecular basis of BC has improved, it has become more and more important to prevent the development of resistance and to identify appropriate therapeutic targets for patients who have developed resistance in fighting this disease. The present invention provides a novel combination of an Mcl-1 inhibitor and a second anticancer agent, wherein the second anticancer agent is Errebine and Fulvestrant. The results showed that the Mcl-1 inhibitor combined with Erreblin (Table 2) exhibited a strong synergistic pro-apoptotic activity in TNBC and ER + /HER2 − breast cancer cell lines. In addition, phase I/II clinical trials are currently underway (Example 2).

根據本發明之第一態樣，提供以下各項之新穎組合： (a) 式(I)之Mcl-1抑制劑：

Figure 02_image001
其中： ♦  D代表環烷基、雜環烷基、芳基或雜芳基， ♦  E代表呋喃基、噻吩基或吡咯基環， ♦  X1 、X3 、X4 及X5 彼此獨立地代表碳原子或氮原子， ♦  X2 代表C-R26 基團或氮原子， ♦
Figure 02_image003
意指環係芳香族， ♦  Y代表氮原子或C-R3 基團， ♦  Z代表氮原子或C-R4 基團， ♦  R1 代表鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、羥基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-Cy8 、 -(C0 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， ♦  R2 、R3 、R4 及R5 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、羥基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R1 , R2 ), (R2 , R3 ), (R3 , R4 )或(R4 , R5 )與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由1至2個選自以下之基團取代：鹵素、直鏈或具支鏈(C1 -C6 )烷基、-(C0 -C6 )烷基-NR11 R11 ’、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， ♦  R6 及R7 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R6 , R7 )在與兩個毗鄰碳原子稠合時與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由選自以下之基團取代：直鏈或具支鏈(C1 -C6 )烷基、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， ♦  W代表-CH2 -基團、-NH-基團或氧原子， ♦  R8 代表氫原子、直鏈或具支鏈(C1 -C8 )烷基、-CHRa Rb 基團、芳基、雜芳基、芳基(C1 -C6 )烷基或雜芳基(C1 -C6 )烷基， ♦  R9 代表氫原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、-Cy2 、-(C1 -C6 )烷基-Cy2 、-(C2 -C6 )烯基-Cy2 、-(C2 -C6 )炔基-Cy2 、-Cy2 -Cy3 、-(C2 -C6 )炔基-O-Cy2 、-Cy2 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 ’， ♦  R10 代表氫原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、芳基(C1 -C6 )烷基、環烷基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )鹵代烷基、或-(C1 -C6 )烷基-O-Cy4 ， 或配對(R9, R10 )在與兩個毗鄰碳原子稠合時與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子， ♦  R11 及R11 ’彼此獨立地代表氫原子、視情況經取代之直鏈或具支鏈(C1 -C6 )烷基或-(C0 -C6 )烷基-Cy1 ， 或配對(R11 , R11 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所述氮可由1至2個代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代，且應理解，可能取代基之一或多個碳原子可經氘化， ♦  R12 代表-Cy5 、-Cy5 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-NR11 -(C0 -C6 )烷基-Cy6 、-Cy5 -Cy6 -O-(C0 -C6 )烷基-Cy7 、-Cy5 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy9 、-Cy5 -(C0 -C6 )烷基-Cy9 、-NH-C(O)-NH-R11 、-Cy5 -(C0 -C6 )烷基-NR11 -(C0 -C6 )烷基-Cy9 、-C(O)-NR11 R11 ’、-NR11 R11 ’、-OR11 、-NR11 -C(O)-R11 ’、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 ， ♦  R13 、R13 ’、R14 及R14 ’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基， ♦  Ra 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， ♦  Rb 代表-O-C(O)-O-Rc 基團、-O-C(O)-NRc Rc ’基團或-O-P(O)(ORc )2 基團， ♦  Rc 及Rc ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C8 )烷基、環烷基、(C1 -C6 )烷氧基(C1 -C6 )烷基或(C1 -C6 )烷氧基羰基(C1 -C6 )烷基， 或配對(Rc , Rc ’)與其附接之氮原子一起形成由5至7個環成員構成之非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧及氮之雜原子，應理解，所述氮可由代表直鏈或具支鏈(C1 -C6 )烷基之基團取代， ♦  Cy1 、Cy2 、Cy3 、Cy4 、Cy5 、Cy6 、Cy7 、Cy8 及Cy10 彼此獨立地代表環烷基、雜環烷基、芳基或雜芳基， ♦  Cy9 代表
Figure 02_image005
，或Cy9 代表由選自以下之基團取代之雜芳基：-O-P(O)(OR20 )2 ；-O-P(O)(O- M+ )2 ；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 ；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；或-U-(CH2 )q -NR21 R21 ’， ♦  R15 代表氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；直鏈或具支鏈(C1 -C6 )烷氧基(C1 -C6 )烷基；-U-(CH2 )q -NR21 R21 ’基團；或-(CH2 )r -U-(CH2 )s -雜環烷基， ♦  R16 代表氫原子；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；(CH2 )r -U-V-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；-O-S(O)2 OR20 基團；-S(O)2 OR20 基團；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-(CH2 )p -O-C(O)-NR22 R23 基團；或-U-(CH2 )q -NR21 R21 ’基團， ♦  R17 代表氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-CH2 -O-P(O)(OR20 )2 基團；-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；-U-(CH2 )q -NR21 R21 ’基團；或醛醣酸， ♦  M+ 代表醫藥上可接受之單價陽離子， ♦  U代表鍵或氧原子， ♦  V代表-(CH2 )s -基團或-C(O)-基團， ♦  R18 代表氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， ♦  R19 代表氫原子或羥基(C1 -C6 )烷基， ♦  R20 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， ♦  R21 及R21 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或羥基(C1 -C6 )烷基， 或配對(R21 , R21 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代， ♦  R22 代表(C1 -C6 )烷氧基(C1 -C6 )烷基、-(CH2 )p -NR24 R24 ’基團或-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團， ♦  R23 代表氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， 或配對(R22 , R23 )與其附接之氮原子一起形成由5至18個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至5個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或雜環烷基之基團取代， ♦  R24 及R24 ’彼此獨立地代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， 或配對(R24 , R24 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代， ♦  R25 代表氫原子、羥基或羥基(C1 -C6 )烷基， ♦  R26 代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基或氰基， ♦  R27 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， ♦  R28 代表-O-P(O)(O- )(O- )基團、-O-P(O)(O- )(OR30 )基團、-O-P(O)(OR30 )(OR30 ’)基團、-(CH2 )p -O-S(O)2 O- 基團；-(CH2 )p -S(O)2 O- 基團；-(CH2 )p -O-S(O)2 OR30 基團；-Cy10 、-O-C(O)-R29 基團、-O-C(O)-OR29 基團或-O-C(O)-NR29 R29 ’基團； ♦  R29 及R29 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或直鏈或具支鏈胺基(C1 -C6 )烷基， ♦  R30 及R30 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或芳基(C1 -C6 )烷基， ♦  R31 代表以下基團：
Figure 02_image007
其中銨離子視情況以兩性離子形式存在或具有單價陰離子相對離子， ♦  n係等於0或1之整數， ♦  p係等於0、1、2或3之整數， ♦  q係等於1、2、3或4之整數， ♦  r及s獨立地係等於0或1之整數， 應理解：　 -   「芳基」意指苯基、萘基、聯苯基、二氫茚基或茚基， -   「雜芳基」意指由5至10個環成員構成、具有至少一個芳香族部分且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環基團， -   「環烷基」意指含有3至10個環成員之任何單環或二環非芳香族碳環基團， -   「雜環烷基」意指含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環非芳香族碳環基團，其可包括稠合、橋接或螺環系統， 如此定義之芳基、雜芳基、環烷基及雜環烷基及烷基、烯基、炔基、烷氧基可由1至4個選自以下之基團取代：視情況經取代之直鏈或具支鏈(C1 -C6 )烷基、視情況經取代之直鏈或具支鏈(C2 -C6 )烯基、視情況經取代之直鏈或具支鏈(C2 -C6 )炔基、視情況經取代之直鏈或具支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或N -氧化物，在適當之情形下)、硝基、氰基、-C(O)-OR’、-O-C(O)-R’、-C(O)-NR’R’’、-NR’R’’、-(C=NR’)-OR’’、直鏈或具支鏈(C1 -C6 )鹵代烷基、三氟甲氧基或鹵素，應理解，R’及R’’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基，且應理解，前述可能取代基之一或多個碳原子可經氘化， 或其鏡像異構物、非鏡像異構物、阻轉異構物或與醫藥上可接受之酸或鹼之加成鹽， 及(b) 第二抗癌劑，其中第二抗癌劑係選自埃雷布林及氟維司群， 用於同時、依序或分開使用。According to the first aspect of the present invention, a novel combination of the following is provided: (a) Mcl-1 inhibitor of formula (I):
Figure 02_image001
Among them: ♦ D represents cycloalkyl, heterocycloalkyl, aryl or heteroaryl, ♦ E represents furyl, thienyl or pyrrolyl ring, ♦ X 1 , X 3 , X 4 and X 5 represent independently of each other Carbon atom or nitrogen atom, ♦ X 2 represents CR 26 group or nitrogen atom, ♦
Figure 02_image003
Refers to the aromatic ring system, ♦ Y represents a nitrogen atom or CR 3 group, ♦ Z represents a nitrogen atom or CR 4 group, ♦ R 1 represents a halogen atom, linear or branched (C 1 -C 6 ) alkyl , Linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkyl, hydroxyl , Hydroxy (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) alkoxy, -S-(C 1 -C 6 ) alkyl, cyano, nitro, -Cy 8 , -(C 0 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl -R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C(O)-OR 11 ', -(C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 )alkyl, ♦ R 2 , R 3 , R 4 and R 5 independently of each other represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group, a linear or branched Chain (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkyl, hydroxyl, hydroxyl (C 1- C 6 ) alkyl, straight or branched (C 1 -C 6 ) alkoxy, -S-(C 1 -C 6 ) alkyl, cyano, nitro, -(C 0 -C 6 ) Alkyl-NR 11 R 11 ', -O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 , -(C 2 -C 6 )alkenyl-Cy 1 , -(C 2 -C 6 )Alkynyl-Cy 1 , -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C(O)-OR 11 ', -( C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 )alkyl, or paired (R 1 , R 2 ), (R 2 , R 3 ), (R 3 , R 4 ) or (R 4 , R 5 ) Together with the carbon atom to which it is attached, form an aromatic or non-aromatic ring composed of 5 to 7 ring members, and these ring members may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that, The resulting ring may be substituted with 1 to 2 groups selected from the group consisting of halogen, linear or branched (C 1 -C 6 )alkyl, -(C 0 -C 6 )alkyl -NR 11 R 11 ', -NR 13 R 13 ', -(C 0 -C 6 )alkyl-Cy 1 or pendant oxy group, ♦ R 6 and R 7 independently of each other represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C 1 -C 6 ) alkyl, linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) Haloalkyl, hydroxyl, linear or branched (C 1 -C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, cyano, nitro, -(C 0 -C 6 )Alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 ,- (C 2 -C 6 )alkenyl-Cy 1 , -(C 2 -C 6 )alkynyl-Cy 1 , -O-(C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C(O)-OR 11 ',- (C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 )alkyl, or pairing (R 6 , R 7 ) When fused with two adjacent carbon atoms, together with the attached carbon atoms, form an aromatic or non-aromatic ring composed of 5 to 7 ring members, and these ring members may contain 1 to 3 Heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted with a group selected from the group consisting of linear or branched (C 1 -C 6 )alkyl, -NR 13 R 13 ', -( C 0 -C 6 ) alkyl -Cy 1 or pendant oxy group, ♦ W represents -CH 2 -group, -NH- group or oxygen atom, ♦ R 8 represents hydrogen atom, straight chain or branched chain (C 1 -C 8 ) alkyl, -CHR a R b group, aryl, heteroaryl, aryl (C 1 -C 6 ) alkyl or heteroaryl (C 1 -C 6 ) alkyl, ♦ R 9 represents a hydrogen atom, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) Alkynyl, -Cy 2 , -(C 1- C 6 )alkyl-Cy 2 , -(C 2 -C 6 )alkenyl-Cy 2 , -(C 2 -C 6 )alkynyl-Cy 2 , -Cy 2 -Cy 3 , -(C 2 -C 6 ) Alkynyl-O-Cy 2 , -Cy 2 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 3 , halogen atom, cyano group, -C(O) -R 14 or -C(O)-NR 14 R 14 ', ♦ R 10 represents a hydrogen atom, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 2 -C 6 ) Alkenyl, straight or branched (C 2 -C 6 )alkynyl, aryl (C 1 -C 6 )alkyl, cycloalkyl (C 1 -C 6 )alkyl, straight chain or Branched chain (C 1 -C 6 ) haloalkyl, or -(C 1 -C 6 ) alkyl -O-Cy 4 , or the pairing (R 9, R 10 ) is attached to two adjacent carbon atoms when fused The connected carbon atoms together form an aromatic or non-aromatic ring composed of 5 to 7 ring members. These ring members may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, ♦ R 11 and R 11 'Representing hydrogen atoms independently of each other, optionally substituted linear or branched (C 1 -C 6 ) alkyl or -(C 0 -C 6 ) alkyl -Cy 1 , or pairing (R 11 , R 11 ') together with the nitrogen atom to which it is attached, form an aromatic or non-aromatic ring composed of 5 to 7 ring members. In addition to the nitrogen atom, these ring members may also contain 1 to 3 selected from oxygen, sulfur and Heteroatoms of nitrogen, it should be understood that the nitrogen can be substituted by 1 to 2 groups representing hydrogen atoms or linear or branched (C 1 -C 6 ) alkyl groups, and it should be understood that one of the possible substituents or Multiple carbon atoms can be deuterated, ♦ R 12 represents -Cy 5 , -Cy 5 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 6 , -Cy 5- (C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -(C 0 -C 6 )alkyl-NR 11 -(C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -Cy 6- O-(C 0 -C 6 )alkyl-Cy 7 , -Cy 5 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 9 , -Cy 5 -(C 0 -C 6 )alkyl-Cy 9 , -NH-C(O)-NH-R 11 , -Cy 5 -(C 0 -C 6 )alkyl-NR 11 -(C 0 -C 6 )alkyl -Cy 9 , -C(O)-NR 11 R 11 ', -NR 11 R 11 ', -OR 11 , -NR 11 -C(O)-R 11 ', -O-alkyl(C 1 -C 6 )-OR 11 , -SO 2 -R 11 , -C(O)-OR 11 , ♦ R 13 , R 13 ', R 14 and R 14 'represent each other independently Hydrogen atom or optionally substituted linear or branched (C 1 -C 6 ) alkyl group, ♦ R a represents a hydrogen atom or linear or branched (C 1 -C 6 ) alkyl group, ♦ R b Representative -OC (O) -OR c group, -OC (O) -NR c R c ' or a group -OP (O) (oR c) 2 group, ♦ R c and R c' independently of one another represent Hydrogen atom, linear or branched (C 1 -C 8 )alkyl, cycloalkyl, (C 1 -C 6 )alkoxy (C 1 -C 6 )alkyl or (C 1 -C 6 ) Alkoxycarbonyl (C 1 -C 6 ) alkyl, or pairing (R c , R c ') together with the nitrogen atom to which it is attached, forms a non-aromatic ring composed of 5 to 7 ring members, except for the nitrogen atom These ring members may also contain 1 to 3 heteroatoms selected from oxygen and nitrogen. It should be understood that the nitrogen may be substituted by a group representing a straight-chain or branched (C 1 -C 6 ) alkyl group, ♦ Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 , Cy 6 , Cy 7 , Cy 8 and Cy 10 independently represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl, ♦ Cy 9 represents
Figure 02_image005
, Or Cy 9 represents a heteroaryl group substituted by a group selected from: -OP(O)(OR 20 ) 2 ; -OP(O)(O - M + ) 2 ; -(CH 2 ) p -O -(CHR 18 -CHR 19 -O) q -R 20 ; hydroxy; hydroxy (C 1 -C 6 )alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; or- U-(CH 2 ) q -NR 21 R 21 ', ♦ R 15 represents a hydrogen atom; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; straight chain or Branched chain (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; -U-(CH 2 ) q -NR 21 R 21 'group; or -(CH 2 ) r -U-( CH 2 ) s -heterocycloalkyl, ♦ R 16 represents a hydrogen atom; hydroxyl; hydroxy (C 1 -C 6 ) alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; (CH 2 ) r -UVOP(O)(OR 20 ) 2 group; -OP(O)(O - M + ) 2 group; -OS(O) 2 OR 20 group; -S(O) 2 OR 20 group; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; -(CH 2 ) p -OC(O)-NR 22 R 23 group; or -U-(CH 2 ) q -NR 21 R 21 'group, R 17 represents a hydrogen atom; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group;- CH 2 -OP(O)(OR 20 ) 2 group; -OP(O)(OR 20 ) 2 group; -OP(O)(O - M + ) 2 group; hydroxyl group; hydroxyl group (C 1- C 6 ) alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; -U-(CH 2 ) q -NR 21 R 21 'group; or aldonic acid, ♦ M + Represents a pharmaceutically acceptable monovalent cation, ♦ U represents a bond or an oxygen atom, ♦ V represents a -(CH 2 ) s -group or -C(O)- group, ♦ R 18 represents a hydrogen atom or (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl group, ♦ R 19 represents a hydrogen atom or a hydroxy (C 1 -C 6 ) alkyl group, ♦ R 20 represents a hydrogen atom or a straight or branched chain (C 1 -C 6 )alkyl, ♦ R 21 and R 21 'independently of each other represent a hydrogen atom, linear or branched (C 1 -C 6 )alkyl or Hydroxy (C 1 -C 6 ) alkyl, or pairing (R 21 , R 21 ') together with the nitrogen atom to which it is attached, forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, except for the nitrogen atom The ring members may also contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may represent a hydrogen atom or a straight-chain or branched (C 1 -C 6 ) alkyl group Group substitution, ♦ R 22 represents (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl, -(CH 2 ) p -NR 24 R 24 'group or -(CH 2 ) p -O -(CHR 18 -CHR 19 -O) q -R 20 group, ♦ R 23 represents a hydrogen atom or (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl group, or a pair (R 22 , R 23 ) together with the nitrogen atom to which it is attached, form an aromatic or non-aromatic ring composed of 5 to 18 ring members. In addition to the nitrogen atom, these ring members may also contain 1 to 5 selected from oxygen, sulfur and Heteroatoms of nitrogen, it should be understood that the resulting ring may be substituted by a group representing a hydrogen atom, linear or branched (C 1 -C 6 ) alkyl or heterocycloalkyl, ♦ R 24 and R 24 'are independently of each other Represents a hydrogen atom or a straight or branched chain (C 1 -C 6 ) alkyl group, or the pairing (R 24 , R 24 ') and the nitrogen atom to which it is attached together form an aromatic group consisting of 5 to 7 ring members or For non-aromatic rings, in addition to nitrogen atoms, these ring members can also contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring can represent hydrogen atoms or linear or branched (C 1 -C 6 ) Alkyl group substitution, ♦ R 25 represents a hydrogen atom, a hydroxyl group or a hydroxy (C 1 -C 6 ) alkyl group, ♦ R 26 represents a hydrogen atom, a halogen atom, straight or branched chain (C 1 -C 6) alkyl or cyano, ♦ R 27 represents a hydrogen atom or a linear or branched (C 1 -C 6) alkyl, ♦ R 28 Representative -OP (O) (O -) (O - ) Group, -OP(O)(O - )(OR 30 ) group, -OP(O)(OR 30 )(OR 30 ') group, -(CH 2 ) p -OS(O) 2 O - group ;-( CH 2) p -S (O ) 2 O - groups ;-( CH 2) p -OS (O ) 2 OR 30 group; -Cy 10, -OC (O) -R 29 Group, -OC(O)-OR 29 group or -OC(O)-NR 29 R 29'group ; ♦ R 29 and R 29 ' independently represent a hydrogen atom, straight chain or branched chain (C 1 -C 6 ) alkyl or straight or branched chain amino (C 1 -C 6 ) alkyl, ♦ R 30 and R 30 'independently of each other represent a hydrogen atom Sub, straight-chain or branched (C 1 -C 6 ) alkyl or aryl (C 1 -C 6 ) alkyl, ♦ R 31 represents the following groups:
Figure 02_image007
Ammonium ions may exist in the form of zwitterions or have monovalent anions as appropriate, ♦ n is an integer equal to 0 or 1, ♦ p is an integer equal to 0, 1, 2 or 3, ♦ q is equal to 1, 2, 3 Or an integer of 4, ♦ r and s are independently an integer equal to 0 or 1. It should be understood that:-"aryl" means phenyl, naphthyl, biphenyl, indenyl or indenyl,-"hetero "Aryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen,-"cycloalkane "Group" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"Heterocycloalkyl" means 3 to 10 ring members and 1 to 3 selected from Any monocyclic or bicyclic non-aromatic carbocyclic group of heteroatoms of oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems, aryl, heteroaryl, cycloalkyl and hetero Cycloalkyl and alkyl, alkenyl, alkynyl, and alkoxy groups may be substituted with 1 to 4 groups selected from the following: optionally substituted linear or branched (C 1 -C 6 )alkyl, Optionally substituted linear or branched (C 2 -C 6 ) alkenyl, optionally substituted linear or branched (C 2 -C 6 ) alkynyl, optionally substituted linear or Branched (C 1 -C 6 ) alkoxy, optionally substituted (C 1 -C 6 ) alkyl-S-, hydroxyl, pendant oxy (or N -oxide, where appropriate) , Nitro, cyano, -C(O)-OR', -OC(O)-R', -C(O)-NR'R'', -NR'R'', -(C=NR' )-OR”, straight or branched (C 1 -C 6 ) haloalkyl, trifluoromethoxy or halogen, it should be understood that R'and R” independently represent a hydrogen atom or be substituted as appropriate the straight-chain or branched (C 1 -C 6) alkyl, and it should be understood that the group may be substituted with one or more carbon atoms may be deuterated, or enantiomers, diastereomeric, Atropisomers or addition salts with pharmaceutically acceptable acids or bases, and (b) a second anticancer agent, wherein the second anticancer agent is selected from Erreblin and Fulvestrant, with Use at the same time, sequentially or separately.

該等式(I)化合物、其合成、其在治療癌症中之用途及其醫藥調配物闡述於WO 2015/097123、WO 2016/207216、WO 2016/207217、WO 2016/207225、WO 2016/207226及WO 2017/125224中，該等專利之內容以引用方式併入。The compounds of formula (I), their synthesis, their use in the treatment of cancer and their pharmaceutical formulations are described in WO 2015/097123, WO 2016/207216, WO 2016/207217, WO 2016/207225, WO 2016/207226 and In WO 2017/125224, the contents of these patents are incorporated by reference.

具體而言，Mcl-1抑制劑係化合物1 (S64315/MIK665)： (2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽，其闡述於WO 2015/097123之實例30中，該專利之內容以引用方式併入。Specifically, the Mcl-1 inhibitor series compound 1 (S64315/MIK665): (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl-4-[2- (4-Methylhexahydropyrazin-1-yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3- d ]pyrimidin-4-yl]oxy)- 3-(2-{[2-(2-Methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid or a pharmaceutically acceptable salt thereof, which is described in WO 2015/097123 In Example 30, the content of the patent is incorporated by reference.

在另一實施例中，Mcl-1抑制劑係化合物2 (S63845)： (2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽，其闡述於WO 2015/097123之實例185中，該專利之內容以引用方式併入。In another embodiment, the Mcl-1 inhibitor is compound 2 (S63845): (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl-4-[2 -(4-Methylhexahydropyrazin-1-yl)ethoxy]phenyl)-6-(5-fluorofuran-2-yl)thieno[2,3- d ]pyrimidin-4-yl] Oxy}-3-(2-{[1-(2,2,2-trifluoroethyl)-1 H -pyrazol-5-yl]methoxy}phenyl)propionic acid or its pharmaceutically acceptable The accepted salt is described in Example 185 of WO 2015/097123, the content of which is incorporated by reference.

在另一實施例中，本發明提供如本文所述之組合，其用於治療癌症，更具體而言治療乳癌。In another embodiment, the present invention provides a combination as described herein for use in the treatment of cancer, more specifically breast cancer.

在另一實施例中，本發明提供醫藥組合物，其包含如本文所述之組合及至少一種醫藥上可接受之載劑。In another embodiment, the present invention provides a pharmaceutical composition comprising a combination as described herein and at least one pharmaceutically acceptable carrier.

定義 「組合」係指一個單位劑型(例如膠囊、錠劑或小藥囊)中之固定劑量組合、非固定劑量組合或組合投與之部分之套組，其中本發明化合物及一或多個組合配偶體(例如如下文揭示之另一藥物，亦稱為「治療劑」或「助劑」)可獨立地同時投與或在時間間隔內分開投與，尤其在該等時間間隔允許組合配偶體顯示協作、例如協同效應之情形下。definition "Combination" refers to a fixed-dose combination, a non-fixed-dose combination, or a set of combined administration parts in a unit dosage form (such as a capsule, lozenge, or sachet), wherein the compound of the present invention and one or more combination partners The body (such as another drug as disclosed below, also known as "therapeutic agent" or "adjuvant") can be independently administered at the same time or separately within a time interval, especially during these time intervals allowing the combination partner to show Collaboration, such as in the case of synergy.

如本文所用，術語「共投與」或「組合投與」或諸如此類意欲涵蓋向有需要之單一個體(例如患者)投與所選組合配偶體，且意欲包括不必藉由相同投與途徑或同時投與藥劑之治療方案。As used herein, the term "co-administration" or "combination administration" or the like is intended to encompass the administration of the selected combination partner to a single individual (eg, patient) in need, and is intended to include not necessarily by the same route of administration or simultaneously The treatment plan of administering medicament.

術語「固定劑量組合」意指將活性成分(例如，式(I)化合物)及一或多種組合配偶體二者以單一實體或劑量的形式同時投與給患者。The term "fixed-dose combination" means that both the active ingredients (for example, a compound of formula (I)) and one or more combination partners are simultaneously administered to a patient in the form of a single entity or dosage.

術語「非固定劑量組合」意指將活性成分(例如本發明化合物)及一或多種組合配偶體二者作為分開之實體同時或依序且無具體時間限制地投與患者，其中此投與在患者體內提供治療有效量之兩種化合物。後者亦適用於雞尾酒療法，例如投與3種或更多種活性成分。The term "non-fixed-dose combination" means that both the active ingredient (such as the compound of the present invention) and one or more combination partners are administered to a patient simultaneously or sequentially and without specific time limits as separate entities, wherein the administration is in A therapeutically effective amount of the two compounds is provided in the patient's body. The latter also applies to cocktail therapy, such as the administration of 3 or more active ingredients.

「癌症」意指其中細胞群組展示不受控生長之疾病之狀態。癌症類型包括乳癌，包括管腔乳癌、HER2+ 乳癌及三陰性乳癌。"Cancer" means a disease state in which cell groups exhibit uncontrolled growth. Cancer types include breast cancer, including luminal breast cancer, HER2 + breast cancer, and triple-negative breast cancer.

「BC」意指乳癌。"BC" means breast cancer.

如本文所用，術語「聯合治療有效」意指治療劑可以在欲治療之溫血動物、尤其人類中仍顯示(較佳協同)相互作用(聯合治療效應)之時間間隔分開(以按時間順序交錯方式、尤其順序特定方式)給與。無論何種情形皆尤其可藉由跟蹤血液濃度來測定，此顯示該兩種化合物至少在某些時間間隔期間皆存在於所治療人類之血液中。As used herein, the term "combination therapy is effective" means that the therapeutic agent can still show (preferably synergistic) interactions (combination therapy effects) in the warm-blooded animals to be treated, especially humans, separated by time intervals (in chronological order) Way, especially order specific way) to give. In any case, it can especially be determined by tracking the blood concentration, which shows that the two compounds are present in the blood of the human being treated at least during certain time intervals.

「標準護理藥物」或「標準護理化學療法」意指埃雷布林及氟維司群。"Standard of care drugs" or "Standard of care chemotherapy" means Erreblin and Fulvestrant.

「協同有效」或「協同」意指在投與兩種或更多種藥劑後觀察到之治療效應大於在投與每一單一藥劑後觀察到之治療效應之總和。"Synergy effective" or "synergistic" means that the therapeutic effect observed after the administration of two or more agents is greater than the sum of the therapeutic effects observed after the administration of each single agent.

在一個實施例中，如本文所用術語「治療」(treat、treating或treatment)任一疾病或病症係指改善該疾病或病症(即，減緩或阻止或減慢該疾病或其至少一種臨床症狀的發展)。在另一實施例中，「治療」(treat、treating或treatment)係指減輕或改善包括患者不能感受到之彼等物理參數的至少一個物理參數。在又一實施例中，「治療」(treat、treating或treatment)係指在物理方面調節疾病或病症(例如，穩定可辨別症狀)、在生理學方面調節疾病或病症(例如，穩定物理參數)或二者均有。In one embodiment, as used herein, the term "treating" (treat, treating or treatment) of any disease or condition refers to ameliorating the disease or condition (ie, slowing down or preventing or slowing down the disease or at least one of its clinical symptoms) development of). In another embodiment, "treat" (treat, treating or treatment) refers to reducing or improving at least one physical parameter including those physical parameters that the patient cannot feel. In yet another embodiment, "treat" (treat, treating or treatment) refers to the physical regulation of the disease or condition (for example, stabilizing discernible symptoms), and the physiological regulation of the disease or condition (for example, stabilizing physical parameters) Or both.

如本文所用，若個體可在生物學方面、醫學方面或生命品質方面受益於治療，則該個體「需要」該治療。As used herein, if an individual can benefit from treatment in terms of biology, medicine, or quality of life, then the individual "needs" the treatment.

術語「緩解」係指癌症之體徵及症狀減少或消失。The term "remission" refers to the reduction or disappearance of the signs and symptoms of cancer.

「藥劑」意指醫藥組合物或若干醫藥組合物之組合，在一或多種賦形劑存在下，其含有一或多種活性成分。"Medicine" means a pharmaceutical composition or a combination of several pharmaceutical compositions, which contains one or more active ingredients in the presence of one or more excipients.

如本文所用術語「鹵代烷基」係指沿烴鏈經一或多個鹵素基團代替氫而取代之直鏈或具支鏈烷基鏈。適於鹵代烷基中之取代之鹵素基團之實例包括氟、溴、氯及碘。鹵代烷基可包括用多個鹵素基團代替烷基鏈中之氫之取代，其中該等鹵素基團可附接至烷基鏈中之同一碳或另一碳。The term "haloalkyl" as used herein refers to a straight or branched alkyl chain substituted along the hydrocarbon chain by one or more halogen groups instead of hydrogen. Examples of halogen groups suitable for substitution in haloalkyl include fluorine, bromine, chlorine and iodine. Haloalkyl groups may include substitutions of replacing hydrogen in the alkyl chain with multiple halogen groups, where the halogen groups may be attached to the same carbon or another carbon in the alkyl chain.

下文闡述本發明之多個實施例，其中為便利起見，E1與下文本發明之第一態樣相同。本文闡述本發明進一步列舉之實施例(E)。應認識到，在每一實施例中所指定之特徵可與其他指定特徵組合以提供本發明之其他實施例。A number of embodiments of the present invention are described below. For convenience, E1 is the same as the first aspect of the following invention. This article describes the further example (E) of the present invention. It should be recognized that the features specified in each embodiment can be combined with other specified features to provide other embodiments of the present invention.

E2. 根據E1之組合，其包含： (a) 式(I)之Mcl-1抑制劑，其中該式(I)之Mcl-1抑制劑具有式(IA)：

Figure 02_image009
其中： ♦  Z代表氮原子或C-R4 基團， ♦  R1 代表直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、氰基、-NR11 R11 ’、-Cy8 或鹵素原子， ♦  R2 、R3 及R4 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R2 , R3 )或(R3 , R4 )與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由選自以下之基團取代：直鏈或具支鏈(C1 -C6 )烷基、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， ♦  R6 及R7 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R6 , R7 )在與兩個毗鄰碳原子稠合時與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由選自以下之基團取代：直鏈或具支鏈(C1 -C6 )烷基、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， ♦  R8 代表氫原子、直鏈或具支鏈(C1 -C8 )烷基、芳基、雜芳基、芳基(C1 -C6 )烷基或雜芳基(C1 -C6 )烷基， ♦  R9 代表直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、-Cy2 、-(C1 -C6 )烷基-Cy2 、-(C2 -C6 )烯基-Cy2 、-(C2 -C6 )炔基-Cy2 、-Cy2 -Cy3 、-(C2 -C6 )炔基-O-Cy2 、-Cy2 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 ’， ♦  R11 及R11 ’彼此獨立地代表氫原子、視情況經取代之直鏈或具支鏈(C1 -C6 )烷基或-(C0 -C6 )烷基-Cy1 ， 或配對(R11 , R11 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所述氮可由代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代，且應理解，可能取代基之一或多個碳原子可經氘化， ♦  R12 代表-Cy5 、-Cy5 -(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-NR11 -(C0 -C6 )烷基-Cy6 、-Cy5 -Cy6 -O-(C0 -C6 )烷基-Cy7 、-C(O)-NR11 R11 ’、-NR11 R11 ’、-OR11 、-NR11 -C(O)-R11 ’、-O-(C1 -C6 )烷基-OR11 、-SO2 -R11 、-C(O)-OR11 或-NH-C(O)-NH-R11 ， ♦  R13 、R13 ’、R14 及R14 ’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基， ♦  R25 代表氫原子、羥基或羥基(C1 -C6 )烷基， ♦  Cy1 、Cy2 、Cy3 、Cy5 、Cy6 、Cy7 及Cy8 彼此獨立地代表環烷基、雜環烷基、芳基或雜芳基， ♦  n係等於0或1之整數， 應理解：　 -   「芳基」意指苯基、萘基、聯苯基、二氫茚基或茚基， -   「雜芳基」意指由5至10個環成員構成、具有至少一個芳香族部分且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環基團， -   「環烷基」意指含有3至10個環成員之任何單環或二環非芳香族碳環基團， -   「雜環烷基」意指含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環非芳香族碳環基團，其可包括稠合、橋接或螺環系統， 如此定義之芳基、雜芳基、環烷基及雜環烷基及烷基、烯基、炔基、烷氧基可由1至4個選自以下之基團取代：視情況經取代之直鏈或具支鏈(C1 -C6 )烷基、視情況經取代之直鏈或具支鏈(C2 -C6 )烯基、視情況經取代之直鏈或具支鏈(C2 -C6 )炔基、視情況經取代之直鏈或具支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或N -氧化物，在適當之情形下)、硝基、氰基、-C(O)-OR’、-O-C(O)-R’、-C(O)-NR’R’’、-NR’R’’、-(C=NR’)-OR’’、直鏈或具支鏈(C1 -C6 )鹵代烷基、三氟甲氧基或鹵素，應理解，R’及R’’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基，且應理解，前述可能取代基之一或多個碳原子可經氘化， 或其鏡像異構物、非鏡像異構物、阻轉異構物或與醫藥上可接受之酸或鹼之加成鹽， 及(b) 第二抗癌劑，其中第二抗癌劑係選自埃雷布林及氟維司群， 用於同時、依序或分開使用。E2. A combination according to E1, comprising: (a) the Mcl-1 inhibitor of formula (I), wherein the Mcl-1 inhibitor of formula (I) has the formula (IA):
Figure 02_image009
Among them: ♦ Z represents a nitrogen atom or a CR 4 group, ♦ R 1 represents a straight chain or branched (C 1 -C 6 ) alkyl, straight chain or branched (C 2 -C 6 ) alkenyl, straight Chain or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) alkoxy, -S-(C 1 -C 6 ) alkyl, linear or branched Chain (C 1 -C 6 ) haloalkyl, hydroxyl, cyano, -NR 11 R 11 ', -Cy 8 or halogen atom, ♦ R 2 , R 3 and R 4 independently represent a hydrogen atom, halogen atom, straight Chain or branched (C 1 -C 6 ) alkyl, straight chain or branched (C 2 -C 6 ) alkenyl, straight chain or branched (C 2 -C 6 ) alkynyl, straight chain or Branched (C 1 -C 6 ) haloalkyl, hydroxyl, straight or branched (C 1 -C 6 ) alkoxy, -S-(C 1 -C 6 ) alkyl, cyano, nitro , -(C 0 -C 6 )alkyl-NR 11 R 11 ', -O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 , -(C 2 -C 6 )alkenyl-Cy 1 , -(C 2 -C 6 )alkynyl-Cy 1 , -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C( O)-OR 11 ', -(C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 ) Alkyl group, or pair (R 2 , R 3 ) or (R 3 , R 4 ) together with the carbon atom to which it is attached to form an aromatic or non-aromatic ring composed of 5 to 7 ring members, and these ring members It may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may be substituted with a group selected from the group consisting of straight or branched (C 1 -C 6 )alkyl, -NR 13 R 13 ', -(C 0 -C 6 )alkyl-Cy 1 or pendant oxy group, ♦ R 6 and R 7 independently of each other represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C 1 -C 6 ) Alkyl, linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkane Group, hydroxyl, straight or branched chain (C 1 -C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, cyano, nitro, -(C 0 -C 6 )alkyl -NR 11 R 11 '、- O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 , -(C 2 -C 6 )alkenyl-Cy 1 , -(C 2 -C 6 )alkynyl-Cy 1 , -O- (C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O )-R 11 ', -NR 11 -C(O)-OR 11 ', -(C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'Or -SO 2 -(C 1 -C 6 ) alkyl, or the pairing (R 6 , R 7 ) when fused with two adjacent carbon atoms together with the attached carbon atoms to form 5 to 7 ring members The constituent aromatic or non-aromatic ring, these ring members may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and it should be understood that the resulting ring may be substituted by a group selected from: straight chain or branched Chain (C 1 -C 6 ) alkyl, -NR 13 R 13 ', -(C 0 -C 6 )alkyl -Cy 1 or pendant oxy group, ♦ R 8 represents a hydrogen atom, linear or branched ( C 1 -C 8 ) alkyl, aryl, heteroaryl, aryl (C 1 -C 6 ) alkyl or heteroaryl (C 1 -C 6 ) alkyl, ♦ R 9 stands for linear or branched Chain (C 1 -C 6 ) alkyl, linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, -Cy 2 , -(C 1 -C 6 )alkyl-Cy 2 , -(C 2 -C 6 )alkenyl-Cy 2 , -(C 2 -C 6 )alkynyl-Cy 2 , -Cy 2 -Cy 3 , -(C 2 -C 6 )alkynyl-O-Cy 2 , -Cy 2 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 3 , halogen atom, cyano group, -C( O)-R 14 or -C(O)-NR 14 R 14 ', ♦ R 11 and R 11 'independently represent a hydrogen atom, optionally substituted straight chain or branched chain (C 1 -C 6 ) Alkyl group or -(C 0 -C 6 )alkyl -Cy 1 , or pairing (R 11 , R 11 ') together with the nitrogen atom to which it is attached, form an aromatic or non-aromatic group consisting of 5 to 7 ring members In addition to the nitrogen atom, the ring members may also contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the nitrogen may represent a hydrogen atom or a linear or branched chain (C 1- C 6 ) Alkyl group is substituted, and it should be understood that one or more of the carbon atoms of the possible substituents can be deuterated, ♦ R 12 represents -Cy 5 , -Cy 5 -(C 0 -C 6 )alkyl -Cy 6 , -Cy 5 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -(C 0 -C 6 )alkyl-NR 11- (C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -Cy 6 -O-(C 0 -C 6 )alkyl-Cy 7 , -C(O)-NR 11 R 11 ', -NR 11 R 11 ', -OR 11 , -NR 11 -C(O)-R 11 ', -O-(C 1 -C 6 )alkyl-OR 11 , -SO 2 -R 11 , -C(O)- OR 11 or -NH-C(O)-NH-R 11 ♦ R 13 , R 13 ', R 14 and R 14 'independently represent a hydrogen atom or optionally substituted straight or branched chain (C 1 -C 6 ) alkyl group, ♦ R 25 represents a hydrogen atom, a hydroxyl group or a hydroxy (C 1 -C 6 ) alkyl group, ♦ Cy 1 , Cy 2 , Cy 3 , Cy 5 , Cy 6 , Cy 7 and Cy 8 each other Independently represents cycloalkyl, heterocycloalkyl, aryl or heteroaryl, n is an integer equal to 0 or 1. It should be understood that:-"aryl" means phenyl, naphthyl, biphenyl, diphenyl Indenyl or indenyl,-"heteroaryl" means any monocyclic ring consisting of 5 to 10 ring members, having at least one aromatic moiety, and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen Or a bicyclic group,-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means 3 to 10 ring members Any monocyclic or bicyclic non-aromatic carbocyclic group having ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems, aryl groups as defined in this way , Heteroaryl, cycloalkyl and heterocycloalkyl and alkyl, alkenyl, alkynyl, alkoxy can be substituted by 1 to 4 groups selected from the following: optionally substituted straight chain or branched chain (C 1 -C 6 )alkyl, optionally substituted linear or branched (C 2 -C 6 )alkenyl, optionally substituted linear or branched (C 2 -C 6 )alkynes Group, optionally substituted linear or branched (C 1 -C 6 ) alkoxy, optionally substituted (C 1 -C 6 ) alkyl-S-, hydroxyl, pendant oxy (or N -Oxide, where appropriate), nitro, cyano, -C(O)-OR', -OC(O)-R', -C(O)-NR'R'', -NR'R'',-(C=NR')-OR'', linear or branched (C 1 -C 6 ) haloalkyl, trifluoromethoxy or halogen, it should be understood that R'and R'' are mutually Independently represents a hydrogen atom or optionally substituted linear or branched (C 1 -C 6 ) alkyl, and it should be understood that the foregoing may be One or more of the carbon atoms of the substituent may be deuterated, or its enantiomers, diastereomers, atropisomers or addition salts with pharmaceutically acceptable acids or bases, and (b ) A second anticancer agent, wherein the second anticancer agent is selected from Erreblin and Fulvestrant for simultaneous, sequential or separate use.

E3. 根據E1或E2之組合，其中該式(I)之Mcl-1抑制劑具有式(IB)：

Figure 02_image011
其中R9 、R11 、R11 ’及R12 係如上文E1或E2中所述。E3. According to the combination of E1 or E2, wherein the Mcl-1 inhibitor of formula (I) has formula (IB):
Figure 02_image011
Wherein R 9 , R 11 , R 11 ′ and R 12 are as described in E1 or E2 above.

E4. 根據E1、E2或E3之組合，其中該式(I)之Mcl-1抑制劑係化合物1：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽。E4. According to the combination of E1, E2 or E3, wherein the Mcl-1 inhibitor of formula (I) is compound 1: (2 R )-2-{[(5 S a )-5-{3-chloro-2 -Methyl-4-[2-(4-methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d ]pyrimidine -4-yl]oxy)-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid or its pharmaceutically acceptable salt .

E5. 根據E1、E2或E3之組合，其中該式(I)之Mcl-1抑制劑係化合物2：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽。E5. According to the combination of E1, E2 or E3, wherein the Mcl-1 inhibitor of formula (I) is compound 2: (2 R )-2-{[(5 S a )-5-{3-chloro-2 - methyl-4- [2- (4-methyl-piperazine-1-yl) ethoxy] phenyl} -6- (5-fluoro-2-yl) thieno [2,3 - d ]pyrimidin-4-yl]oxy)-3-(2-{[1-(2,2,2-trifluoroethyl)-1 H -pyrazol-5-yl]methoxy}phenyl ) Propionic acid or its pharmaceutically acceptable salt.

E6. 根據E1至E5中任一項之組合，其中該第二抗癌劑係埃雷布林。E6. A combination according to any one of E1 to E5, wherein the second anticancer agent is Erreblin.

E7. 根據E1至E5中任一項之組合，其中該第二抗癌劑係氟維司群。E7. The combination according to any one of E1 to E5, wherein the second anticancer agent is fulvestrant.

E8. 根據E1、E2或E3之組合，其包含： (a) 化合物1：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽， 及(b) 第二抗癌劑，其中第二抗癌劑係選自埃雷布林及氟維司群， 用於同時、依序或分開使用。E8. According to the combination of E1, E2 or E3, it contains: (a) Compound 1: (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl-4-[ 2-(4-Methylhexahydropyrazin-1-yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3- d ]pyrimidin-4-yl]oxy }-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid or a pharmaceutically acceptable salt thereof, and (b) the second The anticancer agent, wherein the second anticancer agent is selected from Erreblin and Fulvestrant, for simultaneous, sequential or separate use.

E9. 根據E4或E8之組合，其中在組合治療期間化合物1之劑量係25 mg至1500 mg。E9. According to the combination of E4 or E8, wherein the dose of compound 1 during the combination treatment is 25 mg to 1500 mg.

E10. 根據E4、E8或E9之組合，其中化合物1係在該組合治療期間每週投與一次。E10. According to the combination of E4, E8 or E9, wherein compound 1 is administered once a week during the combination treatment.

E11. 根據E1至E10中任一項之組合，其中該Mcl-1抑制劑係經口投與。E11. The combination according to any one of E1 to E10, wherein the Mcl-1 inhibitor is administered orally.

E12. 根據E1至E10中任一項之組合，其中該Mcl-1抑制劑係靜脈內投與。E12. The combination according to any one of E1 to E10, wherein the Mcl-1 inhibitor is administered intravenously.

E13. 根據E1至E10中任一項之組合，其呈非固定劑量組合形式。E13. The combination according to any one of E1 to E10, which is in the form of a non-fixed dose combination.

E14. 根據E1至E10中任一項之組合，其呈固定劑量組合形式。E14. The combination according to any one of E1 to E10, which is in the form of a fixed-dose combination.

E15. 根據E1至E14中任一項之組合，其用於醫藥中。E15. According to the combination of any one of E1 to E14, it is used in medicine.

E16. 根據E1至E14中任一項之組合，其根據E15使用，其中該用途係用於治療癌症。E16. The combination according to any one of E1 to E14, which is used according to E15, wherein the use is for the treatment of cancer.

E17. 根據E1至E14中任一項之組合，其根據E16使用，其中該癌症係乳癌。E17. A combination according to any one of E1 to E14, which is used according to E16, wherein the cancer is breast cancer.

E18. 根據E1至E14中任一項之組合，其根據E15至E17中任一項使用，其中該Mcl-1抑制劑及該第二抗癌劑係以對於癌症之治療聯合治療有效之量提供。E18. The combination according to any one of E1 to E14, which is used according to any one of E15 to E17, wherein the Mcl-1 inhibitor and the second anticancer agent are provided in an amount effective for the treatment of cancer in combination therapy .

E19. 根據E1至E14中任一項之組合，其根據E15至E17中任一項使用，其中該Mcl-1抑制劑及該第二抗癌劑係以對於癌症之治療協同有效之量提供。E19. The combination according to any one of E1 to E14, which is used according to any one of E15 to E17, wherein the Mcl-1 inhibitor and the second anticancer agent are provided in a synergistically effective amount for the treatment of cancer.

E20. 根據E1至E14中任一項之組合，其根據E15至E17中任一項使用，其中該Mcl-1抑制劑及該第二抗癌劑係以協同有效之量提供，該等協同有效之量使得能夠降低癌症治療中每一化合物所需之劑量，同時提供有效癌症治療，且副作用減少。E20. The combination according to any one of E1 to E14, which is used according to any one of E15 to E17, wherein the Mcl-1 inhibitor and the second anticancer agent are provided in synergistically effective amounts, which are synergistically effective The amount makes it possible to reduce the required dose of each compound in cancer treatment, while providing effective cancer treatment with reduced side effects.

E21. 一種醫藥組合物，其包含根據E1至E14中任一項之組合及至少一種醫藥上可接受之載劑。E21. A pharmaceutical composition comprising a combination according to any one of E1 to E14 and at least one pharmaceutically acceptable carrier.

E22. 一種根據E1至E14中任一項之組合之用途，其用於製造用於治療癌症之藥劑。E22. A use according to the combination of any one of E1 to E14 for the manufacture of a medicament for the treatment of cancer.

E23. 根據E22之用途，其中該癌症係乳癌、更具體而言管腔A乳癌、管腔B乳癌、HER2+ 乳癌及三陰性乳癌。E23. The use according to E22, wherein the cancer is breast cancer, more specifically luminal A breast cancer, luminal B breast cancer, HER2 + breast cancer, and triple-negative breast cancer.

E24. 一種藥劑，其分開或一起含有： (a) 化合物1： (2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽， 及(b) 第二抗癌劑，其中該第二抗癌劑係選自埃雷布林及氟維司群， 用於同時、依序或分開投與，且其中該Mcl-1抑制劑及該第二抗癌劑係以有效治療癌症、具體而言乳癌之量提供。E24. A medicament containing separately or together: (a) Compound 1: (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl-4-[2-( 4-Methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d ]pyrimidin-4-yl]oxy}-3 -(2-{[2-(2-Methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid or a pharmaceutically acceptable salt thereof, and (b) a second anticancer agent , Wherein the second anticancer agent is selected from Erreblin and Fulvestrant for simultaneous, sequential or separate administration, and wherein the Mcl-1 inhibitor and the second anticancer agent are effective Provides the amount of treatment for cancer, specifically breast cancer.

E25. 一種治療癌症、具體而言乳癌之方法，其包含投與聯合治療有效量之： (a) 化合物1： (2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸或其醫藥上可接受之鹽， 及(b) 第二抗癌劑，其中該第二抗癌劑係選自埃雷布林及氟維司群。E25. A method for the treatment of cancer, specifically breast cancer, comprising administering a combined therapeutically effective amount of: (a) Compound 1: (2 R )-2-{[(5 S a )-5-{3-chloro -2-Methyl-4-[2-(4-methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d ]Pyrimidin-4-yl]oxy)-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid or its pharmaceutically acceptable And (b) a second anticancer agent, wherein the second anticancer agent is selected from Erreblin and Fulvestrant.

E26. 一種使患者敏感之方法，該患者(i) 對於至少一種化學療法治療難治，或(ii) 在用化學療法治療後復發，或(i)及(ii)二者，其中該方法包含向該患者投與聯合治療有效量之(a) 如E1、E2或E3中定義之式(I)之Mcl-1抑制劑，及(b) 如本文所述之第二抗癌劑。E26. A method of sensitizing a patient who (i) is refractory to at least one chemotherapy treatment, or (ii) relapses after treatment with chemotherapy, or both (i) and (ii), wherein the method comprises The patient is administered a combined therapeutically effective amount of (a) an Mcl-1 inhibitor of formula (I) as defined in E1, E2 or E3, and (b) a second anticancer agent as described herein.

E27. 一種化合物1，其用於與埃雷布林或氟維司群之組合療法，用於治療癌症、具體而言乳癌。E27. A compound 1 for use in combination therapy with Erreblin or Fulvestrant for the treatment of cancer, specifically breast cancer.

E28. 一種埃雷布林，其用於與化合物1之組合療法，用於治療癌症、具體而言乳癌。E28. An Errebline for use in combination therapy with compound 1 for the treatment of cancer, specifically breast cancer.

E29. 一種氟維司群，其用於與化合物1之組合療法，用於治療癌症、具體而言乳癌。E29. Fulvestrant for use in combination therapy with compound 1 for the treatment of cancer, specifically breast cancer.

在本發明之醫藥組合物中，以重量計活性成分之比例(活性成分之重量對組合物之總重量)係5至50%。In the pharmaceutical composition of the present invention, the ratio of the active ingredient by weight (the weight of the active ingredient to the total weight of the composition) is 5 to 50%.

在本發明之醫藥組合物中，更尤其使用適於藉由經口、非經腸及尤其靜脈內、經皮或透皮、鼻、直腸、經舌、眼或呼吸途徑投與之彼等，更特別地為錠劑、糖衣錠、舌下錠劑、硬明膠膠囊、舌下給藥劑型(glossettes)、膠囊、菱形錠劑、可注射製劑、氣溶膠、眼或鼻滴劑、栓劑、乳霜、軟膏劑、皮膚凝膠等。In the pharmaceutical composition of the present invention, it is more particularly suitable to be administered by oral, parenteral and especially intravenous, transdermal or transdermal, nasal, rectal, lingual, ocular or respiratory routes, More particularly lozenges, sugar-coated tablets, sublingual lozenges, hard gelatin capsules, sublingual dosage forms (glossettes), capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams , Ointment, skin gel, etc.

在一個實施例中，式(I)化合物、具體而言化合物1係例如使用如WO 2018/078064中所述之調配物靜脈內投與。In one embodiment, the compound of formula (I), specifically compound 1 is administered intravenously, for example, using a formulation as described in WO 2018/078064.

本發明之醫藥組合物包含一或多種選自以下之賦形劑或載劑：稀釋劑、潤滑劑、黏合劑、崩解劑、穩定劑、防腐劑、吸收劑、著色劑、甜味劑、調味劑等。The pharmaceutical composition of the present invention contains one or more excipients or carriers selected from the group consisting of diluents, lubricants, binders, disintegrating agents, stabilizers, preservatives, absorbents, coloring agents, sweeteners, Flavoring agents, etc.

藉助非限制性實例 ， 可提及 ： w 作為稀釋劑 ： 乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素、甘油，w 作為潤滑劑 ： 二氧化矽、滑石、硬脂酸及其鎂及鈣鹽、聚乙二醇，w 作為黏合劑 ： 矽酸鎂鋁、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及聚乙烯基吡咯啶酮，w 作為崩解劑 ： 瓊脂、海藻酸及其鈉鹽、泡騰合劑。 By way of non-limiting examples , mention may be made of : w as diluents : lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin, w as lubricants : silica, talc, stearic acid and Magnesium and calcium salts, polyethylene glycol, w as a binder : magnesium aluminum silicate, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone, w as disintegration Antidote : agar, alginic acid and its sodium salt, effervescent mixture.

組合之化合物可同時或依序投與。投與途徑較佳係靜脈內輸注或注射，且相應醫藥組合物可允許活性成分之瞬時或延遲釋放。此外，組合之化合物可以兩種單獨之醫藥組合物之形式投與，每一醫藥組合物含有一種活性成分，或以單一醫藥組合物之形式投與，其中活性成分係混合的。The combined compounds can be administered simultaneously or sequentially. The route of administration is preferably intravenous infusion or injection, and the corresponding pharmaceutical composition can allow instantaneous or delayed release of the active ingredient. In addition, the combined compound can be administered in the form of two separate pharmaceutical compositions, each containing an active ingredient, or in the form of a single pharmaceutical composition in which the active ingredients are mixed.

有用之劑量方案根據患者之性別、年齡及體重、投與途徑、癌症之性質及任何相關治療之性質而變化，且範圍為每週25 mg至1500 mg Mcl-1抑制劑，更佳每週50 mg至1400 mg。Useful dosage regimens vary according to the patient’s gender, age and weight, route of administration, nature of cancer and the nature of any related treatments, and range from 25 mg to 1500 mg of Mcl-1 inhibitor per week, preferably 50 per week mg to 1400 mg.

如本文所述，第二抗癌劑之劑量將與其單獨投與時所使用之劑量相同。根據目前之埃雷布林產品特徵概述(Summary of Product Characteristics，SmPC)，埃雷布林之推薦劑量為1.4 mg/m²，其應在21天週期內之第1天及第8天在2至5分鐘內靜脈內投與。根據目前之氟維司群SmPC，氟維司群之推薦劑量係每月一次500 mg，僅在初始劑量後兩週再給予500 mg劑量。As described herein, the dose of the second anticancer agent will be the same as that used when administered alone. According to the current Summary of Product Characteristics (SmPC), the recommended dose of Erreblin is 1.4 mg/m², which should be between 2 and 8 on the 1st and 8th day of the 21-day cycle. Administer intravenously within 5 minutes. According to the current fulvestrant SmPC, the recommended dose of fulvestrant is 500 mg once a month, and 500 mg is given only two weeks after the initial dose.

藥理學數據 實例 1 ： 乳癌 (BC) 細胞系中組合 MCL-1 抑制劑與埃雷布林對增殖之活體外效應 如表1中所指示，細胞系來源於補充FBS之基礎培養基且在其中維持。另外，所有培養基皆含有青黴素(penicillin) (100 IU/mL)、鏈黴素(streptomycin) (100 μg/mL)及L-麩醯胺酸(2 mM)。 Pharmacological data example 1 : The in vitro effects of the combination of MCL-1 inhibitor and Erreblin on proliferation in breast cancer (BC) cell lines are as indicated in Table 1. The cell lines are derived from and maintained in a basic medium supplemented with FBS . In addition, all media contain penicillin (100 IU/mL), streptomycin (100 μg/mL) and L-glutamic acid (2 mM).

將細胞系於37℃下在含有5% CO2 之加濕氣氛中培養，且在T-150燒瓶中擴增。在所有情形下，將細胞自冷凍儲液中解凍，使用適當稀釋液擴增≥1次傳代，計數且使用CASY細胞計數器評價存活率，然後以表1中所指示之密度將150μL/孔平鋪至96孔板中。所有細胞系經確定內部無黴漿菌屬(mycoplasma)污染。製備化合物之原液，其在DMSO中之濃度為5 mM，且儲存於-20℃下。The cell line was cultured at 37°C in a humidified atmosphere containing 5% CO 2 and expanded in a T-150 flask. In all cases, the cells were thawed from the frozen stock solution, amplified with an appropriate diluent for ≥1 passage, counted and evaluated with a CASY cell counter to evaluate the survival rate, and then 150μL/well was flattened at the density indicated in Table 1. Spread into a 96-well plate. All cell lines were confirmed to be free of mycoplasma contamination. The stock solution of the compound was prepared at a concentration of 5 mM in DMSO and stored at -20°C.

為了分析化合物作為單一試劑之活性，接種細胞並用九個2倍系列稀釋之每一化合物處理，將每一化合物個別地直接分配至細胞分析板中。於37℃/5% CO2 下培育144小時後，藉由使用CellTiterGlo以75 μL試劑/孔量化細胞ATP含量來評價化合物對細胞存活率之效應。所有實驗一式三份實施。利用多用途讀板儀量化發光。使用標準四參數曲線擬合計算單一試劑IC50 。IC50 定義為化合物濃度，在該濃度下，CTG信號降低至對媒劑(DMSO)對照量測之信號之50% (表2)。To analyze the activity of a compound as a single reagent, cells were seeded and treated with nine 2-fold serial dilutions of each compound, and each compound was directly distributed to the cell analysis plate individually. After incubating at 37°C/5% CO 2 for 144 hours, the effect of the compound on cell survival was evaluated by using CellTiterGlo to quantify the cell ATP content with 75 μL reagent/well. All experiments were carried out in triplicate. Use a multi-purpose plate reader to quantify luminescence. Using a standard four parameter curve fitting calculation single agent IC 50. The IC 50 is defined as the concentration of the compound at which the CTG signal decreases to 50% of the signal measured against the vehicle (DMSO) control (Table 2).

為了分析化合物與埃雷布林之組合之活性(表2)，接種細胞並用七種或八種2倍系列稀釋之每一化合物處理，每一化合物個別地或以棋盤方式以所有可能排列直接分配至細胞分析板中。於37℃/5% CO2 下培育144小時後，藉由使用CellTiterGlo以75 μL試劑/孔量化細胞ATP含量來評價單一試劑以及其棋盤組合對細胞存活率的效應。實施兩個獨立之實驗，每一實驗一式兩份實施。利用多用途讀板儀量化發光。In order to analyze the activity of the combination of compound and Erreblin (Table 2), cells were seeded and treated with seven or eight 2-fold serial dilutions of each compound. Each compound was directly distributed individually or in a checkerboard manner in all possible arrangements. To the cell analysis plate. After incubating at 37°C/5% CO 2 for 144 hours, the cell ATP content was quantified by using CellTiterGlo with 75 μL reagent/well to evaluate the effect of a single reagent and its checkerboard combination on cell survival. Perform two independent experiments, each in duplicate. Use a multi-purpose plate reader to quantify luminescence.

根據Loewe相加性模型使用過量抑制2D矩陣評價化合物組合之間之潛在協同相互作用，且報告為協同評分(Lehar等人，Nature Biotechnology 2009, 27(7), 659-66)。所有計算皆係使用Horizon網站中可獲得之ChaliceTM 生物資訊學軟體實施。The potential synergistic interaction between compound combinations was evaluated using an excessive inhibition 2D matrix according to the Loewe additive model, and reported as a synergy score (Lehar et al., Nature Biotechnology 2009, 27(7), 659-66). All calculations are performed using the Chalice TM bioinformatics software available on the Horizon website.

表1中所指示之倍增時間係自細胞解凍至其接種於96孔板中實施之不同傳代(在T-150燒瓶中)中獲得之倍增時間的平均值。表 1 .用於組合實驗之8個BC細胞系之一致性及分析條件. 亞型 細胞系 倍增時間 ( 小時 ) 完全培養基 TNBC BT-20 55-65 RPMI 1640 GlutaMAX + 20% FBS + 1% HEPES + 1%青黴素-鏈黴素 TNBC SUM149PT 30-40 Ham’s F-12 + 5% FBS  + 1% HEPES + 1%青黴素-鏈黴素 + 1 µg/ml氫化可體松(hydrocortisone) + 5 µg/ml人類胰島素 TNBC MDA-MB-468 25-35 L-15 Glutamax + 20% FBS + 1% HEPES + 1%青黴素-鏈黴素 + 1.5 g/l碳酸氫鈉 ER+ HER2- T47D 50-60 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1%青黴素-鏈黴素 ER+ HER2- CAMA-1 60-70 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1%青黴素-鏈黴素 ER+ HER2- MDA-MB-134-VI 120-150 L-15 Glutamax + 10% FBS + 1% HEPES + 1%青黴素-鏈黴素 + 1.5 g/l碳酸氫鈉 ER+ HER2- ZR-75-1 50-70 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1%青黴素-鏈黴素 ER+ HER2- MCF-7 30-40 RPMI 1640 GlutaMAX + 10% FBS 表 2 .在所指示BC細胞系中Mcl-1抑制劑與埃雷布林之組合的協同評分。當觀察到評分≥3.0時，認為相互作用係協同的。 化合物 1 x 埃雷布林 (144h) GI 之 Loewe 過量 * 生長抑制 (%)* GI 之協同評分 ** 化合物 1 sens. (IC50 nM) 埃雷布林 sens. (Cmax, % res. Pop.) TNBC BT-20 53 150 5.9 710 15 SUM149PT 59 169 9.6 68 無 MDA-MB-468 94 191 8.6 197 無 ER+ HER2- CAMA-1 60 193 18 71 無 MDA-MB-134-VI 48 184 11 53 15 MCF-7 12 93 1 337 10 T47D 8 95 0.9 9700 15 ZR-75-1 8 96 0.81 12400 15 The doubling time indicated in Table 1 is the average of the doubling time obtained from the thawing of the cells to the different passages (in T-150 flasks) performed in the 96-well plate. Table 1. The consistency and analysis conditions of the 8 BC cell lines used in the combination experiment. Subtype Cell line Double time ( hours ) Complete medium TNBC BT-20 55-65 RPMI 1640 GlutaMAX + 20% FBS + 1% HEPES + 1% penicillin-streptomycin TNBC SUM149PT 30-40 Ham's F-12 + 5% FBS + 1% HEPES + 1% penicillin-streptomycin + 1 µg/ml hydrocortisone + 5 µg/ml human insulin TNBC MDA-MB-468 25-35 L-15 Glutamax + 20% FBS + 1% HEPES + 1% penicillin-streptomycin + 1.5 g/l sodium bicarbonate ER + HER2 - T47D 50-60 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1% penicillin-streptomycin ER + HER2 - CAMA-1 60-70 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1% penicillin-streptomycin ER + HER2 - MDA-MB-134-VI 120-150 L-15 Glutamax + 10% FBS + 1% HEPES + 1% penicillin-streptomycin + 1.5 g/l sodium bicarbonate ER + HER2 - ZR-75-1 50-70 RPMI 1640 GlutaMAX + 10% FBS + 1% HEPES + 1% penicillin-streptomycin ER + HER2 - MCF-7 30-40 RPMI 1640 GlutaMAX + 10% FBS Table 2. Synergy score of the combination of Mcl-1 inhibitor and Erreblin in the indicated BC cell line. When a score ≥ 3.0 is observed, the interaction system is considered to be synergistic. Compound 1 x Erreblin (144h) GI excess of Loewe * Growth inhibition (%)* GI Synergy Score ** Compound 1 sens. (IC 50 nM) Ereblin sens. (Cmax,% res. Pop.) TNBC BT-20 53 150 5.9 710 15 SUM149PT 59 169 9.6 68 no MDA-MB-468 94 191 8.6 197 no ER + HER2 - CAMA-1 60 193 18 71 no MDA-MB-134-VI 48 184 11 53 15 MCF-7 12 93 1 337 10 T47D 8 95 0.9 9700 15 ZR-75-1 8 96 0.81 12400 15

結果 在8個BC細胞系之組中評價本發明之Mcl-1抑制劑與埃雷布林之組合對細胞生長的效應。作為單一藥劑之Mcl-1抑制劑抑制8個測試之BC細胞系中之大多數的生長(IC50 值為50 nM-12.4 μM-表2)。與標準護理藥物埃雷布林組合，對於大多數測試之細胞系觀察到協同生長抑制或GI (即協同評分高於3 (Lehar等人，2009))。在8個細胞系中，在Mcl-1抑制劑及埃雷布林之組合治療之後，在5個BC細胞系中量測到實質性細胞死亡(即GI ＞ 150%)。該等資料指示，用於治療乳癌之Mcl-1抑制劑與標準護理藥物之組合可為BC患者之治療提供益處。 Results The effect of the combination of the Mcl-1 inhibitor of the present invention and Erreblin on cell growth was evaluated in a group of 8 BC cell lines. The Mcl-1 inhibitor as a single agent inhibited the growth of most of the 8 BC cell lines tested (IC 50 value 50 nM-12.4 μM-Table 2). In combination with the standard care drug Errebine, synergistic growth inhibition or GI was observed for most of the cell lines tested (ie a synergy score higher than 3 (Lehar et al., 2009)). In 8 cell lines, after the combined treatment of Mcl-1 inhibitor and Erreblin, substantial cell death (ie, GI> 150%) was measured in 5 BC cell lines. These data indicate that the combination of Mcl-1 inhibitors and standard care drugs for the treatment of breast cancer can provide benefits for the treatment of BC patients.

實例 2 ： 臨床試驗 在患有局部晚期或轉移性BC之患者中實施I/II期、開放標籤、非隨機化研究以評估(2R)-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸(化合物1)與激素及細胞毒性劑之組合之安全性、耐受性、藥物動力學及臨床活性(EudraCT編號：2019-000998-23；https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-000998-23/ES)。 Example 2 : Clinical trial A phase I/II, open-label, non-randomized study is implemented in patients with locally advanced or metastatic BC to evaluate (2R)-2-{[(5S a )-5-{3- Chloro-2-methyl-4-[2-(4-methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid (compound 1) and The safety, tolerability, pharmacokinetics and clinical activity of the combination of hormones and cytotoxic agents (EudraCT number: 2019-000998-23; https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-000998 -23/ES).

I期多臂研究之目的係： -   作為主要目標，根據國家癌症研究院常見不良事件評價準則(National Cancer Institute Common Terminology Criteria for Adverse Events，NCI-CTCAE) v5.0確定組合之安全性概況(包括劑量限制毒性DLT、最大耐受劑量MTD)、耐受性及擴增之推薦劑量(RDE)； -   作為次要目標，測定血漿藥物動力學(PK)特性並研究組合之任何初步抗腫瘤活性。The purpose of the Phase I multi-arm study is: -As the main goal, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 to determine the safety profile of the combination (including dose-limiting toxicity DLT, maximum tolerated dose MTD), tolerability and recommended dose (RDE) for expansion; -As a secondary goal, determine plasma pharmacokinetic (PK) properties and study any preliminary anti-tumor activity of the combination.

II期多臂研究之目的係： -   作為主要目標，評估組合之客觀反應率(ORR)； -   作為次要目標，根據實體腫瘤中之反應評估準則(Response Evaluation Criteria In Solid Tumours) 1.1版(RECIST v1.1, 2009)在組合之反應持續時間(RD)、總體存活(OS)、無進展存活(PFS)、最佳總體反應(BOR)、安全性、耐受性及血漿PK特性方面評價抗腫瘤活性。The purpose of the Phase II multi-arm study is: -As the main goal, evaluate the objective response rate (ORR) of the portfolio; -As a secondary goal, according to the Response Evaluation Criteria In Solid Tumours Version 1.1 (RECIST v1.1, 2009), the combination of response duration (RD), overall survival (OS), and no progress The anti-tumor activity was evaluated in terms of survival (PFS), best overall response (BOR), safety, tolerability and plasma PK characteristics.

此研究將在兩個連續部分中執行：1. 多臂劑量遞增 I 期部分 ：設計為具有三個獨立之臂(每個臂30名患者)，其將平行登記患者(實施三個獨立之劑量遞增)。治療之臂將由研究者考慮BC之類型、階段及先前之治療線來決定。 •臂 1 ：在局部晚期或轉移性TNBC或HR+ /HER2− BC中化合物1與太平洋紫杉醇(paclitaxel)之組合。患者將經由靜脈內(IV)輸注接受化合物1，根據患者之體重及觀察到之毒性，輸注30分鐘及高達3小時。在I期部分中，劑量遞增將以100 mg開始，且可研究高達1000 mg之劑量。化合物1將在28天週期期間在D2、D9、D16及D23投與。平行地，相同患者在28天週期(3週服藥及1週停藥)期間在D1、D8及D15經由IV輸注以一小時輸注之形式接受80 mg/m²之太平洋紫杉醇。可調整太平洋紫杉醇之劑量。 •臂 2 ：在局部晚期或轉移性TNBC或HR+ /HER2− BC中化合物1與埃雷布林之組合。患者將經由IV輸注接受化合物1，根據患者之體重及觀察到之毒性，輸注30分鐘及高達3小時。在I期部分中，劑量遞增將以100 mg開始，且可研究高達1000 mg之劑量。化合物1將在21天週期之D2、D9及D16投與。平行地，根據埃雷布林之SmPC，相同患者將在21天週期之D1及D8經由IV輸注在2-5分鐘內接受1.4 mg/m2 之埃雷布林。可調整埃雷布林之劑量。 •臂 3 ：在絕經後婦女中，在局部晚期或轉移性HR+ /HER2− BC中化合物1與氟維司群之組合。患者將經由IV輸注接受化合物1，根據患者之體重及觀察到之毒性，輸注30分鐘及高達3小時。在I期部分中，劑量遞增將以100 mg開始，且可研究高達1000 mg之劑量。在28天週期期間，化合物1將在週期1中之D2、D8、D15及D22投與，且在隨後之週期中之D1、D8、D15及D22投與。平行地，根據氟維司群之SmPC，在28天週期期間，相同患者將在第1週期之D1及D15以及在隨後之週期之D1經由肌內(IM)注射接受500 mg氟維司群。This study will be carried out in two consecutive parts: 1. Multi-arm dose escalation phase I part: Designed to have three independent arms (30 patients in each arm), which will register patients in parallel (implement three independent doses) Increment). The treatment arm will be determined by the researcher considering the type, stage and previous treatment line of BC. • Arm 1 : The combination of compound 1 and paclitaxel in locally advanced or metastatic TNBC or HR + /HER2 − BC. The patient will receive Compound 1 via an intravenous (IV) infusion. Depending on the patient's weight and observed toxicity, the infusion will be 30 minutes and up to 3 hours. In the Phase I portion, dose escalation will start at 100 mg, and doses up to 1000 mg can be studied. Compound 1 will be administered on D2, D9, D16, and D23 during the 28-day cycle. In parallel, the same patient received 80 mg/m² of paclitaxel via IV infusion on D1, D8, and D15 during a 28-day cycle (3 weeks of medication and 1 week of drug withdrawal). The dose of paclitaxel can be adjusted. • Arm 2 : Combination of compound 1 and Erreblin in locally advanced or metastatic TNBC or HR + /HER2 − BC. The patient will receive Compound 1 via IV infusion. Depending on the patient's weight and observed toxicity, the infusion will be 30 minutes and up to 3 hours. In the Phase I portion, dose escalation will start at 100 mg, and doses up to 1000 mg can be studied. Compound 1 will be administered on D2, D9, and D16 in a 21-day cycle. In parallel, according to Erreblin's SmPC, the same patient will receive 1.4 mg/m 2 of Errebulin within 2-5 minutes via IV infusion on D1 and D8 of a 21-day cycle. The dosage of Ereblin can be adjusted. • Arm 3 : The combination of compound 1 and fulvestrant in locally advanced or metastatic HR + /HER2 − BC in postmenopausal women. The patient will receive Compound 1 via IV infusion. Depending on the patient's weight and observed toxicity, the infusion will be 30 minutes and up to 3 hours. In the Phase I portion, dose escalation will start at 100 mg, and doses up to 1000 mg can be studied. During the 28-day cycle, compound 1 will be administered on D2, D8, D15, and D22 in cycle 1, and D1, D8, D15, and D22 in subsequent cycles. In parallel, according to the SmPC of fulvestrant, during the 28-day cycle, the same patient will receive 500 mg of fulvestrant via intramuscular (IM) injection on D1 and D15 of the first cycle and D1 of the subsequent cycle.

2. 多臂劑量擴增 II 期部分 ：設計成RDE下之四個平行獨立臂(每一臂50個患者)。治療之臂將由研究者藉由考慮BC之類型、階段及先前之治療線來決定。 •   對於化合物1及太平洋紫杉醇之組合，根據疾病將考慮兩個臂： ▪臂 1a ：在局部晚期或轉移性TNBC中化合物1與太平洋紫杉醇之組合 ▪臂 1b ：在局部晚期或轉移性HR+ /HER2− BC中化合物1與太平洋紫杉醇之組合 將按照在遞增I期部分期間鑑別之投與時間表以RDE之化合物1 + 太平洋紫杉醇治療患者。 •臂 2 ：在局部晚期或轉移性TNBC或HR+ /HER2− BC中化合物1與埃雷布林之組合。將按照在遞增I期部分期間鑑別之投與時間表以RDE之化合物1 + 埃雷布林治療患者。 •臂 3 ：在絕經後婦女中，在局部晚期或轉移性HR+ /HER2− BC中化合物1與氟維司群之組合。在擴增II期部分中，將按照在遞增I期部分期間鑑別之投與時間表以RDE之化合物1 + 氟維司群治療患者。 2. Multi-arm dose amplification phase II part: Designed as four parallel independent arms under RDE (50 patients in each arm). The treatment arm will be determined by the researcher by considering the type, stage and previous treatment line of BC. • For the combination of compound 1 and paclitaxel, two arms will be considered depending on the disease: ▪ Arm 1a : combination of compound 1 and paclitaxel in locally advanced or metastatic TNBC ▪ Arm 1b : in locally advanced or metastatic HR + / The combination of compound 1 and paclitaxel in HER2 − BC will treat patients with compound 1 of the RDE + paclitaxel according to the dosing schedule identified during the escalating phase I portion. • Arm 2 : Combination of compound 1 and Erreblin in locally advanced or metastatic TNBC or HR + /HER2 − BC. Patients will be treated with RDE's Compound 1 + Erreblin according to the dosing schedule identified during the escalating phase I portion. • Arm 3 : The combination of compound 1 and fulvestrant in locally advanced or metastatic HR + /HER2 − BC in postmenopausal women. In the expansion phase II portion, patients will be treated with RDE's compound 1 + fulvestrant according to the dosing schedule identified during the escalation phase I portion.

週期之總數由研究者自行決定。將用化合物1與太平洋紫杉醇、埃雷布林或氟維司群之組合治療患者，直至疾病進展或患者或醫師決定為止。The total number of cycles is determined by the researcher. The patient will be treated with the combination of compound 1 and paclitaxel, erebulin, or fulvestrant until the disease progresses or the patient or physician decides.

Claims (14)

一種組合，其包含： (a) 式(I)之Mcl-1抑制劑：
Figure 03_image013
其中： D代表環烷基、雜環烷基、芳基或雜芳基， E代表呋喃基、噻吩基或吡咯基環， X1 、X3 、X4 及X5 彼此獨立地代表碳原子或氮原子， X2 代表C-R26 基團或氮原子，
Figure 03_image003
意指環係芳香族， Y代表氮原子或C-R3 基團， Z代表氮原子或C-R4 基團， R1 代表鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、羥基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-Cy8 、-(C0 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， R2 、R3 、R4 及R5 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、羥基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R1 , R2 )、(R2 , R3 )、(R3 , R4 )或(R4 , R5 )與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由1至2個選自以下之基團取代：鹵素、直鏈或具支鏈(C1 -C6 )烷基、-(C0 -C6 )烷基-NR11 R11 ’、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， R6 及R7 彼此獨立地代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、直鏈或具支鏈(C1 -C6 )鹵代烷基、羥基、直鏈或具支鏈(C1 -C6 )烷氧基、-S-(C1 -C6 )烷基、氰基、硝基、-(C0 -C6 )烷基-NR11 R11 ’、-O-(C1 -C6 )烷基-NR11 R11 ’、-O-Cy1 、-(C0 -C6 )烷基-Cy1 、-(C2 -C6 )烯基-Cy1 、-(C2 -C6 )炔基-Cy1 、-O-(C1 -C6 )烷基-R12 、-C(O)-OR11 、-O-C(O)-R11 、-C(O)-NR11 R11 ’、-NR11 -C(O)-R11 ’、-NR11 -C(O)-OR11 ’、-(C1 -C6 )烷基-NR11 -C(O)-R11 ’、-SO2 -NR11 R11 ’或-SO2 -(C1 -C6 )烷基， 或配對(R6 , R7 )在與兩個毗鄰碳原子稠合時與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由選自以下之基團取代：直鏈或具支鏈(C1 -C6 )烷基、-NR13 R13 ’、-(C0 -C6 )烷基-Cy1 或側氧基， W代表-CH2 -基團、-NH-基團或氧原子， R8 代表氫原子、直鏈或具支鏈(C1 -C8 )烷基、-CHRa Rb 基團、芳基、雜芳基、芳基(C1 -C6 )烷基或雜芳基(C1 -C6 )烷基， R9 代表氫原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、-Cy2 、-(C1 -C6 )烷基-Cy2 、-(C2 -C6 )烯基-Cy2 、-(C2 -C6 )炔基-Cy2 、-Cy2 -Cy3 、-(C2 -C6 )炔基-O-Cy2 、-Cy2 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy3 、鹵素原子、氰基、-C(O)-R14 或-C(O)-NR14 R14 ’， R10 代表氫原子、直鏈或具支鏈(C1 -C6 )烷基、直鏈或具支鏈(C2 -C6 )烯基、直鏈或具支鏈(C2 -C6 )炔基、芳基(C1 -C6 )烷基、環烷基(C1 -C6 )烷基、直鏈或具支鏈(C1 -C6 )鹵代烷基或-(C1 -C6 )烷基-O-Cy4 ， 或配對(R9 , R10 )在與兩個毗鄰碳原子稠合時與其附接之碳原子一起形成由5至7個環成員構成之芳香族或非芳香族環，該等環成員可含有1至3個選自氧、硫及氮之雜原子， R11 及R11 ’彼此獨立地代表氫原子、視情況經取代之直鏈或具支鏈(C1 -C6 )烷基或-(C0 -C6 )烷基-Cy1 ， 或配對(R11 , R11 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所述氮可由1至2個代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代，且應理解，可能取代基之一或多個碳原子可經氘化， R12 代表-Cy5 、-Cy5 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-Cy6 、-Cy5 -(C0 -C6 )烷基-NR11 -(C0 -C6 )烷基-Cy6 、-Cy5 -Cy6 -O-(C0 -C6 )烷基-Cy7 、-Cy5 -(C0 -C6 )烷基-O-(C0 -C6 )烷基-Cy9 、-Cy5 -(C0 -C6 )烷基-Cy9 、-NH-C(O)-NH-R11 、-Cy5 -(C0 -C6 )烷基-NR11 -(C0 -C6 )烷基-Cy9 、-C(O)-NR11 R11 ’、-NR11 R11 ’、-OR11 、-NR11 -C(O)-R11 ’、-O-烷基(C1 -C6 )-OR11 、-SO2 -R11 、-C(O)-OR11 ， R13 、R13 ’、R14 及R14 ’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基， Ra 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， Rb 代表-O-C(O)-O-Rc 基團、-O-C(O)-NRc Rc ’基團或-O-P(O)(ORc )2 基團， Rc 及Rc ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C8 )烷基、環烷基、(C1 -C6 )烷氧基(C1 -C6 )烷基或(C1 -C6 )烷氧基羰基(C1 -C6 )烷基， 或配對(Rc , Rc ’)與其附接之氮原子一起形成由5至7個環成員構成之非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧及氮之雜原子，應理解，所述氮可由代表直鏈或具支鏈(C1 -C6 )烷基之基團取代， Cy1 、Cy2 、Cy3 、Cy4 、Cy5 、Cy6 、Cy7 、Cy8 及Cy10 彼此獨立地代表環烷基、雜環烷基、芳基或雜芳基， Cy9 代表
Figure 03_image016
，或Cy9 代表由選自以下之基團取代之雜芳基：-O-P(O)(OR20 )2 ；-O-P(O)(O- M+ )2 ；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 ；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；或-U-(CH2 )q -NR21 R21 ’， R15 代表氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；直鏈或具支鏈(C1 -C6 )烷氧基(C1 -C6 )烷基；-U-(CH2 )q -NR21 R21 ’基團；或-(CH2 )r -U-(CH2 )s -雜環烷基， R16 代表氫原子；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；(CH2 )r -U-V-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；-O-S(O)2 OR20 基團；-S(O)2 OR20 基團；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-(CH2 )p -O-C(O)-NR22 R23 基團；或-U-(CH2 )q -NR21 R21 ’基團， R17 代表氫原子；-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團；-CH2 -O-P(O)(OR20 )2 基團；-O-P(O)(OR20 )2 基團；-O-P(O)(O- M+ )2 基團；羥基；羥基(C1 -C6 )烷基；-(CH2 )r -U-(CH2 )s -雜環烷基；-U-(CH2 )q -NR21 R21 ’基團；或醛醣酸， M+ 代表醫藥上可接受之單價陽離子， U代表鍵或氧原子， V代表-(CH2 )s -基團或-C(O)-基團， R18 代表氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， R19 代表氫原子或羥基(C1 -C6 )烷基， R20 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， R21 及R21 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或羥基(C1 -C6 )烷基， 或配對(R21 , R21 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代， R22 代表(C1 -C6 )烷氧基(C1 -C6 )烷基、-(CH2 )p -NR24 R24 ’基團或-(CH2 )p -O-(CHR18 -CHR19 -O)q -R20 基團， R23 代表氫原子或(C1 -C6 )烷氧基(C1 -C6 )烷基， 或配對(R22 , R23 )與其附接之氮原子一起形成由5至18個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至5個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或雜環烷基之基團取代， R24 及R24 ’彼此獨立地代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， 或配對(R24 , R24 ’)與其附接之氮原子一起形成由5至7個環成員構成之芳香族或非芳香族環，除了氮原子外，該等環成員亦可含有1至3個選自氧、硫及氮之雜原子，應理解，所得環可由代表氫原子或直鏈或具支鏈(C1 -C6 )烷基之基團取代， R25 代表氫原子、羥基或羥基(C1 -C6 )烷基， R26 代表氫原子、鹵素原子、直鏈或具支鏈(C1 -C6 )烷基或氰基， R27 代表氫原子或直鏈或具支鏈(C1 -C6 )烷基， R28 代表-O-P(O)(O- )(O- )基團、-O-P(O)(O- )(OR30 )基團、-O-P(O)(OR30 )(OR30 ’)基團、-(CH2 )p -O-S(O)2 O- 基團；-(CH2 )p -S(O)2 O- 基團；-(CH2 )p -O-S(O)2 OR30 基團；-Cy10 、-O-C(O)-R29 基團、-O-C(O)-OR29 基團或-O-C(O)-NR29 R29 ’基團； R29 及R29 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或直鏈或具支鏈胺基(C1 -C6 )烷基， R30 及R30 ’彼此獨立地代表氫原子、直鏈或具支鏈(C1 -C6 )烷基或芳基(C1 -C6 )烷基， R31 代表以下基團：
Figure 03_image018
其中銨離子視情況以兩性離子形式存在或具有單價陰離子相對離子， n係等於0或1之整數， p係等於0、1、2或3之整數， q係等於1、2、3或4之整數， r及s獨立地係等於0或1之整數， 應理解：　 「芳基」意指苯基、萘基、聯苯基、二氫茚基或茚基， 「雜芳基」意指由5至10個環成員構成、具有至少一個芳香族部分且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環基團， 「環烷基」意指含有3至10個環成員之任何單環或二環非芳香族碳環基團， 「雜環烷基」意指含有3至10個環成員且含有1至3個選自氧、硫及氮之雜原子之任何單環或二環非芳香族碳環基團，其可包括稠合、橋接或螺環系統， 如此定義之該等芳基、雜芳基、環烷基及雜環烷基及該等烷基、烯基、炔基、烷氧基可由1至4個選自以下之基團取代：視情況經取代之直鏈或具支鏈(C1 -C6 )烷基、視情況經取代之直鏈或具支鏈(C2 -C6 )烯基、視情況經取代之直鏈或具支鏈(C2 -C6 )炔基、視情況經取代之直鏈或具支鏈(C1 -C6 )烷氧基、視情況經取代之(C1 -C6 )烷基-S-、羥基、側氧基(或N -氧化物，在適當之情形下)、硝基、氰基、-C(O)-OR’、-O-C(O)-R’、-C(O)-NR’R’’、-NR’R’’、-(C=NR’)-OR’’、直鏈或具支鏈(C1 -C6 )鹵代烷基、三氟甲氧基或鹵素，應理解，R’及R’’彼此獨立地代表氫原子或視情況經取代之直鏈或具支鏈(C1 -C6 )烷基，且應理解，該等前述可能取代基之一或多個碳原子可經氘化， 或其鏡像異構物、非鏡像異構物、阻轉異構物或與醫藥上可接受之酸或鹼之加成鹽， 及(b) 第二抗癌劑，其中該第二抗癌劑係選自埃雷布林(eribulin)及氟維司群(fulvestrant)， 其用於同時、依序或分開使用。A combination comprising: (a) Mcl-1 inhibitor of formula (I):
Figure 03_image013
Wherein: D represents cycloalkyl, heterocycloalkyl, aryl or heteroaryl, E represents furyl, thienyl or pyrrolyl ring, X 1 , X 3 , X 4 and X 5 independently represent carbon atoms or Nitrogen atom, X 2 represents CR 26 group or nitrogen atom,
Figure 03_image003
Refers to the aromatic ring system, Y represents a nitrogen atom or a CR 3 group, Z represents a nitrogen atom or a CR 4 group, R 1 represents a halogen atom, linear or branched (C 1 -C 6 ) alkyl, linear Or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkyl, hydroxyl, hydroxyl ( C 1 -C 6 )alkyl, linear or branched (C 1 -C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, cyano, nitro, -Cy 8 ,- (C 0 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC(O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C( O)-OR 11 ', -(C 1 -C 6 )alkyl-NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 ) Alkyl group, R 2 , R 3 , R 4 and R 5 independently represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group, a linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkyl, hydroxy, hydroxy (C 1 -C 6 ) alkane Group, linear or branched (C 1 -C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, cyano, nitro, -(C 0 -C 6 )alkyl-NR 11 R 11 ', -O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 , -(C 2 -C 6 )alkenyl -Cy 1 , -(C 2 -C 6 )alkynyl- Cy 1 , -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-R 12 , -C(O)-OR 11 , -OC( O)-R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C(O)-OR 11 ', -(C 1 -C 6 ) Alkyl -NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 )alkyl, or pairing (R 1 , R 2 ) , (R 2 , R 3 ), (R 3 , R 4 ) or (R 4 , R 5 ) and the carbon atom to which it is attached Together to form an aromatic or non-aromatic ring composed of 5 to 7 ring members, these ring members may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may have 1 to 2 Substitution selected from the following groups: halogen, linear or branched (C 1 -C 6 )alkyl, -(C 0 -C 6 )alkyl -NR 11 R 11 ', -NR 13 R 13 ', -(C 0 -C 6 )alkyl-Cy 1 or pendant oxy group, R 6 and R 7 independently represent a hydrogen atom, a halogen atom, a linear or branched (C 1 -C 6 ) alkyl group, a straight Chain or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 ) alkynyl, linear or branched (C 1 -C 6 ) haloalkyl, hydroxyl, straight Chain or branched (C 1 -C 6 )alkoxy, -S-(C 1 -C 6 )alkyl, cyano, nitro, -(C 0 -C 6 )alkyl -NR 11 R 11 ', -O-(C 1 -C 6 )alkyl-NR 11 R 11 ', -O-Cy 1 , -(C 0 -C 6 )alkyl-Cy 1 , -(C 2 -C 6 )ene -Cy 1 , -(C 2 -C 6 )alkynyl -Cy 1 , -O-(C 1 -C 6 )alkyl -R 12 , -C(O)-OR 11 , -OC(O)- R 11 , -C(O)-NR 11 R 11 ', -NR 11 -C(O)-R 11 ', -NR 11 -C(O)-OR 11 ', -(C 1 -C 6 )alkane Group -NR 11 -C(O)-R 11 ', -SO 2 -NR 11 R 11 'or -SO 2 -(C 1 -C 6 )alkyl, or pairing (R 6 , R 7 ) with two When two adjacent carbon atoms are fused together with the attached carbon atoms to form an aromatic or non-aromatic ring composed of 5 to 7 ring members, these ring members may contain 1 to 3 selected from oxygen, sulfur and nitrogen Heteroatoms, it should be understood that the resulting ring may be substituted by a group selected from the group consisting of linear or branched (C 1 -C 6 )alkyl, -NR 13 R 13 ', -(C 0 -C 6 )alkyl -Cy 1 or pendant oxy group, W represents -CH 2 -group, -NH- group or oxygen atom, R 8 represents hydrogen atom, linear or branched (C 1 -C 8 ) alkyl group, -CHR a R b group, aryl, heteroaryl, aryl (C 1 -C 6 ) alkyl or heteroaryl (C 1 -C 6 ) alkyl, R 9 represents a hydrogen atom, linear or branched (C 1 -C 6 )alkyl, linear or branched (C 2 -C 6 )alkenyl, linear or branched (C 2 -C 6 )alkynyl, -Cy 2 , -(C 1 -C 6 )alkyl-Cy 2 , -(C 2 -C 6 )alkenyl -Cy 2 , -(C 2 -C 6 )alkynyl -Cy 2 , -Cy 2 -Cy 3 , -(C 2 -C 6 )alkynyl -O-Cy 2 , -Cy 2 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 3 , halogen atom, cyano group, -C(O)-R 14 or -C(O)-NR 14 R 14 ', R 10 represents a hydrogen atom, linear or branched (C 1 -C 6 ) alkyl, linear or branched (C 2 -C 6 ) alkenyl, linear or branched (C 2 -C 6 )alkynyl, aryl (C 1 -C 6 ) alkyl, cycloalkyl (C 1 -C 6 ) alkyl, linear or branched (C 1 -C 6 ) haloalkyl or -( C 1 -C 6 )alkyl-O-Cy 4 , or the pairing (R 9 , R 10 ), when fused with two adjacent carbon atoms, together with the carbon atom to which it is attached, forms a ring consisting of 5 to 7 ring members Aromatic or non-aromatic ring, these ring members may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, R 11 and R 11 'independently represent a hydrogen atom, optionally substituted straight chain or Branched (C 1 -C 6 ) alkyl group or -(C 0 -C 6 ) alkyl group -Cy 1 , or pairing (R 11 , R 11 ') and the nitrogen atom to which it is attached together form 5 to 7 For the aromatic or non-aromatic ring composed of ring members, in addition to nitrogen atoms, these ring members may also contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the nitrogen may be 1 to 2 Represents the substitution of a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group, and it should be understood that one or more of the carbon atoms of the possible substituents can be deuterated, R 12 represents -Cy 5 , -Cy 5 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -(C 0 -C 6 )alkyl-Cy 6 , -Cy 5- (C 0 -C 6 )alkyl-NR 11 -(C 0 -C 6 )alkyl-Cy 6 , -Cy 5 -Cy 6 -O-(C 0 -C 6 )alkyl-Cy 7 , -Cy 5 -(C 0 -C 6 )alkyl-O-(C 0 -C 6 )alkyl-Cy 9 , -Cy 5 -(C 0 -C 6 )alkyl-Cy 9 , -NH-C(O )-NH-R 11 , -Cy 5 -(C 0 -C 6 )alkyl-NR 11 -(C 0 -C 6 )alkyl-Cy 9 , -C(O)-NR 11 R 11 ',- NR 11 R 11 ', -OR 11 , -NR 11 -C(O)-R 11 ', -O-alkyl(C 1 -C 6 )-OR 11 ,- SO 2 -R 11 , -C(O)-OR 11 , R 13 , R 13 ', R 14 and R 14 'independently of each other represent a hydrogen atom or optionally substituted straight or branched chain (C 1- C 6 ) alkyl group, R a represents a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group, R b represents a -OC(O)-OR c group, -OC(O)-NR c R c 'or a group -OP (O) (oR c) 2 group, R c and R c' each independently represent a hydrogen atom, a linear or branched (C 1 -C 8) alkyl, cycloalkyl Group, (C 1 -C 6 )alkoxy (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxycarbonyl (C 1 -C 6 )alkyl, or pairing (R c , R c ') together with the nitrogen atom to which it is attached, form a non-aromatic ring composed of 5 to 7 ring members. In addition to nitrogen atoms, these ring members may also contain 1 to 3 heteroatoms selected from oxygen and nitrogen, It should be understood that the nitrogen may be substituted by a group representing a linear or branched (C 1 -C 6 ) alkyl group, Cy 1 , Cy 2 , Cy 3 , Cy 4 , Cy 5 , Cy 6 , Cy 7 , Cy 8 and Cy 10 independently of each other represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and Cy 9 represents
Figure 03_image016
, Or Cy 9 represents a heteroaryl group substituted by a group selected from: -OP(O)(OR 20 ) 2 ; -OP(O)(O - M + ) 2 ; -(CH 2 ) p -O -(CHR 18 -CHR 19 -O) q -R 20 ; hydroxy; hydroxy (C 1 -C 6 )alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; or- U-(CH 2 ) q -NR 21 R 21 ', R 15 represents a hydrogen atom; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; straight chain or branched Chain (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl; -U-(CH 2 ) q -NR 21 R 21 'group; or -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl, R 16 represents a hydrogen atom; hydroxyl; hydroxy (C 1 -C 6 ) alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; (CH 2 ) r -UVOP(O)(OR 20 ) 2 group; -OP(O)(O - M + ) 2 group; -OS(O) 2 OR 20 group; -S(O) 2 OR 20 Group; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; -(CH 2 ) p -OC(O)-NR 22 R 23 group; or -U -(CH 2 ) q -NR 21 R 21 'group, R 17 represents a hydrogen atom; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; -CH 2- OP(O)(OR 20 ) 2 group; -OP(O)(OR 20 ) 2 group; -OP(O)(O - M + ) 2 group; hydroxyl group; hydroxyl group (C 1 -C 6 ) Alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; -U-(CH 2 ) q -NR 21 R 21 'group; or aldonic acid, M + stands for medicine Acceptable monovalent cations, U represents a bond or an oxygen atom, V represents a -(CH 2 ) s -group or -C(O)- group, R 18 represents a hydrogen atom or (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl group, R 19 represents a hydrogen atom or a hydroxy (C 1 -C 6 ) alkyl group, R 20 represents a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group, R 21 and R 21 'independently of each other represent a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group or a hydroxy (C 1 -C 6 ) alkyl group, or a pair (R 21 , R 21 ') together with the nitrogen atom to which it is attached, form an aromatic or non-aromatic ring composed of 5 to 7 ring members. In addition to the nitrogen atom, these ring members may also contain 1 to 3 options. From the heteroatoms of oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (C 1 -C 6 ) alkyl group, and R 22 represents (C 1 -C 6 ) Alkoxy (C 1 -C 6 ) alkyl, -(CH 2 ) p -NR 24 R 24 'group or -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 Group, R 23 represents a hydrogen atom or a (C 1 -C 6 ) alkoxy (C 1 -C 6 ) alkyl group, or the pairing (R 22 , R 23 ) together with the nitrogen atom to which it is attached is formed from 5 to 18 In addition to nitrogen atoms, these ring members may also contain 1 to 5 heteroatoms selected from oxygen, sulfur and nitrogen. It should be understood that the resulting ring may represent hydrogen, Straight chain or branched chain (C 1 -C 6 ) alkyl or heterocycloalkyl group substituted, R 24 and R 24 'independently of each other represent a hydrogen atom or straight chain or branched chain (C 1 -C 6 ) Alkyl group, or the pairing (R 24 , R 24 ') together with the nitrogen atom to which it is attached, forms an aromatic or non-aromatic ring composed of 5 to 7 ring members. In addition to the nitrogen atom, these ring members can also be Containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it should be understood that the resulting ring may be substituted by a group representing a hydrogen atom or a straight or branched chain (C 1 -C 6 ) alkyl group, and R 25 represents hydrogen Atom, hydroxy or hydroxy (C 1 -C 6 ) alkyl group, R 26 represents hydrogen atom, halogen atom, linear or branched (C 1 -C 6 ) alkyl group or cyano group, R 27 represents hydrogen atom or straight chain or branched (C 1 -C 6) alkyl, R 28 Representative -OP (O) (O -) (O -) group, -OP (O) (O - ) (oR 30) group, -OP (O) (OR 30) (OR 30 ') group, - (CH 2) p -OS (O) 2 O - groups ;-( CH 2) p -S (O ) 2 O - groups ; -(CH 2 ) p -OS(O) 2 OR 30 group; -Cy 10 , -OC(O)-R 29 group, -OC(O)-OR 29 group or -OC(O)- NR 29 R 29 'group; R 29 and R 29 ' independently of each other represent a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group, or a linear or branched amine group (C 1 -C 6 ) Alkyl group, R 30 and R 30 ′ independently of each other represent a hydrogen atom, a linear or branched (C 1 -C 6 ) alkyl group or an aryl (C 1 -C 6 ) alkyl group, R 31 represents the following groups:
Figure 03_image018
Wherein ammonium ions may exist as zwitterions or have monovalent anions as appropriate, n is an integer equal to 0 or 1, p is an integer equal to 0, 1, 2 or 3, and q is an integer equal to 1, 2, 3 or 4. Integers, r and s are independently integers equal to 0 or 1. It should be understood that: "aryl" means phenyl, naphthyl, biphenyl, indenyl or indenyl, and "heteroaryl" means Any monocyclic or bicyclic group consisting of 5 to 10 ring members, having at least one aromatic moiety and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, "cycloalkyl" means containing 3 to Any monocyclic or bicyclic non-aromatic carbocyclic group with 10 ring members, "heterocycloalkyl" means 3 to 10 ring members and 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen Any monocyclic or bicyclic non-aromatic carbocyclic group, which may include fused, bridged or spiro ring systems, such aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups as defined in this way, and such Alkyl, alkenyl, alkynyl, and alkoxy may be substituted with 1 to 4 groups selected from the following: optionally substituted linear or branched (C 1 -C 6 ) alkyl, optionally substituted The straight chain or branched chain (C 2 -C 6 ) alkenyl group, optionally substituted straight chain or branched chain (C 2 -C 6 ) alkynyl group, optionally substituted straight chain or branched chain ( C 1 -C 6 )alkoxy, optionally substituted (C 1 -C 6 )alkyl-S-, hydroxyl, pendant oxy (or N -oxide, where appropriate), nitro, Cyano, -C(O)-OR', -OC(O)-R', -C(O)-NR'R'', -NR'R'', -(C=NR')-OR'', straight or branched (C 1 -C 6 ) haloalkyl, trifluoromethoxy or halogen, it should be understood that R'and R” independently represent a hydrogen atom or optionally substituted straight chain or It has a branched (C 1 -C 6 ) alkyl group, and it should be understood that one or more of the carbon atoms of the aforementioned possible substituents may be deuterated, or its enantiomers, diastereomers, atrophic Isomers or addition salts with pharmaceutically acceptable acids or bases, and (b) a second anticancer agent, wherein the second anticancer agent is selected from eribulin and fulvestrant (fulvestrant), which is used for simultaneous, sequential or separate use. 如請求項1之組合，其中該式(I)之Mcl-1抑制劑具有式(IB)：
Figure 03_image020
其中R9 、R11 、R11 ’及R12 係如上文請求項1中所述。Such as the combination of claim 1, wherein the Mcl-1 inhibitor of formula (I) has formula (IB):
Figure 03_image020
Wherein R 9 , R 11 , R 11 ′ and R 12 are as described in claim 1 above. 如請求項1或2之組合，其中該式(I)之Mcl-1抑制劑係化合物1：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(4-氟苯基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[2-(2-甲氧基苯基)嘧啶-4-基]甲氧基}苯基)丙酸，或其醫藥上可接受之鹽。Such as the combination of claim 1 or 2, wherein the Mcl-1 inhibitor of formula (I) is compound 1: (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl 4-[2-(4-methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3- d ]pyrimidine-4 -Yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propionic acid, or a pharmaceutically acceptable salt thereof. 如請求項1或2之組合，其中該式(I)之Mcl-1抑制劑係化合物2：(2R )-2-{[(5Sa )-5-{3-氯-2-甲基-4-[2-(4-甲基六氫吡嗪-1-基)乙氧基]苯基}-6-(5-氟呋喃-2-基)噻吩并[2,3-d ]嘧啶-4-基]氧基}-3-(2-{[1-(2,2,2-三氟乙基)-1H -吡唑-5-基]甲氧基}苯基)丙酸，或其醫藥上可接受之鹽。Such as the combination of claim 1 or 2, wherein the Mcl-1 inhibitor of formula (I) is compound 2: (2 R )-2-{[(5 S a )-5-{3-chloro-2-methyl 4-[2-(4-methylhexahydropyrazin-1-yl)ethoxy]phenyl}-6-(5-fluorofuran-2-yl)thieno[2,3- d ] Pyrimidine-4-yl]oxy)-3-(2-{[1-(2,2,2-trifluoroethyl)-1 H -pyrazol-5-yl]methoxy}phenyl)propane Acid, or a pharmaceutically acceptable salt thereof. 如請求項1之組合，其中該第二抗癌劑係埃雷布林。Such as the combination of claim 1, wherein the second anticancer agent is Erreblin. 如請求項1之組合，其中該第二抗癌劑係氟維司群。Such as the combination of claim 1, wherein the second anticancer agent is fulvestrant. 如請求項1之組合，其係呈非固定劑量組合之形式。Such as the combination of claim 1, which is in the form of a non-fixed dose combination. 如請求項1之組合，其用於治療癌症。Such as the combination of claim 1, which is used for the treatment of cancer. 如請求項1之組合，其根據請求項8使用，其中該癌症係乳癌。Such as the combination of claim 1, which is used according to claim 8, wherein the cancer is breast cancer. 如請求項1之組合，其根據請求項8或請求項9使用，其中該Mcl-1抑制劑及該第二抗癌劑係以對於癌症之治療協同有效之量提供。Such as the combination of claim 1, which is used according to claim 8 or claim 9, wherein the Mcl-1 inhibitor and the second anticancer agent are provided in a synergistically effective amount for the treatment of cancer. 一種醫藥組合物，其包含如請求項1至7中任一項之組合及至少一種醫藥上可接受之載劑。A pharmaceutical composition comprising the combination of any one of claims 1 to 7 and at least one pharmaceutically acceptable carrier. 一種如請求項1至7中任一項之組合之用途，其用於製造用於治療癌症之藥劑。A use of the combination according to any one of claims 1 to 7, which is used to manufacture a medicament for the treatment of cancer. 如請求項12之用途，其中該癌症係乳癌。Such as the use of claim 12, wherein the cancer is breast cancer. 如請求項12之用途，其中該Mcl-1抑制劑及該第二抗癌劑係以對於癌症之治療協同有效之量提供。The use of claim 12, wherein the Mcl-1 inhibitor and the second anticancer agent are provided in a synergistically effective amount for the treatment of cancer.
TW109120291A 2019-06-17 2020-06-16 Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof TW202114682A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201962862161P 2019-06-17 2019-06-17
US62/862,161 2019-06-17

Publications (1)

Publication Number Publication Date
TW202114682A true TW202114682A (en) 2021-04-16

Family

ID=71103384

Family Applications (1)

Application Number Title Priority Date Filing Date
TW109120291A TW202114682A (en) 2019-06-17 2020-06-16 Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof

Country Status (3)

Country Link
AR (1) AR119156A1 (en)
TW (1) TW202114682A (en)
WO (1) WO2020254299A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202315637A (en) 2021-06-11 2023-04-16 美商基利科學股份有限公司 Combination mcl-1 inhibitors with anti-cancer agents
TW202317200A (en) 2021-06-11 2023-05-01 美商基利科學股份有限公司 Combination mcl-1 inhibitors with anti-body drug conjugates

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3015483B1 (en) 2013-12-23 2016-01-01 Servier Lab NOVEL THIENOPYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3037957B1 (en) 2015-06-23 2019-01-25 Les Laboratoires Servier NOVEL HYDROXYESTER DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3037956B1 (en) 2015-06-23 2017-08-04 Servier Lab NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3037958B1 (en) 2015-06-23 2019-01-25 Les Laboratoires Servier NOVEL HYDROXY ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR3037959B1 (en) 2015-06-23 2017-08-04 Servier Lab NOVEL BICYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3046792B1 (en) 2016-01-19 2018-02-02 Les Laboratoires Servier NOVEL AMMONIUM DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
JP7221699B2 (en) * 2016-06-22 2023-02-14 エリプセス ファーマ エルティーディー AR+ methods of treating breast cancer
LT3532067T (en) 2016-10-28 2022-08-25 Les Laboratoires Servier Liposomal formulation for use in the treatment of cancer
UY37560A (en) * 2017-01-06 2018-07-31 Servier Lab COMBINATION OF AN MCL-1 INHIBITOR AND A TAXAN COMPOUND, USES AND PHARMACEUTICAL COMPOSITIONS OF THIS
EP3565547B1 (en) * 2017-01-06 2024-03-13 Les Laboratoires Servier Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof

Also Published As

Publication number Publication date
WO2020254299A1 (en) 2020-12-24
AR119156A1 (en) 2021-11-24

Similar Documents

Publication Publication Date Title
Shrestha et al. Exploring the therapeutic potential of mitochondrial uncouplers in cancer
KR20160023816A (en) Use of eribulin and lenvatinib as combination therapy for treatment of cancer
EP3074028B1 (en) Activity enhancing curcumin compositions and methods of use
TW202114682A (en) Combination of a mcl-1 inhibitor and a standard of care treatment for breast cancer, uses and pharmaceutical compositions thereof
TW201609094A (en) Novel methods for treating cancer
US10080807B2 (en) Combination chemotherapy comprising a liposomal prodrug of mitomycin C
WO2022028615A1 (en) Method for treating tumor
EP2538935B1 (en) Suppression of cancer growth and metastasis using nordihydroguaiaretic acid derivatives with 7-hydroxystaurosporine
RU2763544C2 (en) Combination of mcl-1 inhibitor and taxane compound, their applications and pharmaceutical compositions
KR20070066947A (en) Cancer chemotherapy
CA2825790A1 (en) Combinations
JP7311177B2 (en) Combined use of A-NOR-5α androstane drugs with anticancer drugs
TW202135792A (en) Methods of treating cancer
JP2016008215A (en) Use of eribulin and s-1(or 5-fu) as combination therapy for cancer treatment
CN105753724A (en) Compounds for killing cancer cells
US20240115582A1 (en) Use of sodium trans-[tetrachloridobis(1h-indazole)ruthenate(iii)] for treating cancers
CN111728960B (en) Application of bisoprolol fumarate and docetaxel in preparation of antitumor drugs
US10736873B2 (en) Medical uses of N-(2-aminoethyl)-N-(4-benzyloxy)-3-methoxybenzyl)thiophene-2-formamide hydrochloride
CN111718328A (en) Application of 4-methyl-1H-diaryl pyrazole derivatives in preparation of antitumor drugs
TWI307628B (en) Use of zd0473 in combination with a non-platinum based anti-cancer agent
WO2023159048A2 (en) Small molecule stat3 inhibitor for treating triple negative breast cancer
CN118217279A (en) Use of butylphthalide and derivatives thereof
KR20060036058A (en) Compositions comprising zd6126 together with 5-fu, cpt-11 or 5-fu and cpt-11 having vascular damaging activity for treating e.g. colorectal cancer
EA040162B1 (en) COMBINATION OF MCL-1 INHIBITOR AND TAXANE COMPOUND, THEIR APPLICATIONS AND PHARMACEUTICAL COMPOSITIONS
TW201206449A (en) Methods of treating platinum-resistant recurrent ovarian cancer with 4-iodo-3-nitrobenzamide in combination with an anti-metabolite and a platinum compound