TW201806600A - Combination of BCL-2 inhibitor and MCL1 inhibitor, use thereof and pharmaceutical composition - Google Patents

Abstract

A combination comprising a BCL-2 inhibitor and a MCL1 inhibitor, and compositions and uses thereof.

Description

Combination of BCL-2 inhibitor and MCL1 inhibitor, its use and pharmaceutical composition

The present invention relates to a combination of a BCL-2 inhibitor and an MCL1 inhibitor. The invention also relates to the use of the combination in the treatment of cancer, in particular, leukemia, lymphoma, multiple myeloma, neuroblastoma and lung cancer, and more particularly, acute myeloid leukemia, T-cell acute lymphoblastic leukemia , B-cell acute lymphoblastic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma and small cell lung cancer. Pharmaceutical formulations suitable for administering such combinations are also provided.

Apoptosis is a highly regulated cell death pathway initiated by various cytotoxic stimuli, including carcinogenic stress and chemotherapeutic agents. It has been shown that evading the characteristics of apoptotic cancers and that the efficacy of various chemotherapeutic agents depends on the activation of the intrinsic mitochondrial pathway. Three distinct subpopulations of BCL-2 family proteins control intrinsic apoptotic pathways: (i) only pro-apoptotic BH3 (BCL-2 homology 3) proteins; (ii) pro-survival members such as BCL-2 itself, BCL-XL, Bcl-w, MCL1, and BCL-2a1; and (iii) pro-apoptotic effector proteins BAX and BAK (Czabotar et al., Nature Reviews Molecular cell biology 2014 vol. 15: 49-63). Overexpression of anti-apoptotic members of the BCL-2 family has been observed in a variety of cancers, specifically in hematological malignancies such as mantle cell lymphoma (MCL), follicular lymphoma / diffuse large B-cell lymphoma (FL / D) and multiple myeloma (Adams and Cory Oncogene 2007 Vol. 26: 1324-1337). The recently developed BH3 mimic drugs (such as ABT-199 and ABT-263) have been used as therapeutic strategies to prevent the apoptosis of BCL-2, BCL-XL and Bcl-w. Tumor regression (Zhang et al., Drug Resist Updat 2007 Vol. 10 (6): 207-17). Nevertheless, the mechanisms of tolerance of these drugs have been observed and studied (Choudhary GS et al., Cell Death and Disease 2015 Vol. 6, e1593; doi: 10.1038 / cddis. 2014.525). Acute myeloid leukemia (AML) is a rapidly fatal blood cancer caused by a pure line transformation of hematopoietic stem cells, which results in paralysis of normal bone marrow function and death due to complications of severe cytopenia. AML accounts for 25% of all adult leukemias, with the highest incidence occurring in the United States, Australia, and Europe (WHO. GLOBOCAN 2012, 2012 Worldwide Estimated Cancer Incidence, Mortality, and Prevalence, International Cancer Research Agency). Globally, there are approximately 88,000 new diagnostic cases each year. AML maintains the lowest survival rate of all leukemias, with only 24% expected to have a 5-year survival period. Although standard therapies for AML (cytarabine combined with anthracycline) have been conceived more than 40 years ago, the introduction of successful targeted therapies for this disease remains an elusive goal. In addition, there is still a need for chemotherapy-free treatment options for patients with AML. Since the development of the disease into a multipure line, the concept of targeted therapy for AML has been hindered. The rapid overgrowth of leukemia subpure lines has become the main cause of drug resistance and disease recurrence (Ding L et al., Nature 2012 481: 506- 10). Recent clinical studies have shown the efficacy of BCL-2 inhibitors in the treatment of AML (Konopleva M et al., American Society of Hematology 2014: 118). Although these inhibitors work clinically, it is likely that other BCL-2 family members will need to be targeted to enhance the overall efficacy of AML. In addition to BCL-2, MCL1 has also been identified as an important regulator of cell survival in AML (Glaser SP et al., Genes & development 2012 26: 120-5). Multiple myeloma (MM) is a rare and incurable disease characterized by the accumulation of pure lineage plasma cells in the bone marrow (BM) and accounting for 10% of all hematological malignancies. In Europe, there are approximately 27,800 new cases each year. In recent years, survival rates have improved due to the availability of new agents including bortezomib and lenalidomide, and autologous stem cell transplantation (ASCT). However, the response to these new agents is often not long-lasting, and it becomes an indication that new treatment is needed, especially for patients with relapsed / refractory patients and patients with adverse prognosis (adverse cytogenetic characteristics). Recent studies have shown that BCL-2 inhibitors have viable activity in a subgroup of patients with multiple myeloma (Touzeau C, Dousset C, Le Gouill S et al., Leukemia . 2014; 28 (1): 210-212). MCL1 has also been identified as an important regulator of cell survival in multiple myeloma (Derenne S, Monia B, Dean NM et al., Blood . 2002; 100 (1): 194-199; Zhang B, Gojo I, Fenton RG Blood . 2002; 99 (6): 1885-1893). Diffuse large B-cell lymphoma (DLBCL) is the most common type (25-35%) of non-Hodgkin Lymphoma, with 24 000 new patients each year. The DLBCL line has more than 12 subtypes of heterogeneous diseases, including double-hit / MYC translocation, activated B cells (ABC), and germinal center B cells (GCB). Modern immunochemotherapy (R-CHOP) cures approximately 60% of patients with DLBCL, but for the remaining 40%, there are few therapeutic options and poor prognosis. Therefore, there is a high medical need to increase the cure rate and clinical outcome of high-risk DLBCL such as ABC subtype (35% of DLBCL), which demonstrates the constitutive activation of the pro-survival NF-κB pathway. Neuroblastoma (NB) is the most common solid extracranial tumor in infants and children, representing 8% -10% of all childhood tumors currently classified as lower risk, moderate risk, or higher risk. It accounts for approximately 15% of all cancer-related deaths in the pediatric population. The prevalence of NB in children under 15 years of age is 10.2 cases per million, and nearly 500 new cases are reported each year. The median age at diagnosis was 22 months. Results for patients with NB have steadily improved over the past 30 years, with 5-year survival rates rising from 52% to 74%. However, 50% to 60% of patients in the high-risk group are predicted to experience relapses, and it has been found that their mortality has only moderately decreased. The median time to relapse was 13.2 months, and 73% of those with relapses were 18 months or more. All in all, the overall survival rate of NB is still extremely unfathomable (about 20% for 5 years), even with more active therapies (Colon and Chung, Adv Pediatr 2013 58: 297-311). The main treatment consists of chemotherapy, surgical ablation and / or radiation therapy. However, a variety of aggressive NBs have been developed that are tolerant to chemotherapeutic agents, making the likelihood of relapse quite high (Pinto et al., J Clin Oncol 201533: 3008-11). Depending on the level of risk, the standard care of NB is often carboplatin, cisplatin cyclophosphamide, doxorubicin, etoposide, cytokines (GM-CSF and IL2) and vincristine. Relapses following an initial response to chemotherapy are the leading cause of treatment failure, especially in high-risk NBs. Chemical resistance can be derived from the activation of pro-survival BCL-2 proteins, such as the BCL-2 and MCL1 proteins. NB performed higher levels of BCL-2 and MCL1 and lower levels of BCL-XL. Inhibition of BCL-2 sensitizes cells to death and induces regression of NB tumors in vivo (Ham et al., Cancer Cell 29: 159-172). Antagonism of BCL-2 and MCL1 resumes chemotherapy for higher risk NBs (Lestini et al., Cancer Biol Ther 2009 8: 1587-1595; Tanos et al., BMC Cancer 2016 16:97). Therefore, it is extremely reasonable to combine BCL-2 and MCL1 inhibitors in untreated or resistant patients. The present invention provides a novel combination of a BCL-2 inhibitor and an MCL1 inhibitor. The results show that with the development of effective small molecules targeting BCL-2 and MCL1, highly synergistic proapoptotic activity was revealed in primary human AML samples (Figures 2A and 17) and AML (Figures 9, 13 and Figures) 14), multiple myeloma (Example 4), lymphoma (Figures 4 and 12), neuroblastoma (Figure 10), T-ALL, B-ALL cell lines (Figure 11), and small cell lung cancer cells Strains (Fig. 15 (a) to Fig. 15 (e)). We have also shown that targeted in vivo combinations of BCL-2 and MCL1 are effective at AML and lymphoma xenograft models in mice and rats at tolerated doses (Figure 2, Figure 5, Figure 6, Figure 7. Figure 8 and Figure 16), and significantly increase the relapse time of AML (Figure 2B and Figure 2C). In addition, in the cell community assay, we show that BCL-2 + MCL1 targeting is particularly toxic to leukemic cell lines, but not to normal hematopoietic stem cells (Figure 3). This is the result of previous mouse MCL1 gene targeting experiments Compared. Until these effective and selective inhibitors are developed, the feasibility of targeting both BCL-2 and MCL1 remains uncertain. Previously missing model specific lineages indicated by the potential long-term risk of the following persons caused by the removal of MCL1: cardiac (Wang X, et al., Genes & development 2013; 27 ( 12):. 1351-1364; Thomas RL , et al., Genes & development 2013; 27 (12): . 1365-1377), granulocyte / hematopoietic (Opferman J et al., Science 's STKE 2005; 307 (5712.): 1101; Dzhagalov I et al., Blood 2007; 109 (4. ): 1620-1626; Steimer DA et al., Blood . 2009; 113 (12): 2805-2815), Thymocytes (Dunkle A et al., Cell Death & Differentiation . 2010; 17 (6): 994-1002), Neurons (Arbour N et al., Journal of Neuroscience . 2008; 28 (24): 6068-6078) and liver function (Hikita H et al., Hepatology . 2009; 50 (4): 1217-1226; Vick B et al., Hepatology . 2009; 49 (2): 627-636). Despite these concerns, recently, new effective short-acting pharmacological inhibitors of MCL1 delivered intravenously once a week, twice a week, and even once a day (during 5 consecutive days) still show good tolerance Sex and works against a range of cancers in vivo, including AML (Kotschy A et al., Nature . 2016; 538 (7626): 477-482; WO 2015/097123). The short half-life of MCL1 protein allows sufficient time for its regeneration in key organs, thereby making it physiologically tolerant of short-term exposure to MCL1 inhibitors (Yang T et al., Journal of cellular physiology . 1996; 166 (3): 523-536). To date, pulsed inhibition of BCL-2 and MCL1, which mimics similar drug effects, has not been possible using genetic engineering approaches. Studies using BCL-2 and MCL1 inhibitors according to the present invention provide the following proof of concept: Intermittent exposure to these drugs may be sufficient to trigger clinical responses in apoptosis and highly sensitive diseases such as AML. No concurrent toxicity in organ systems. When targeting both anti-apoptotic proteins, the synergistic effect of targeting both BCL-2 and MCL1 in vitro and in vivo and the non-toxicity to normal bone marrow are only demonstrated by a combination of effective small molecule inhibitors. These aspects are not expected from the results of gene targeting experiments, which predict that hematopoietic stem cells will be less resistant to MCL1 deletion.

The invention relates to a combination comprising (a) a BCL-2 inhibitor of formula (I): Among them: ¨ X and Y represent carbon atom or nitrogen atom, it should be understood that they may not represent two carbon atoms or two nitrogen atoms at the same time, ¨ A ₁ and A ₂ together with the atoms they carry form 5 and 6 which are substituted as appropriate. An aromatic or non-aromatic heterocyclic Het consisting of 7 or 7 ring members, in addition to the nitrogen represented as X or Y, may also contain 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen. It is understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a straight or branched (C ₁ -C ₆ ) alkyl, or a group -C (O) -O-Alk, where Alk is straight or branched (C ₁ -C ₆ ) alkyl, or A ₁ and A ₂ each independently represent a hydrogen atom, straight or branched (C ₁ -C ₆ ) polyhaloalkyl, straight or branched (C _1- C ₆ ) alkyl or cycloalkyl, ¨ T represents a hydrogen atom, optionally a straight or branched chain (C ₁ -C ₆ ) alkyl, or a group (C ₁ -C ₄ ) Alkyl-NR ₁ R ₂ or (C ₁ -C ₄ ) alkyl-OR ₆ , ¨ R ₁ and R ₂ each independently represent a hydrogen atom or a straight or branched chain (C ₁ -C ₆ ) alkane group, or R ₁ and R ₂ form a heterocyclic ring with the nitrogen atom which carries the group, ¨ R ₃ represents a linear or branched (C ₁ -C ₆₎ alkyl, linear or branched (C ₂ -C ₆₎ alkenyl group, a linear or branched (C ₂ -C ₆₎ alkynyl, cycloalkyl, (C ₃ -C ₁₀ ) Cycloalkyl- (C ₁ -C ₆ ) alkyl, in which the alkyl moiety is a straight or branched heterocycloalkyl, aryl or heteroaryl, it should be understood that the carbon atom of the foregoing group or its possible One or more of the carbon atoms of the substituent may be deuterated. ¨ R ₄ represents an aryl group, a heteroaryl group, a cycloalkyl group, or a linear or branched (C ₁ -C ₆ ) alkyl group. It should be understood that One or more of the carbon atoms of the carbon atom or its possible substituents may be deuterated, ¨ R ₅ represents a hydrogen or halogen atom, a straight or branched (C ₁ -C ₆ ) alkyl or a straight or branched chain Chain (C ₁ -C ₆ ) alkoxy, ¨ R ₆ represents a hydrogen atom or a straight or branched chain (C ₁ -C ₆ ) alkyl, ¨ R _a , R _b , R _c and R _d are independent of each other R ₇ , a halogen atom, a linear or branched (C ₁ -C ₆ ) alkoxy group, a hydroxyl group, a linear or branched (C ₁ -C ₆ ) polyhaloalkyl group, a trifluoromethoxy group, -NR ₇ R ₇ ', nitro, R ₇ -CO- (C ₀ -C ₆ ) alkyl-, R ₇ -CO-NH- (C ₀ -C ₆ ) alkyl-, NR ₇ R ₇ ' -CO- (C ₀ -C ₆ ) alkyl-, NR ₇ R ₇ '-CO- (C ₀ -C ₆ ) alkyl-O-, R ₇ -SO ₂ -NH- (C ₀ -C ₆ ) alkyl-, R ₇ -NH-CO-NH- (C _0- C ₆ ) alkyl-, R ₇ -O-CO-NH- (C ₀ -C ₆ ) alkyl-, heterocycloalkyl, or (R _a , R _b ), (R _b , R _c ), or ( A substituent of one of R _c , _Rd ) forms a ring composed of 5 to 7 ring members together with the carbon atom carrying it, which may contain 1 to 2 heteroatoms selected from oxygen and sulfur, and should also It is understood that one or more carbon atoms of the ring defined above may be deuterated or substituted with 1 to 3 groups selected from halogen and linear or branched (C ₁ -C ₆ ) alkyl, ¨ R ₇ and R ₇ 'each independently represent hydrogen, straight or branched (C ₁ -C ₆ ) alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) Alkynyl, aryl or heteroaryl, or R ₇ and R ₇ 'together with the nitrogen atom carrying it to form a heterocyclic ring consisting of 5 to 7 ring members, it should be understood that when the compound of formula (I) contains a hydroxyl group when the latter is optionally converted by one of the following groups: -OPO (OM) (OM ' ), - OPO (OM) (OM 1 +), - OPO (OM 1 +) (O - ^{_{M 2 +), - OPO (}} O -) (O -) M 3 2 +, -OPO (OM) (O [CH 2 CH 2 O] n CH 3) or -OPO (O ^{_{- M 1 +) (O [}} CH 2 CH 2 O] n CH 3), where M and M 'each independently represent a hydrogen atom, a linear or branched (C ₁ -C ₆₎ alkyl, linear or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, cycloalkyl or heterocycloalkyl, both of which are composed of 5 to 6 ring members, and M ₁ ⁺ independently of one another and M ₂ ⁺ represents a pharmaceutically acceptable monovalent cation, M ₃ ^{2 +} represents a pharmaceutically acceptable divalent cation, and n is an integer of 1 to 5, it should be understood that: - "aryl" is intended to Means phenyl, naphthyl, biphenyl or indenyl, "heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogen),-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"hetero "Cycloalkyl" means any monocyclic or bicyclic non-aromatic fused group consisting of 3 to 10 ring members and containing 1 to 3 heteroatoms selected from oxygen, sulfur, SO, SO ₂ and nitrogen, or Spiro, aryl, heteroaryl, naphthenes that may be so defined And heterocycloalkyl, and the groups alkyl, alkenyl, alkynyl, and alkoxy are substituted by 1 to 3 groups selected from the group consisting of hydroxyl, morpholine, and 3-3-difluoro, as appropriate Piperidine or 3-3-difluoropyrrolidine substituted linear or branched (C ₁ -C ₆ ) alkyl; (C ₃ -C ₆ ) spirocyclic ring; optionally linear or branched with morpholine (C ₁ -C ₆ ) alkoxy; (C ₁ -C ₆ ) alkyl-S-; hydroxyl; side oxygen; N -oxide; nitro; cyano; -COOR ';-OCOR'; NR 'R "; linear or branched (C ₁ -C ₆ ) polyhaloalkyl; trifluoromethoxy; (C ₁ -C ₆ ) alkylsulfonyl; halogen; optionally one or more halogens Substituted aryl groups; heteroaryl groups; aryloxy groups; arylthio groups; cycloalkyl groups; heterocycloalkyl groups optionally substituted with one or more halogen atoms or alkyl groups, wherein R 'and R "are independent of each other Represents a hydrogen atom or optionally a linear or branched (C ₁ -C ₆ ) alkyl group substituted with a methoxy group. The Het group defined in formula (I) may be selected from 1 to 3 straight or branched chains. (C ₁ -C ₆ ) alkyl, hydroxyl, linear or branched (C ₁ -C ₆ ) alkoxy, NR ₁ 'R ₁ "and halogen group substitution, it should be understood that R ₁ ' and R ₁ " As defined above with regard to the groups R 'and R ", or their enantiomers, diastereomers, or addition salts thereof with pharmaceutically acceptable acids or bases, and (b) MCL1 inhibitor. The compounds of formula (I), their synthesis, their use in the treatment of cancer, and their pharmaceutical formulations are described in WO 2013/110890, WO 2015/011397, WO 2015/011399, and WO 2015/011400. Incorporated by reference. In certain embodiments, the MCL1 inhibitor is selected from A-1210477 ( Cell Death and Disease 2015 6, e1590; doi: 10.1038 / cddis.2014.561) and is described in WO 2015/097123, WO 2016/207216, WO 2016 / The compounds of 207217, WO 2016/207225, WO 2016/207226 or WO 2016/033486, the contents of which are incorporated by reference. The invention also relates to a combination comprising (a) a BCL-2 inhibitor and (b) an MCL1 inhibitor of formula (II): Where: ¨ A represents a straight or branched (C ₁ -C ₆ ) alkyl, a straight or branched (C ₂ -C ₆ ) alkenyl, a straight or branched (C ₂ -C ₆ ) alkynyl, Linear or branched (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxyl, cyano , -NW ₁₀ W ₁₀ ', -Cy ₆ or a halogen atom, ¨ W ₁ , W ₂ , W ₃ , W ₄ and W ₅ independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C ₁ -C ₆ ) Alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, straight or branched (C ₁ -C ₆ ) polyhaloalkane Group, hydroxy, linear or branched (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, cyano, nitro, -alkyl (C ₀ -C ₆ )- NW ₈ W ₈ ', -O-Cy ₁ , -alkyl (C ₀ -C ₆ ) -Cy ₁ , -alkenyl (C ₂ -C ₆ ) -Cy ₁ , -alkynyl (C ₂ -C ₆ ) -Cy ₁ , -O-alkyl (C ₁ -C ₆ ) -W ₉ , -C (O) -OW ₈ , -OC (O) -W ₈ , -C (O) -NW ₈ W ₈ ', -NW ₈ -C (O) -W ₈ ', -NW ₈ -C (O) -OW ₈ ', -alkyl (C ₁ -C ₆ ) -NW ₈ -C (O) -W ₈ ',- SO ₂ -NW ₈ W ₈ ', -SO ₂ -alkyl (C ₁ -C ₆ ), or when grafted to two adjacent carbon atoms, The substituents on one of (W ₁ , W ₂ ), (W ₂ , W ₃ ), (W ₁ , W ₃ ), (W ₄ , W ₅ ) together with the carbon atom carrying it form from 5 to An aromatic or non-aromatic ring composed of 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the resulting ring may be selected from straight or branched chains (C ₁ -C ₆ ) Alkyl, -NW ₁₀ W ₁₀ ', -alkyl (C ₀ -C ₆ ) -Cy ₁ or side oxygen group substitution, ¨ X' represents a carbon atom or nitrogen atom, ¨ W ₆ represents hydrogen, Linear or branched (C ₁ -C ₈ ) alkyl, aryl, heteroaryl, arylalkyl (C ₁ -C ₆ ) groups, heteroarylalkyl (C ₁ -C ₆ ) groups , ¨ W ₇ represents straight or branched (C ₁ -C ₆ ) alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, -Cy ₃ , -alkyl (C ₁ -C ₆ ) -Cy ₃ , -alkenyl (C ₂ -C ₆ ) -Cy ₃ , -alkynyl (C ₂ -C ₆ ) -Cy ₃ , -Cy _3- Cy ₄ , -alkynyl (C ₂ -C ₆ ) -O-Cy ₃ , -Cy ₃ -alkyl (C ₀ -C ₆ ) -O-alkyl (C ₀ -C ₆ ) -Cy ₄ , halogen atom , Cyano, -C (O) -W ₁₁ or -C (O) -NW ₁₁ W ₁₁ ', ¨ W ₈ and W ₈ ' each independently represent a hydrogen atom, a straight chain or a branched chain (C ₁ -C ₆ ) Alkyl or -alkyl (C ₀ -C ₆ ) -Cy ₁ , or (W ₈ , W ₈ ′) together with the nitrogen atom carrying it forms an aromatic or non-aromatic ring consisting of 5 to 7 ring members In addition to the nitrogen atom, it may also contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the nitrogen in question may represent a hydrogen atom, or a straight or branched chain (C ₁ -C ₆ ) Alkyl group substitution, and it should be understood that one or more carbon atoms of possible substituents can be deuterated, ¨ W ₉ represents -Cy ₁ , -Cy ₁ -alkyl (C ₀ -C ₆ ) -Cy ₂ , -Cy ₁ -alkyl (C ₀ -C ₆ ) -O-alkyl (C ₀ -C ₆ ) -Cy ₂ , -Cy ₁ -alkyl (C ₀ -C ₆ ) -NW ₈ -alkyl ( C ₀ -C ₆ ) -Cy ₂ , -Cy ₁ -Cy ₂ -O-alkyl (C ₀ -C ₆ ) -Cy ₅ , -C (O) -NW ₈ W ₈ ', -NW ₈ W ₈ ' , -OW ₈ , -NW ₈ -C (O) -W ₈ ', -O-alkyl (C ₁ -C ₆ ) -OW ₈ , -SO ₂ -W ₈ , -C (O) -OW ₈ , -NH-C (O) -NH-W ₈ , , or The ammonium thus defined may exist in the form of zwitterions or have a monovalent anion counter ion. ¨ W ₁₀ , W ₁₀ ′, W ₁₁ and W ₁₁ ′ independently represent a hydrogen atom or a straight or branched chain (C _1- C ₆₎ alkyl, ¨ W ₁₂ represents hydrogen or hydroxyl, ¨ W ₁₃ represents a hydrogen atom or a linear or branched (C ₁ -C ₆₎ alkyl, ¨ W ₁₄ represents ^{-OP (O) (O -)} ( O ^{-) group, -OP (O) (O -} ) (OW 16) _{group, -OP (O) (OW 16} ) (OW 16 ') groups, -O-SO ₂ -O ^- group, -O-SO ₂ -OW ₁₆ group, -Cy ₇ , -OC (O) -W ₁₅ group, -OC (O) -OW ₁₅ group, or -OC (O) -NW ₁₅ W ₁₅ 'group , ¨ W ₁₅ and W ₁₅ 'independently of each other represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl group or a linear or branched amine (C ₁ -C ₆ ) alkyl group, ¨ W ₁₆ And W ₁₆ 'independently of each other represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl or arylalkyl (C ₁ -C ₆ ) group, ¨ Cy ₁ , Cy ₂ , Cy ₃ , Cy ₄ , Cy ₅ , Cy ₆ and Cy ₇ each independently represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and ¨ n is an integer equal to 0 or 1, it should be understood that:-"aryl" means Refers to phenyl, naphthyl, biphenyl, dihydro Or indenyl, "heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 3 selected from oxygen, sulfur and nitrogen Heteroatoms,-"cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means any group containing 3 to 10 ring members and Monocyclic or bicyclic non-aromatic carbocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems, aryl, heteroaromatic, as may be defined as such Group, cycloalkyl group and heterocycloalkyl group, and alkyl group, alkenyl group, alkynyl group, and alkoxy group are substituted by 1 to 4 groups selected from the group consisting of straight or branched chain (C ₁ -C ₆ ) alkyl, which can be represented by a straight-chain or branched (C ₁ -C ₆₎ alkoxy substituted with a group of the straight-chain or branched (C ₁ -C ₆₎ alkoxy can be a straight-chain or branched ( C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxyl, halogen, pendant oxygen, -NW'W ", -OC (O) -W 'or -CO-NW'W "substituted; straight or branched (C ₂ -C ₆₎ alkenyl group; a straight-chain or can be represented by Branched (C ₁ -C ₆₎ alkoxy groups of the substituted straight-chain or branched (C ₂ -C ₆₎ alkynyl; may be represented by a straight-chain or branched (C ₁ -C ₆₎ alkoxy, Straight or branched (C ₁ -C ₆ ) polyhaloalkyl, straight or branched (C ₂ -C ₆ ) alkynyl, -NW'W "or hydroxyl group substituted straight or branched chain ( C ₁ -C ₆ ) alkoxy; (C ₁ -C ₆ ) alkyl-S- substituted by a group representing a linear or branched (C ₁ -C ₆ ) alkoxy; hydroxyl; pendant oxy N -oxide; nitro; cyano; -C (O) -OW '; -OC (O) -W';-CO-NW'W";-NW'W";-(C = NW ' ) -OW "; linear or branched (C ₁ -C ₆ ) polyhaloalkyl; trifluoromethoxy; or halogen; it should be understood that W 'and W" independently represent a hydrogen atom or may be represented by a straight chain Or branched (C ₁ -C ₆ ) alkoxy group substituted linear or branched (C ₁ -C ₆ ) alkyl; and it should be understood that one or more of the foregoing possible substituents may be deuterated , Its enantiomers, diastereomers or configuration isomers, or addition salts thereof with pharmaceutically acceptable acids or bases. The compounds of formula (II), their synthesis, their use in the treatment of cancer, and their pharmaceutical formulations are described in WO 2015/097123, the contents of which are incorporated by reference. In certain embodiments, the BCL-2 inhibitor is selected from the group consisting of 4- (4-{[2- (4-chlorophenyl) -4,4-dimethylcyclohex-1-ene-1 -Yl] methyl} piperazin-1-yl) -N -[(3-nitro-4-{[(oxane-4-yl) methyl] amino} phenyl) fluorenyl] -2- [(1 H -pyrrolo [2,3- b ] pyridin-5-yl) oxy] benzamidine (venetoclax or ABT-199); 4- (4-{[2- (4-chlorophenyl) -5,5-dimethyl-cyclohex-1-en-1-yl] methyl} piperazin-l-yl) - N - (4 - { [(2 R) -4 -(Morpholin-4-yl) -1- (phenylthio) but-2-yl] amino} -3- (trifluoromethanesulfonyl) benzenesulfonyl] benzidine (Ritu) (Navitoclax or ABT-263); oblimersen (G3139); obatoclax (GX15-070); HA14-1; (±) -gossypol (BL-193); ( -)-Gossypol (AT-101); apogossypol; TW-37; antimycin A, ABT-737 (Oltersdorf T et al., Nature June 2, 2005; 435 ( 7042): 677-81), and the compounds described in WO 2013/110890, WO 2015/011397, WO 2015/011399 and WO 2015/011400, the contents of which are incorporated by reference. According to the first aspect of the present invention Thus, a combination is provided that includes: (a) as A BCL-2 inhibitor of formula (I) described herein, and (b) an MCL1 inhibitor of formula (II) as described herein. In another embodiment, the invention provides a combination comprising: ( a) Compound 1: N- (4-hydroxyphenyl) -3- {6-[((3 S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1 H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5,6,7,8-tetrahydro-1-indolinazine Amidine, or a pharmaceutically acceptable salt thereof, and (b) an MCL1 inhibitor are used simultaneously, sequentially, or separately. In another embodiment, the present invention provides a combination comprising: (a) compound 4 : 5- (5-chloro-2-{[(3 S ) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoline-2 ( 1H ) -yl] carbonyl} phenyl) - N - (5- cyano-1,2-dimethyl -1 H - pyrrole-3-yl) - N - (4- hydroxyphenyl) -1,2-dimethyl -1 H -Pyrrole-3-formamidine, or a pharmaceutically acceptable salt thereof, and (b) an MCL1 inhibitor, used simultaneously, sequentially, or separately. Alternatively, the present invention provides a combination comprising: (a) a BCL-2 inhibitor, and (b) compound 2: ( 2R ) -2-{[( 5S _a ) -5- {3-chloro-2 -Methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl) thieno [2,3- d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl] methoxy} phenyl) propanoic acid , Simultaneously, sequentially or separately. In another embodiment, the present invention provides a combination comprising: (a) a BCL-2 inhibitor, and (b) compound 3: ( 2R ) -2-{[( 5S _a ) -5- {3- Chloro-2-methyl-4- [2- (4-methylpiperazin-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, simultaneously, sequentially or separately use. In another embodiment, the invention provides a combination as described herein for use in treating cancer. In another embodiment, the invention provides the use of a combination as described herein in the manufacture of a medicament for the treatment of cancer. In another embodiment, the present invention provides a medicament separately or together, comprising (a) a BCL-2 inhibitor of formula (I) and (b) an MCL1 inhibitor, or (a) a BCL- 2 inhibitors and (b) MCL1 inhibitors of formula (II) for simultaneous, sequential or separate administration, and wherein BCL-2 inhibitors and MCL1 inhibitors are provided in effective amounts for the treatment of cancer. In another embodiment, the present invention provides a method for treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of each of: (a) a BCL-2 inhibitor of formula (I) and (b ) MCL1 inhibitors, or (a) BCL-2 inhibitors and (b) MCL1 inhibitors of formula (II). In another embodiment, the present invention provides a method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii) Wherein the method includes administering to the patient a co-therapeutic effective amount of each of: (a) a BCL-2 inhibitor of formula (I) and (b) an MCL1 inhibitor, or (a) a BCL-2 inhibitor and (b) an MCL1 inhibitor of formula (II). In a specific embodiment, the BCL-2 inhibitor is N- (4-hydroxyphenyl) -3- {6-[((3 S ) -3- (4-morpholinylmethyl) -3,4 -Dihydro-2 ( 1H ) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5,6,7,8-tetra Hydro-1-indolazine formamidine hydrochloride (Compound 1, HCl). In a specific embodiment, the BCL-2 inhibitor is 5- (5-chloro-2-{[(3 S ) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquine morpholine -2 (1 H) - yl] carbonyl} phenyl) - N - (5- cyano-1,2-dimethyl -1 H - pyrrole-3-yl) - N - (4- hydroxyphenyl ) -1,2-dimethyl- 1H -pyrrole-3-carboxamide hydrochloride (Compound 4, HCl). In another embodiment, the BCL-2 inhibitor is ABT-199. In another embodiment, the MCL1 inhibitor is ( 2R ) -2-{[(( 5S _a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazine-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) propanoic acid (compound 2). In another embodiment, the MCL1 inhibitor is ( 2R ) -2-{[(( 5S _a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazine-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 3).

Therefore, the present invention provides a combination in Example E1, which comprises (a) a BCL-2 inhibitor of formula (I):Where: ¨ X and Y represent carbon or nitrogen atoms, it should be understood that they may not represent two carbon atoms or two nitrogen atoms at the same time, ¨ A₁ And A₂ With the atom carrying it to form an optionally substituted aromatic or non-aromatic heterocyclic ring consisting of 5, 6, or 7 ring members, Het, in addition to the nitrogen indicated as X or Y, may also contain 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, it should be understood that the nitrogen in question may be represented by a hydrogen atom, a straight chain or a branched chain (C₁ -C₆ ) Alkyl, or group substitution of the group -C (O) -O-Alk, where Alk is a straight or branched chain (C₁ -C₆ ) Alkyl, or A₁ And A₂ Independently represent a hydrogen atom, a straight chain or a branched chain (C₁ -C₆ ) Polyhaloalkyl, linear or branched (C₁ -C₆ ) Alkyl or cycloalkyl, ¨ T represents a hydrogen atom, optionally a straight or branched chain substituted with 1 to 3 halogen atoms (C₁ -C₆ ) Alkyl, group (C₁ -C₄ Alkyl-NR₁ R₂ Or group (C₁ -C₄ Alkyl-OR₆ , ¨ R₁ And R₂ Independently represent a hydrogen atom or a straight or branched chain (C₁ -C₆ ) Alkyl, or R₁ And R₂ Forms a heterocycloalkyl group with the nitrogen atom carrying it, ¨ R₃ Represents a straight or branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, cycloalkyl, (C₃ -C₁₀ ) Cycloalkyl- (C₁ -C₆ ) Alkyl, in which the alkyl moiety is straight or branched, heterocycloalkyl, aryl or heteroaryl, it should be understood that one or more of the carbon atoms of the foregoing group or the carbon atoms of its possible substituents Can be deuterated, ¨ R₄ Represents aryl, heteroaryl, cycloalkyl, or straight or branched chain (C₁ -C₆ ) Alkyl, it should be understood that one or more of the carbon atoms of the foregoing group or the carbon atoms of its possible substituents may be deuterated, ¨ R₅ Represents a hydrogen or halogen atom, straight or branched chain (C₁ -C₆ Alkyl or straight or branched chain (C₁ -C₆ ) Alkoxy, ¨ R₆ Represents a hydrogen atom or a straight or branched chain (C₁ -C₆ ) Alkyl, ¨ R_a , R_b , R_c And R_d Each independently represents R₇ , Halogen atom, straight or branched chain (C₁ -C₆ ) Alkoxy, hydroxyl, linear or branched (C₁ -C₆ ) Polyhaloalkyl, trifluoromethoxy, -NR₇ R₇ ', Nitro, R₇ -CO- (C₀ -C₆ Alkyl-, R₇ -CO-NH- (C₀ -C₆ Alkyl-, NR₇ R₇ '-CO- (C₀ -C₆ Alkyl-, R₇ -SO₂ -NH- (C₀ -C₆ Alkyl-, R₇ -NH-CO-NH- (C₀ -C₆ Alkyl-, R₇ -O-CO-NH- (C₀ -C₆ ) Alkyl-, heterocycloalkyl, or p- (R_a , R_b ), (R_b , R_c ) Or (R_c , R_d The substituent of one of), together with the carbon atom carrying it, forms a ring consisting of 5 to 7 ring members, which may contain 1 to 2 heteroatoms selected from oxygen and sulfur. It is also understood that One or more carbon atoms of the ring can be deuterated or selected from 1 to 3 halogens and straight or branched chains (C₁ -C₆ ) Alkyl group substitution, ¨ R₇ And R₇ 'Independent of each other means hydrogen, straight chain, or branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, aryl or heteroaryl, or R₇ And R₇ 'Together with the nitrogen atom carrying it to form a heterocyclic ring consisting of 5 to 7 ring members, it should be understood that when the compound of formula (I) contains a hydroxyl group, the latter may optionally be converted into one of the following groups: -OPO (OM) (OM '), -OPO (OM) (O^- M₁ ⁺ ), -OPO (O^- M₁ ⁺ ) (O^- M₂ ⁺ ), -OPO (O^- ) (O^- ) M₃ ^{2 +} , -OPO (OM) (O [CH₂ CH₂ O]_n CH₃ ) Or -OPO (O^- M₁ ⁺ ) (O [CH₂ CH₂ O]_n CH₃ ), Where M and M 'independently represent a hydrogen atom, a straight chain, or a branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, cycloalkyl, or heterocycloalkyl, both of which are composed of 5 to 6 ring members, and M₁ ⁺ And M₂ ⁺ Independently represent pharmaceutically acceptable monovalent cations, M₃ ^{2 +} Represents a pharmaceutically acceptable divalent cation, and n is an integer from 1 to 5, it should be understood:-"aryl" means phenyl, naphthyl, biphenyl or indenyl,-"heteroaryl" means Means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogen),-" "Cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means any consisting of 3 to 10 ring members and contains 1 to 3 Selected from oxygen, sulfur, SO, SO₂ Monocyclic or bicyclic non-aromatic condensed group or spiro group of hetero atom of nitrogen , Alkynyl and alkoxy are substituted by 1 to 3 groups selected from the group consisting of: Chain or branched chain (C₁ -C₆ ) Alkyl; (C₃ -C₆ ) Spiro ring; optionally a straight or branched chain substituted with morpholine (C₁ -C₆ ) Alkoxy; (C₁ -C₆ ) Alkyl-S-; hydroxyl; pendant oxygen;N -Oxide; nitro; cyano; -COOR '; -OCOR'; NR'R ";₁ -C₆ ) Polyhaloalkyl; trifluoromethoxy; (C₁ -C₆ ) Alkylsulfonyl; halogen; aryl optionally substituted with one or more halogens; heteroaryl; aryloxy; arylthio; cycloalkyl; -Substituted heterocycloalkyl, wherein R 'and R "independently of each other represent a hydrogen atom or optionally a straight or branched chain substituted with methoxy (C₁ -C₆ ) Alkyl, the Het group defined in formula (I) may be selected from 1 to 3 straight or branched chain (C₁ -C₆ ) Alkyl, hydroxy, linear or branched (C₁ -C₆ ) Alkoxy, NR₁ 'R₁ "And halogen group substitution, it is understood that R₁ 'And R₁ "As defined for the aforementioned groups R 'and R", or its enantiomers, diastereomers, or addition salts thereof with a pharmaceutically acceptable acid or base, And (b) MCL1 inhibitors, used simultaneously, sequentially or separately. The invention also provides in Example E2 a combination comprising (a) a BCL-2 inhibitor and (b) an MCL1 inhibitor of formula (II):Among them: ¨ A means straight or branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, linear or branched (C₁ -C₆ ) Alkoxy, -S- (C₁ -C₆ ) Alkyl, linear or branched (C₁ -C₆ ) Polyhaloalkyl, hydroxyl, cyano, -NW₁₀ W₁₀ ', -Cy₆ Or a halogen atom, ¨ W₁ , W₂ , W₃ , W₄ And W₅ Independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, linear or branched (C₁ -C₆ ) Polyhaloalkyl, hydroxy, linear or branched (C₁ -C₆ ) Alkoxy, -S- (C₁ -C₆ ) Alkyl, cyano, nitro, -alkyl (C₀ -C₆ ) -NW₈ W₈ ', -O-Cy₁ , -Alkyl (C₀ -C₆ ) -Cy₁ , -Alkenyl (C₂ -C₆ ) -Cy₁ , -Alkynyl (C₂ -C₆ ) -Cy₁ , -O-alkyl (C₁ -C₆ ) -W₉ , -C (O) -OW₈ , -O-C (O) -W₈ , -C (O) -NW₈ W₈ ', -NW₈ -C (O) -W₈ ', -NW₈ -C (O) -OW₈ ', -Alkyl (C₁ -C₆ ) -NW₈ -C (O) -W₈ ', -SO₂ -NW₈ W₈ ', -SO₂ -Alkyl (C₁ -C₆ ), Or when grafted to two adjacent carbon atoms, for (W₁ , W₂ ), (W₂ , W₃ ), (W₁ , W₃ ), (W₄ , W₅ A substituent of one of), together with the carbon atom carrying it, forms an aromatic or non-aromatic ring composed of 5 to 7 ring members, which may contain 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen Atom, it should be understood that the resulting ring may be selected from straight or branched chains (C₁ -C₆ ) Alkyl, -NW₁₀ W₁₀ ', -Alkyl (C₀ -C₆ ) -Cy₁ Or pendant oxygen groups, ¨ X 'represents a carbon atom or a nitrogen atom, ¨ W₆ Represents hydrogen, straight or branched chain (C₁ -C₈ ) Alkyl, aryl, heteroaryl, arylalkyl (C₁ -C₆ ) Group, heteroarylalkyl (C₁ -C₆ ) Group, ¨ W₇ Represents a straight or branched chain (C₁ -C₆ ) Alkyl, linear or branched (C₂ -C₆ ) Alkenyl, linear or branched (C₂ -C₆ ) Alkynyl, -Cy₃ , -Alkyl (C₁ -C₆ ) -Cy₃ , -Alkenyl (C₂ -C₆ ) -Cy₃ , -Alkynyl (C₂ -C₆ ) -Cy₃ , -Cy₃ -Cy₄ , -Alkynyl (C₂ -C₆ ) -O-Cy₃ , -Cy₃ -Alkyl (C₀ -C₆ ) -O-alkyl (C₀ -C₆ ) -Cy₄ , Halogen atom, cyano, -C (O) -W₁₁ Or -C (O) -NW₁₁ W₁₁ ', ¨ W₈ And W₈ 'Independently of each other means a hydrogen atom, a straight or branched chain (C₁ -C₆ ) Alkyl or -alkyl (C₀ -C₆ ) -Cy₁ , Or (W₈ , W₈ ') Together with the nitrogen atom carrying it to form an aromatic or non-aromatic ring composed of 5 to 7 ring members, which may contain 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in addition to nitrogen It should be understood that the nitrogen in question may be represented by a hydrogen atom, or a straight or branched chain (C₁ -C₆ ) Alkyl group substitution, and it is understood that one or more carbon atoms of possible substituents may be deuterated, ¨ W₉ Means -Cy₁ , -Cy₁ -Alkyl (C₀ -C₆ ) -Cy₂ , -Cy₁ -Alkyl (C₀ -C₆ ) -O-alkyl (C₀ -C₆ ) -Cy₂ , -Cy₁ -Alkyl (C₀ -C₆ ) -NW₈ -Alkyl (C₀ -C₆ ) -Cy₂ , -Cy₁ -Cy₂ -O-alkyl (C₀ -C₆ ) -Cy₅ , -C (O) -NW₈ W₈ ', -NW₈ W₈ ', -OW₈ , -NW₈ -C (O) -W₈ ', -O-alkyl (C₁ -C₆ ) -OW₈ , -SO₂ -W₈ , -C (O) -OW₈ , -NH-C (O) -NH-W₈ ,,orThe ammonium thus defined may exist in the form of a zwitterion or have a monovalent counter ion, ¨ W₁₀ , W₁₀ ', W₁₁ And W₁₁ 'Independently of each other means a hydrogen atom or a straight or branched chain (C₁ -C₆ ) Alkyl, ¨ W₁₂ Represents hydrogen or hydroxyl, ¨ W₁₃ Represents a hydrogen atom or a straight or branched chain (C₁ -C₆ ) Alkyl, ¨ W₁₄ Represents -O-P (O) (O^- ) (O^- ) Group, -O-P (O) (O^- ) (OW₁₆ ) Group, -O-P (O) (OW₁₆ ) (OW₁₆ ') Group, -O-SO₂ -O^- Group, -O-SO₂ -OW₁₆ Group, -Cy₇ , -O-C (O) -W₁₅ Group, -O-C (O) -OW₁₅ Group or -O-C (O) -NW₁₅ W₁₅ 'Group, ¨ W₁₅ And W₁₅ 'Independently of each other means a hydrogen atom, a straight or branched chain (C₁ -C₆ ) Alkyl or linear or branched amine (C₁ -C₆ ) Alkyl, ¨ W₁₆ And W₁₆ 'Independently of each other means a hydrogen atom, a straight or branched chain (C₁ -C₆ ) Alkyl or arylalkyl (C₁ -C₆ ) Group, ¨ Cy₁ , Cy₂ , Cy₃ , Cy₄ , Cy₅ , Cy₆ And Cy₇ Each independently represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and n is an integer equal to 0 or 1, it should be understood that: "aryl" means phenyl, naphthyl, biphenyl, Dihydroindenyl or indenyl,-"heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 3 members selected from oxygen, Heteroatoms of sulfur and nitrogen,-"Cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members,-"heterocycloalkyl" means any containing 3 to 10 A monocyclic or bicyclic non-aromatic carbocyclic group of a ring member containing 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen, which may include a fused, bridged, or spiro ring system, an aryl group as may be defined as such , Heteroaryl, cycloalkyl, and heterocycloalkyl, and alkyl, alkenyl, alkynyl, and alkoxy are substituted by 1 to 4 groups selected from the group consisting of straight or branched (C₁ -C₆ ) Alkyl, which may be represented by a straight or branched chain (C₁ -C₆ ) Alkoxy group substitution, the linear or branched chain (C₁ -C₆ Alkoxy can be straight or branched (C₁ -C₆ ) Alkoxy, linear or branched (C₁ -C₆ ) Polyhaloalkyl, hydroxy, halogen, pendant oxy, -NW'W ", -O-C (O) -W 'or -CO-NW'W' 'substitution; straight or branched chain (C₂ -C₆ ) Alkenyl; can be represented by straight or branched chain (C₁ -C₆ ) Linear or branched chain substituted with alkoxy groups (C₂ -C₆ ) Alkynyl; may be represented by a straight or branched chain (C₁ -C₆ ) Alkoxy, linear or branched (C₁ -C₆ ) Polyhaloalkyl, linear or branched (C₂ -C₆ ) Alkynyl, -NW'W '' or hydroxyl-substituted straight or branched chain (C₁ -C₆ ) Alkoxy; can be represented by straight or branched chain (C₁ -C₆ (C) alkoxy group substituted (C₁ -C₆ ) Alkyl-S-; hydroxyl; pendant oxygen;N -Oxide; nitro; cyano; -C (O) -OW '; -OC (O) -W'; -CO-NW'W ''; -NW'W '';-(C = NW ' ) -OW ''; linear or branched chain (C₁ -C₆ ) Polyhaloalkyl; trifluoromethoxy; or halogen; it should be understood that W ′ and W ″ independently represent a hydrogen atom or may represent a straight or branched chain (C₁ -C₆ ) Linear or branched chain substituted with alkoxy groups (C₁ -C₆ ) Alkyl; and it is understood that one or more of the carbon atoms of the foregoing possible substituents may be deuterated, their enantiomers, diastereomers or configuration isomers, or their pharmaceutically acceptable Addition salts of accepted acids or bases are used simultaneously, sequentially or separately. A further enumerated example (E) of the invention is described herein. It should be recognized that features specified in each embodiment may be combined with other specified features to provide other embodiments of the present invention. E3. A combination according to E1, wherein the MCL1 inhibitor is a compound of formula (II) as defined in E2. E4. A combination according to any one of E1 to E3, wherein the BCL-2 inhibitor isN -(4-hydroxyphenyl) -3- {6-[((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl}-N -Phenyl-5,6,7,8-tetrahydro-1-indolinazinecarboxamide. E5. A combination according to any one of E1 to E3, wherein the BCL-2 inhibitor is 5- (5-chloro-2-{[(3S ) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoline-2 (1H ) -Yl] carbonyl} phenyl)-N -(5-cyano-1,2-dimethyl-1H -Pyrrole-3-yl)-N -(4-hydroxyphenyl) -1,2-dimethyl-1H -Pyrrole-3-carboxamide. E6. A combination according to E4, whereinN -(4-hydroxyphenyl) -3- {6-[((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl}-N -Phenyl-5,6,7,8-tetrahydro-1-indolinazinecarboxamide is in the form of the hydrochloride salt. E7. A combination according to E5, wherein 5- (5-chloro-2-{[((3S ) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoline-2 (1H ) -Yl] carbonyl} phenyl)-N -(5-cyano-1,2-dimethyl-1H-pyrrole-3-yl)-N -(4-hydroxyphenyl) -1,2-dimethyl-1H -Pyrrole-3-formamidine is in the form of the hydrochloride. E8. A combination according to E4 or E6, wherein during the combination therapy,N -(4-hydroxyphenyl) -3- {6-[((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl}-N The dosage of -phenyl-5,6,7,8-tetrahydro-1-indolinazinecarboxamide is 50 mg to 1500 mg. E9. A combination according to any one of E1 to E8, wherein the BCL-2 inhibitor is administered once a week. E10. A combination according to E6 or E8, wherein during the combination treatment,N -(4-hydroxyphenyl) -3- {6-[((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl}-N -Phenyl-5,6,7,8-tetrahydro-1-indolinazine formamide is administered once a day. E11. A combination according to any one of E1 to E3, wherein the BCL-2 inhibitor is ABT-199. E12. A combination according to any one of E1 to E11, wherein the MCL1 inhibitor is (2R )-2-{[(5S _a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl ) Thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H-pyrazol-5-yl] methoxy} phenyl) propyl acid. E13. A combination according to any one of E1 to E11, wherein the MCL1 inhibitor is (2R )-2-{[(5S _a ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-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. E14. A combination according to any one of E1 to E13, wherein the BCL-2 inhibitor and the MCL1 inhibitor are administered orally. E15. A combination according to any one of E1 to E13, wherein the BCL-2 inhibitor is administered orally and the MCL1 inhibitor is administered intravenously. E16. A combination according to any one of E1 to E13, wherein the BCL-2 inhibitor and the MCL1 inhibitor are administered intravenously. E17. A combination according to any one of E1 to E16, for use in treating cancer. E18. The combination for use according to E17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in a co-therapeutic effective amount for treating cancer. E19. The combination for use according to E17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in a synergistically effective amount for treating cancer. E20. The combination for use according to E17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in a synergistically effective amount to achieve the required dose reduction of each compound in cancer treatment, while providing effective cancer treatment and ultimately reducing side effects. E21. The combination used according to any one of E17 to E20, wherein the cancer is leukemia. E22. The combination for use according to E21, wherein the cancer is acute myeloid leukemia, T-ALL or B-ALL. E23. The combination for use according to any one of E17 to E20, wherein the cancer is a myelodysplastic syndrome or a myeloproliferative disease. E24. The combination for use according to any one of E17 to E20, wherein the cancer is lymphoma. E25. The combination for use according to any one of E24, wherein the lymphoma is a non-Hodgkin's lymphoma. E26. The combination for use according to any one of E25, wherein the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma or a mantle-cell lymphoma. E27. The combination for use according to any one of E17 to E20, wherein the cancer is multiple myeloma. E28. The combination for use according to any one of E17 to E20, wherein the cancer is a neuroblastoma. E29. The combination for use according to any one of E17 to E20, wherein the cancer is small cell lung cancer. E30. A combination according to any one of E1 to E16, further comprising one or more excipients. E31. Use of a combination according to any one of E1 to E16 in the manufacture of a medicament for treating cancer. E32. The use according to E31, wherein the cancer is leukemia. E33. The use according to E32, wherein the cancer is acute myeloid leukemia, T-ALL or B-ALL. E34. The use according to E31, wherein the cancer is a myelodysplastic syndrome or a myeloproliferative disease. E35. The use according to E31, wherein the cancer is lymphoma. E36. The use according to E35, wherein the lymphoma is a non-Hodgkin's lymphoma. E37. The use according to E36, wherein the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma or mantle cell lymphoma. E38. The use according to E31, wherein the cancer is multiple myeloma. E39. The use according to E31, wherein the cancer is a neuroblastoma. E40. The use according to E31, wherein the cancer is small cell lung cancer. E41. A drug which contains, separately or together, (a) a BCL-2 inhibitor of formula (I) as defined in E1, and (b) an MCL1 inhibitor for simultaneous, sequential or separate administration And wherein BCL-2 inhibitor and MCL1 inhibitor are provided in effective amounts for the treatment of cancer. E42. A drug that contains, separately or together, (a) a BCL-2 inhibitor, and (b) an MCL1 inhibitor of formula (II) as defined in E2 for simultaneous, sequential or separate administration And wherein BCL-2 inhibitor and MCL1 inhibitor are provided in effective amounts for the treatment of cancer. E43. A method for treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of (a) a BCL-2 inhibitor of formula (I) as defined in E1, and (b) an MCL1 inhibitor. E44. A method for treating cancer, comprising administering to a subject in need thereof a (a) BCL-2 inhibitor, and (b) a MCL1 inhibitor of formula (II) as defined in E2. E45. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient A co-therapeutic effective amount is administered of (a) a BCL-2 inhibitor of formula (I) as defined in El, and (b) an MCL1 inhibitor. E46. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient And (a) a BCL-2 inhibitor, and (b) an MCL1 inhibitor of formula (II) as defined in E2. "Combination" means a fixed-dose combination, non-fixed-dose combination, or divided portion of a unit dosage form (e.g., capsule, lozenge, or sachet) for combined administration, in which the compound of the invention and Combinations (for example, another drug explained below, also known as a "therapeutic agent" or "adjuvant") can be administered simultaneously and independently or separately at time intervals, especially during these time intervals that the combination matches When things show cooperation, such as synergy. The term "co-administration" or "combination administration" or similar terms as used herein is intended to cover the administration of a selected combination partner to a single individual in need (e.g., a patient), and is intended to include the medicament not necessarily by the same The route of administration administers or concurrently administers the treatment plan. The term "fixed dose combination" means that the active ingredients, such as a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "unfixed dose combination" means that the active ingredients, such as the compound of the present invention and one or more combination combinations, are administered to a patient simultaneously or sequentially in the form of separate entities without specific time limits, wherein the administration provides treatment An effective amount of both compounds is administered to the patient. The latter is also suitable for admixture therapy, such as administration of 3 or more active ingredients. "Cancer" means a type of disease in which the cell population exhibits uncontrolled growth. Cancer types include hematological cancers (lymphoma and leukemia) and solid tumors including cancer, sarcoma or blastoma. In particular, "cancer" refers to leukemia, lymphoma, or multiple myeloma, and more particularly to acute myeloid leukemia. The term `` co-therapeutic effect '' means that the therapeutic agent can be administered separately in such time intervals that its preferences still show (preferably synergistic) interactions (co-therapeutic effects) in warm-blooded animals (especially humans to be treated) ( Staggered in chronological order, especially in a specific sequential manner). Regardless of whether this can be done, in particular, based on blood content determinations, it appears that both compounds are present in the human blood to be treated at least for some time interval. "Synergistically effective" or "synergistic" means that the therapeutic effect observed after the administration of two or more agents is greater than the total therapeutic effect observed after the administration of each single agent. As used herein, the term "treat / treating / treatment" of any disease or condition refers in one embodiment to ameliorating the disease or condition (ie, slowing or stagnating or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat / treating / treatment" refers to relieving or improving at least one physiological parameter, including a physiological parameter that the patient may not be able to discern. In yet another embodiment, "treat / treating / treatment" refers to physical (e.g., stabilization of discernible symptoms), physiological (e.g., stabilization of physiological parameters), or both Disease or illness. As used herein, an individual "needs" that treatment if it will benefit biologically, medically, or quality of life. In another aspect, a method for making (i) difficult to treat with at least one chemotherapy or (ii) relapse after treatment with chemotherapy, or (i) and (ii) both human sensitive is provided, wherein The method comprises administering to the patient a BCL-2 inhibitor of formula (I) as described herein, and an MCL1 inhibitor. Sensitive patients are patients who respond to treatment involving administration of a BCL-2 inhibitor of formula (I) as described herein, as well as MCL1 inhibitors, or patients who have not yet developed tolerance to this treatment. "Drug" 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. "AML" means acute myeloid leukemia. "T-ALL" and "B-ALL" mean T-cell acute lymphoblastic leukemia and B-cell acute lymphoblastic leukemia. "Free base" refers to a compound that is not yet in the form of a salt. In the pharmaceutical composition according to the present invention, the proportion of the active ingredient by weight (the weight of the active ingredient in the total weight of the composition) is 5 to 50%. In the pharmaceutical composition according to the invention, more particularly those which are suitable for oral, parenteral and especially intravenous, whole skin or anti-skin, nasal, rectal, tongue, eye or respiratory administration, More precisely, lozenges, dragees, sublingual lozenges, hard gelatin capsules, rectal dosage forms, capsules, lozenges, injectables, sprays, eye or nasal drops, suppositories, creams, ointments , Transdermal gel, etc. The pharmaceutical composition according to the present invention comprises one or more excipients or carriers selected from the group consisting of a diluent, a lubricant, a binder, a disintegrant, a stabilizer, a preservative, an adsorbent, a colorant, and a sweetener. , Flavoring, etc.By way of non-limiting example, mention may be made of: wAs a diluent : Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol, wAs lubricant : Silicon dioxide, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, wAs a binder : Magnesium aluminum silicate, starch, gelatin, scutellaria, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone, wAs a disintegrant : Agar, alginic acid and its sodium salt, foaming mixture. The combined compounds can be administered simultaneously or sequentially. The route of administration is preferably the oral route, and the corresponding pharmaceutical composition may allow the instant or delayed release of the active ingredient. In addition, the combined compounds may be administered in the form of two separate pharmaceutical compositions each containing one of the active ingredients, or in the form of a single pharmaceutical composition in which the active ingredients are in the form of a mixture. Preference is given to pharmaceutical compositions in the form of tablets.contain 50 mg and 100 mg API compounds 1 hydrochloric acid Pharmaceutical composition of salt-coated film-coated tablet Pharmacological information Examples 1 - 3 Materials and methods : Primary AML Patient sample : Following informed consent, bone marrow or peripheral blood samples were collected from patients with AML according to guidelines approved by the Alfred Hospital Human research ethics committees. Monocytes were isolated by Ficoll-Paque (GE Healthcare, VIC, Aus) density gradient centrifugation, and red blood cells were then incubated at 37 ° C in ammonium chloride (NH₄ Cl) Consumed in lysis buffer for 10 minutes. Subsequently, the cells were resuspended in phosphate buffered saline (Sigma, NSW, Aus) containing 2% fetal bovine serum. Monocytes were then suspended in RPMI-1640 (GIBCO VIC, Aus) culture containing penicillin and streptomycin (GIBCO) and non-heat-activated fetal bovine serum 15% (Sigma). Cell lines, cell culture and luciferase-producing cell lines : Cell lines MV4; 11, OCI-AML3, HL-60, HEL, K562, KG-1 and EOL-1 at 37 ° C, 5% CO₂ It was maintained in RPMI-1640 (GIBCO) supplemented with 10% (v / v) fetal bovine serum (Sigma) and penicillin and streptomycin (GIBCO). The MV4; 11 luciferase cell line is produced by lentiviral transduction. antibody : The primary antibodies used for western blot analysis were MCL1, BCL-2, Bax, Bak, Bim, BCL-XL (produced by internal WEHI) and microtubule proteins (T-9026, Sigma). Cell viability : Regulating newly purified monocytes from AML patient samples to 2.5 × 10⁵ Concentrations / ml and 100 μL cells per well were aliquoted into 96-well plates (Sigma). Cells were then treated with Compound 1, HCl, Compound 2, ABT-199 (Active Biochem, NJ, USA) or Idarubicin (Sigma) for 48 hours across a 6 logarithmic concentration range from 1 nM to 10 μM. For combinatorial analysis, drugs were added from 1 nM to 10 μM in a 1: 1 ratio at 37 ° C, 5% CO₂ Under culture. Subsequently, the cells were stained with sytox blue nucleic acid stain (Invitrogen, VIC, Aus) and fluorescent light, and the fluorescence was measured by flow cytometry using LSR-II Fortessa (Becton Dickinson, NSW, Aus). Measurement analysis measurement. FACSDiva software is used for data collection, and FlowJo software is used for analysis. Blast cells are gated using forward and lateral dispersive properties. For each drug, live cells excluding sytox blue were measured at 6 concentrations, and a lethal concentration (LC of 50%) was measured₅₀ , In μM). LC ₅₀ Measurement and collaboration : Graphpad Prism is used to calculate LC using nonlinear regression₅₀ . Synergy is determined by calculating the composite index (CI) based on the described Chou Talalay method (Chou Cancer Res; 70 (2), January 15, 2010). Community analysis : The community formation analysis was performed on newly purified and frozen mononuclear sections from AML patients. Primary cells were cultured in a 35 mm culture dish (Griener-bio, Germany) at 1 × 10⁴ Up to 1 × 10⁵ Double replicates. Cells were 0.6% agar (Difco NSW, Aus): AIMDM 2 × (IMDM powder-Invitrogen) supplemented with NaHCO at a 2: 1: 1 ratio₃ , Polydextrose, penicillin / streptomycin, B-mercaptoethanol and asparagine): fetal bovine serum (Sigma) coating. For optimal growth conditions, all plates contain GM-CSF (100 ng per plate), IL-3 (100 ng / plate R & D system, USA) SCF (100 ng / plate R & D system), and EPO (4U / plate) ( In the presence and absence of drugs, at 37 ° C, 5% CO₂ Then, grow in a high humidity incubator for 2 to 3 weeks. After incubation, the dishes were fixed in saline with 2.5% glutaraldehyde and counted using GelCount from Oxford Optronix (Abingdon, United Kingdom). Western blot method : Lysates were prepared in NP40 lysis buffer (10 mM Tris-HCl pH 7.4, 137 mM NaCl, 10% glycerol, 1% NP40) supplemented with a protease inhibitor mixture (Roche, Dee Why, NSW, Australia). Protein samples were boiled in a reduced load dye, then separated on a 4% to 12% Bis-Tris polypropylene ammonium gel (Invitrogen, Mulgrave, VIC, Australia) and transferred to a Hybond C nitrocellulose membrane (GE, Rydalmere, NSW, Australia) for incubation with specific antibodies. All membrane blocking steps and antibody dilutions were performed using 5% (v / v) skim milk in 0.1% (v / v) Tween-20 phosphate buffered saline (PBST) or Tris buffered saline. It was performed in PBS, and the washing step was performed using PBST or TBST. Western blots are observed with enhanced chemiluminescence (GE). In vivo experiment AML transplant : Animal research was carried out under institutional guidelines approved by the Alfred Committee on Animal Ethics in the Field of Medical Research and Education.⁵ Cells were injected intravenously into mice that had been irradiated (100 Rad) with non-obese diabetes / severe combined immunodeficiency (NOD / SCID / IL2rγnull) as previously described (Jin et al.,Cell Stem Cell 2 July 2009, Volume 5, Issue 1, pages 31-42). Transplantation was measured on day 7 by quantification of the percentage of hCD45 + cells in PB by flow cytometry and by IVIS imaging of bioluminescent MV4; 11 cells. On the 10th day, mice were orally gavaged with compound 1: 1 dissolved in PEG400 (Sigma) at 40:10:60 daily, HCl (expressed as a 200 µL 100 mg / kg dose of free base), and absolute ethanol (Sigma ) And distilled water, or receive Compound 2 (200 µL 25 mg / kg) dissolved in 50% 2-hydroxypropyl) -β-cyclodextrin (Sigma) and 50% 50 mM HCl or a drug combination or Vehicle for 4 weeks. Hematology analyzers (BioRad, Gladesville, NSW) were used to determine blood counts. IVIS Imaging : Bioluminescence imaging was performed using the caliper IVIS Lumina III XR imaging system. Mice were anesthetized with isoflurane and injected 100 μL of 125 mg / kg luciferin (Perkin Elmer, Springvale, VIC) intraperitoneally.Examples 4 Materials and methods : Cell line : Human myeloma cell line (HMCL) is derived from primary myeloma cells cultured in RPMI 1640 culture supplemented with 5% fetal bovine serum and 3 ng / ml for recombination of IL-6 related cell lines IL-6. HMCL is representative of the phenotype and genomic heterogeneity and variation of patients responding to therapy. MTT analysis : Cell viability was measured using MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazole salt) colorimetric survival analysis. Cells were incubated with the compound each time in a 96-well dish containing a final volume of 100 µl / well. Use at 9 different concentrations depending on the sensitivity of a single agent (2R )-2-{[(5Sa ) -5- {3-chloro-2-methyl-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -6- (5-fluorofuran-2-yl ) Thieno [2,3-d ] Pyrimidin-4-yl] oxy} -3- (2-{[1- (2,2,2-trifluoroethyl) -1H -Pyrazol-5-yl] methoxy} phenyl) propionic acid (compound 2). Used at a fixed dose of 1 µMN -(4-hydroxyphenyl) -3- {6-[((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) -Isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl}-N -Phenyl-5,6,7,8-tetrahydro-1-indolinazinecarboxamide hydrochloride (compound 1, HCl). At the end of each treatment, cells were incubated with 1 mg / mL MTT (50 µl MTT solution 2.5 mg / ml per well) at 37 ° C for 3 hours to allow MTT metabolism. Add lysis buffer (100 µl lysis buffer: DMF (2: 3) / SDS (1: 3)) to each well to dissolve formazan cristal, and after 18 hours of incubation, use a spectrophotometer Measure the absorbance in living cells at 570 nm. As a control, cells were cultured using only cultures and cultures containing 0.1% DMSO. As a myeloma cell growth control, absorbance (D0, D1, D2, D3, and D4) of myeloma cells was recorded daily. All experiments were repeated 3 times, and each experimental condition was repeated at least three times in each experiment. The inhibition effect is calculated using the following formula: Inhibition effect (%) = (1- absorbance value of treated cells / absorbance value of control cells) * 100Examples 1 : BCL - 2 and MCL1 For performance in AML Dominant survival protein Seven AML cell lines with> 70% blasts and 13 primary AML samples were subjected to immunostaining for the indicated proteins in FIG. 1. As illustrated in Figure 1, proteome measurements of the performance of BCL-2 family members in AML show that with the exception of BCL-2, most primary AML samples and AML cell lines co-express the pro-survival protein MCL1. BCL-XL does not often appear in AML.Examples 2 : combination BCL - 2 and MCL1 Targeted at AML Co-kill 54 AML patient samples were incubated with RPMI / 15% FCS for 48 hours in 6 logarithmic concentration ranges of compound 1 (hydrochloride), compound 2 or 1: 1 concentration and measured LC₅₀ (Figure 2A). Approximately 20% of the primary AML samples are highly sensitive to either Compound 1 or Compound 2, which requires a lethal concentration of the drug that kills 50% of the primary AML blasts after 48 hours (LC₅₀ ) In the low Nemour range (LC₅₀ <10 nM) (Figure 2A). In contrast, when Compound 1 and Compound 2 were combined, the proportion of sensitive AML samples increased significantly to 70%, indicating a synergistic activity when BCL-2 and MCL1 were simultaneously targeted (Figure 2A). Some results are shown in Figure 17. To verify the in vivo activity of this pathway, MV4; 11 AML cells expressing luciferase were transplanted into NSG mice and treated with only compound 1 (hydrochloride) or compound 2 or a combination, and within 14 days of therapy and Tumor burden was assessed after 21 days (Figure 2B). Upon completion of the 28-day therapy, the mice continued to survive (Figure 2C). These experiments show that the combination of compound 1 and compound 2 is highly effective in vivo, verifying the impressive activity observed in vitro using primary AML cells. The data presented here in Figures 2A to 2C indicate a synergistic combination activity between Compound 1, HCl and Compound 2 in AML.Examples 3 : combination BCL - 2 and MCL1 Inhibition of target leukemia , But no normal progenitor function To analyze the toxicity of BCL-2 inhibition combined with MCL1 inhibition on normal human CD34 + cells or Ficolled mother cells from patients with AML, the cell population potential was analyzed after 2 weeks of exposure to combination therapy. The colonies grew on agar supplemented with 10% FCS, IL3, SCF, GM-CSF, and EPO for 14 days, and the colonies were counted using an automatic Gelcount® analyzer. The analysis of primary AML samples was performed in two and averaged. The CD34 + error represents the mean +/- SD of 2 independent normal donor samples. Results are corrected relative to the number of communities counted in the DMSO control. The specified drug concentration was spread on D1. In particular, Compound 1 + Compound 2 inhibited AML community-forming activity without affecting the function of normal CD34 + community growth. In summary, Examples 2 and 3 show that the dual pharmacological inhibition of BCL-2 and MCL1 is a novel approach for treating AML that does not require additional chemotherapy and utilizes an acceptable therapeutic safety window.Examples 4 : In response to being a single potion MCL1 Inhibitor or BCL - 2 In vitro evaluation of multiple myeloma cell survival with inhibitor combination The sensitivity of 27 human multiple myeloma cell lines to Compound 1, Compound 2, or Compound 2 in the presence of 1 μM Compound 1 was analyzed by using the MTT cell survival assay. Determination of 50% inhibitory concentration (IC₅₀ , In nM). The results are shown in the following table: When compound 1 and compound 2 were combined, a stronger synergistic activity was shown in most cell lines compared to the compound alone.Examples 5 : combination MCL1 Inhibitor with BCL - 2 Inhibitor in 17 Diffuse B Cell lymphoma ( DLBCL ) In vitro effects on proliferation in a cell line group Materials and methods The cell lines were derived from and maintained in alkaline culture supplemented with FCS (fetal bovine serum) as indicated in Table 1. In addition, all cultures contained penicillin (100 IU / ml), streptomycin (100 µg / ml), and L-glutamine (2 mM). Unless otherwise mentioned, cultures and supplements were from Amimed / Bioconcept (Allschwil, Switzerland). Cell lines at 37 ° C containing 5% CO₂ Incubate in a humid atmosphere and expand in a T-75 flask. In all cases, the cells were thawed from the frozen stock solution, expanded ≥1 passage with a suitable dilution, counted and tested for survival using a CASY cell counter (Omni Life Science, Bremen, Germany), and subsequently at the density specified in Table 1. Plate 25 μl / well into a 384-well plate (Corning). All cell lines were determined to be free of mold contamination by PCR assays performed at Idexx Radil (Columbia, MO, USA), and 48 small nucleotides were assayed by Asuragen (Austin, TX, USA) or internally The polymorphism (SNP) group excluded identification errors. Stock solutions of the compounds were prepared at a concentration of 10 mM in DMSO (Sigma) and stored at -20 ° C. When the full dose-response curve needs to be obtained, the stock solution is pre-diluted in DMSO to 1'000 times the desired starting concentration (see Table 2). On the day after cell seeding, eight 2.5-fold serial dilutions of each compound were dispensed directly to all possible arrangements individually or in a checkerboard using a non-contact 300D digital dispenser (TECAN, Männedorf, Switzerland) Cell analysis plates, as outlined in Figure 4. The final DMSO concentration in all wells was 0.2%. After 2 days of incubation, the effect of a single agent and its checkerboard combination on cell survival was analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo (Promega, Madison, WI, USA) to quantify the cell ATP content with 25 μL reagent / well and n = 2 replication disks according to the conditions. Luminescence was quantified on a M1000 multipurpose disk reader (TECAN, Männedorf, Switzerland). The number of cells / viability was similarly analyzed at compound addition and used to analyze the degree of population doubling time of a particular cell line. Calculate single-drug IC using standard four-parameter curve fit₅₀ . The potential synergistic interactions between the combinations of compounds were analyzed according to the Loewe additivity model using an excess inhibition 2D matrix and reported as a Synergy Score (Lehar et al.,Nat Biotechnol .2009 year July; 27 (7): 659-666). All calculations are performed using the internal software of the Combination Analysis Module. IC₅₀ It is defined as the concentration of the compound at which the CTG signal is reduced to 50% as measured by the vehicle (DMSO) control. The interpretation of the synergy score is as follows: SS ~ 0 → Additive SS ＞ 1 → Weak synergy SS ＞ 2 → Synergytable 1 . Conditions for identification and analysis of 17 diffuse large B-cell lymphoma cell lines in combination experiments. * This culture is further supplemented with 50 µM 2-mercaptoethanol. The doubling time was calculated based on the difference in ATP content at the end compared to the start of compound incubation.table 2. Single-agent IC for designated compound 3 and compound 1, HCl₅₀ Value, and the synergy score of the combination. When the observed score is ≥ 2.0, the interaction is considered synergistic. "Start conc" means the starting concentration. "Anhydrous IC₅₀ (Abs IC₅₀ ) '' Means anhydrous IC₅₀ . "Max Inh" means maximum inhibition. result The effects of combining MCL1 inhibitor compound 3 and BCL-2 inhibitor compound 1, HCl on proliferation were analyzed in 17 groups of diffuse large B-cell lymphoma (DLBCL) cell lines. Compound 3 as a single agent potently inhibited the growth of most of the 17 DLBCL cell lines tested (Table 1). Therefore, 14 cell lines showed an IC of less than 100 nM₅₀ And an additional 1 cell line showed 100 nM and 1μ IC between M₅₀ . Only 2 cell lines show greater than 1μ M's IC₅₀ . Compound 1, HCl as a single agent also inhibited the growth of most of the 17 DLBCL cell lines tested, although less effective (Table 2). Therefore, 2 cell lines showed an IC of less than 100 nM₅₀ And 6 cell lines showed 100 nM vs. 1μ IC between M₅₀ . 9 cell lines show greater than 1μ M's IC₅₀ (4 of them are greater than 10μ M). The combined treatment of compound 3 and compound 1, HCl caused a synergistic growth inhibition of 16 of the 17 DLBCL cell lines tested (ie, a synergy score higher than 2-Lehar et al.,Nat Biotechnol .2009 July; 27 (7): 659-666) (Table 2). Among 5 cell lines, the synergy effect was marked with a synergy score between 5 and 10. Among the 4 cell lines, the synergistic effect was superior, and a synergy score between 10 and 17.3 was obtained. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations where Compound 3 and Compound 1 themselves do not exhibit antiproliferative effects. For example, in DB cells, the second lowest concentration of compound 3 and compound 1 tested caused only 1% and 2% growth inhibition, respectively, and the corresponding combination of the two compounds achieved 96% growth inhibition (Figure 4A , Left), so it is 91% higher than the calculated additive based on single agent activity (Figure 4A, right). As another example, in Toledo cells, where compound 3 is less effective and only partial growth inhibition (46%) is obtained at the highest concentration tested, the combination with the second lowest concentration of compound 1 results in 98% synergistic growth Inhibition (Figure 4B, left panel) is therefore 52% higher than the additiveity calculated based on single agent activity (Figure 4B, right panel). In addition, it is worth noting that synergistic effects occur over a wide range of single agent concentrations, which should prove beneficial in vivo with regard to the flexibility of the dosage and arrangement. In summary, the combination of Compound 3 and Compound 1 achieved strong to superior synergistic growth inhibition in most of the DLBCL cell lines tested.Examples 6 : MCL1 Inhibitor ( Compound 3 ) and BCL - 2 Inhibitor ( Compound 1 ) Combination pair Karpas422 In vivo efficacy of xenografts Materials and methods Tumor cell culture and cell seeding Karpas 422 human B-cell non-Hodgkin's lymphoma (NHL) cell line was established from the pleural effusion of patients with anti-chemotherapy NHL. Cells were obtained from the DSMZ cell bank and contained 5% CO in the air₂ In an atmosphere at 37 ° C, supplemented with 10% FCS (BioConcept Ltd. Amimed), 2 mM L-glutamate (BioConcept Ltd. Amimed), 1 mM sodium pyruvate (BioConcept Ltd. Amimed), and 10 mM HEPES (Gibco) was cultured in a RPMI-1640 culture (BioConcept Ltd. Amimed,). The cells were maintained between 0.5 x 106 and 1.5 x 106 cells / mL. To establish Karpas 422, xenograft cells were collected and resuspended in HBSS (Gibco) and mixed with Matrigel (BD Bioscience) (1: 1 v / v), and then subcutaneously on the right abdomen of anesthetized animals with isoflurane Inject 200 µL containing 1 × 107 cells. Twenty-four hours before cell seeding, all animals were irradiated with 5 Gy for more than 2 minutes using a gadolinium-irradiator.Tumor growth After cell inoculation, tumor growth was monitored regularly and animals were randomly distributed into the treatment group when the tumor volume reached a suitable volume (n = 5). During the treatment period, calipers were used to measure tumor volume approximately twice a week. In mm³ Tumor size in units is calculated by (L × W2 × π / 6). Where W = tumor width and L = tumor length.treatment Animals (rats) carrying tumors were enrolled in the treatment group (n = 5) when their tumors reached a suitable size to form a tumor with approximately 450 mm³ The average tumor volume of the group. The treatment groups are summarized in Table 3. In vehicle for compound 3 or compound 3 over 15 minutesiv 1 h before administration of infusion, vehicle for compound 1, HCl or compound 1, HCl by oral administration (po ) Tube feeding. foriv Infusion, isoflurane / O for animals₂ Anesthesia and vehicle or Compound 3 is administered via a cannula in the tail vein. Animals were weighed on the day of dosing and the dose was adjusted according to body weight. For both compounds, the dose was 10 ml / kg.body weight Animals are weighed at least twice a week and are often tested for any obvious signs of adverse effects.Data analysis and statistical evaluation GraphPad Prism 7.00 (GraphPad Software) was used to statistically analyze tumor data. If the changes in the data are normal distribution, the data is analyzed using one-way ANOVA with post hoc Dunnett's test for comparison between the treatment group and the control group. Post hoc Tukey's test was used for comparison. Alternatively, a Kruskal-Wallis rating post hoc Dunn's test is used. Where appropriate, results are presented as mean ± SEM. As a measure of efficacy, the T / C% value was calculated at the end of the experiment according to the following formula: (Δ tumor volume^treatment / Tumor volume^Contrast ) * 100 Tumor regression is calculated according to the following formula:-(Δ tumor volume^treatment / Tumor volume^{When starting treatment} ) * 100 where Δ tumor volume represents the average tumor volume on the evaluation day minus the average tumor volume at the start of the experiment.table 3 Therapeutic group for combined efficacy of rats carrying Karpass422 xenograft When the average tumor volume is about 450 mm³ Start treatment. Compound 1, HCl was formulated in PEG400 / EtOH / Phosal 50 PG (30/10/60) and compound 3 was placed in solution. QW means once a week. result At 20 mg / kgiv Compound 3 1 hour before infusion at 150 mg / kgpo The combination treatment of Compound 1 free base caused complete regression of all Karpas422 tumors on day 30 of the start of treatment (Figure 5). After treatment was stopped on days 35 to 90, all animals in the treatment group remained tumor-free. A positive combination effect compared to the activity of a single agent was observed in the combination group. On day 34, the tumor response in the single agent Compound 3 and the combination group was significantly different from that in the vehicle group (p <0.05). The combination therapy was well tolerated based on changes in body weight (Figure 6).Examples 7 : MCL1 Inhibitor ( Compound 3 ) and BCL - 2 Inhibitor ( Compound 1 , HCl) Combination pair DLBCL Toledo In vivo efficacy of xenografts Materials and methods Cell implantation The xenograft model was established by directly subcutaneously (sc) implanting a 3 million Toledo cell suspension with 50% matrigel into the subcutaneous area of SCID / beige mice. All procedures were performed using aseptic technique. Mice were anesthetized throughout the procedure period. In general, a total of 6 animals from each group participated in the efficacy study. For single agent and combination studies, animals were administered Compound 1 via oral gavage (po) and Compound 3 was administered intravenously (iv) via the tail vein. Compound 1, HCl was formulated as a solution in PEG300 / EtOH / water (40/10/50), and compound 3 was placed in the solution. When the tumor reached approximately 220 mm on day 26 after cell implantation³ At that time, tumor-bearing mice were randomly distributed into the treatment group. The study design including dosing schedules for all treatment groups is summarized in the table below. Animals were weighed on the day of dosing and the dose was adjusted according to body weight, the dose was 10 ml / kg. Tumor size and weight were collected at randomization and thereafter collected twice a week during the study. After data collection on each day, the following data were provided: the incidence of death, the average weight of individuals and groups, and the average tumor volume of individuals and groups. For the study in the Toledo model, on day 26 after cell implantation, when the average tumor volume was about 218 to 228 mm³ At the beginning of treatment. QW means once a week.body weight ( BW ) Calculate the percentage change in weight as follows: (BW_current -BW_initial ) / (BW_initial ) × 100. Data are presented as percent weight change since the day treatment started.Tumor volume and percentage of mice remaining in the study The treatment / control (T / C) percentage value is calculated using the following formula: T / C% = 100 ´ DT / DC if DT ＞ 0 fades out% = 100 ´ DT / T₀ If DT <0 where: T = average tumor volume of the drug treatment group on the last study day; DT = average tumor volume of the drug treatment group on the last study day-average tumor volume of the drug treatment group on the initial administration day; T₀ = Average tumor volume of the drug treatment group on the fixed group day; C = average tumor volume of the control group on the last study day; and DC = average tumor volume of the control group on the last study day-average tumor of the control group on the initial administration day volume. Percentage of mice remaining in the study = 6-number of mice reaching the end point / 6 * 100Statistical Analysis All data are presented as mean ± standard error of the mean (SEM). △ Tumor volume and percent change in body weight were used for statistical analysis. Comparisons between groups were performed using a single factor ANOVA followed by a post hoc Tukey test. For all statistical evaluations, the significance level was set at p <0.05. Unless otherwise stated, the significance compared to the vehicle control group is reported. result In the Toledo model, 100 mg / kg of Compound 1 free base produced a statistically significant antitumor effect of 37% T / C. 25 mg / kg of Compound 3 produced 102% T / C with no antitumor effect (Figure 7). The combination of compound 1 + compound 3 produced 3% T / C tumor arrest, which was statistically significant compared to tumors treated with vehicle, compound 1 and compound 3 (p <0.05, analyzed by single factor variation number Test (one-way ANOVA test). Therefore, the combined inhibition of BCL-2 and MCL1 in DLBCL can produce clinical therapeutic benefits. In addition, Figure 8 shows the change in average body weight for Toledo. Compound 1, HCl and Compound 3 mice showed weight gain (1.081% and 2.3%, respectively). The combination group showed a small amount of weight loss (-3.2%). No other adverse event symptoms were observed in this study. All 6 animals survived throughout the study. In summary, Example 2, Example 6 and Example 7 show that the combination of MCL1 inhibitor and BCL-2 inhibitor is tolerated in mice and rats carrying xenografts derived from acute myeloid leukemia and human lymphoma cell lines Effective at dose, this indicates that this combination can be used to achieve a suitable therapeutic window in these diseases.Examples 8 : combination MCL1 Inhibitors and BCL - 2 Inhibitor 13 Acute myeloid leukemia ( AML ) Effects of Cell Lines on Proliferation in vitro. Materials and methods The cell lines were derived and maintained in alkaline culture supplemented with FBS (fetal bovine serum) as indicated in Table 1. In addition, all cultures contained penicillin (100 IU / ml), streptomycin (100 µg / ml), and L-glutamine (2 mM). Cell lines at 37 ° C containing 5% CO₂ Incubate in a humid atmosphere and expand in a T-150 flask. In all cases the cells were thawed from the frozen stock solution, ≥1 passage was expanded with a suitable dilution, counted using a CASY cytometer and assayed for viability, and then plated at 150 μl / well to 96 wells at the density indicated in Table 1. Intraday. All cell lines were determined to be free of internal mold contamination. Stock solutions of the compounds were prepared at a concentration of 5 mM in DMSO and stored at -20 ° C. To analyze the activity of a compound as a single agent, cells were seeded and treated with nine 2-fold serial dilutions of each compound directly administered directly to a cell analysis plate. After 3 days of incubation, the effect of compounds on cell viability was analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 75 μL reagent / well. All experiments were performed in triplicate. Luminescence is quantified on a multi-purpose disk reader. Calculate single-drug IC using standard four-parameter curve fit₅₀ . IC₅₀ It is defined as the concentration of the compound at which the CTG signal is reduced to 50% as measured by the vehicle (DMSO) control. To analyze compound activity in combination, cells were seeded and treated with 7 or 8 3.16-fold serial dilutions of each compound, and each compound was dispensed directly or in a checkerboard of all possible permutations directly into the cell analysis plate , As indicated in Figure 9. After 3 days of incubation, the effects of a single agent and its checkerboard combination on cell survival were analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 75 μL reagent / well. Two independent experiments were performed, each performed twice. Luminescence is quantified on a multi-purpose disk reader. The potential synergistic interactions between the combinations of compounds were analyzed according to the Loewe additivity model using an excess inhibition 2D matrix and reported as synergy scores (Lehar et al.,Nat Biotechnol .2009 year 7 month 27 (7): 659-666). All calculations use Clalice^TM Bioinformatics software. The doubling times indicated in Table 3 are the average of the doubling times obtained from the different generations (in T-150 flasks) of the implementation from the thawing of the cells to their inoculation in a 96-well plate. The interpretation of the synergy score is as follows: SS ~ 0 → Additive SS ＞ 1 → Weak synergy SS ＞ 2 → Synergytable 3. Conditions for identification and analysis of 13 acute myeloid leukemia (AML) cell lines in combination experiments. table 4a. Single-agent IC indicating compound 3, compound 1, HCl and ABT-199 in 13 AML cell lines₅₀ value. The compound was incubated with the cells over a period of 3 days. table 4b. Single agent IC indicating compound 4, HCl in 5 AML cell lines₅₀ value. The compound was incubated with the cells over a period of 3 days. table 5a. Synergy scores for compound 3 and compound 1 combinations in 13 AML cell lines are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. The standard deviation (sd) of the initial concentration of the compound, the mean of the maximum inhibition, and the synergy score. The compound was incubated with the cells over a period of 3 days. table 5b. Synergy scores for the combination of compound 3 and ABT-199 in 8 AML cell lines are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. The standard deviation (sd) of the initial concentration of the compound, the mean of the maximum inhibition, and the synergy score. The compound was incubated with the cells over a period of 3 days. table 5c. Synergy scores of compound 3, compound 4, and HCl combinations in 5 AML cell lines are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. The standard deviation (sd) of the initial concentration of the compound, the mean of the maximum inhibition, and the synergy score. The compound was incubated with the cells over a period of 3 days. result combination ( a ). The effects of the combined MCL1 inhibitor compound 3 and BCL-2 inhibitor compound 1 on proliferation were analyzed in a group of 13 acute myeloid leukemia (AML) cell lines. Compound 3 as a single agent potently inhibited the growth of most of the 13 AML cell lines tested (Table 4a). As a result, 10 cell lines displayed an IC of less than 100 nM₅₀ And 2 additional cell lines show ICs between 100 nM and 1 μM₅₀ . Only 1 cell line exhibits IC greater than 1 μM₅₀ . Compound 1, HCl as a single agent also inhibited the growth of several tested AML cell lines, although less effective (Table 4a). Therefore, 5 cell lines showed an IC of less than 100 nM₅₀ And 2 cell lines show ICs between 100 nM and 1 μM₅₀ . 6 cell lines display ICs greater than 1 μM₅₀ . The combined treatment of compound 3 and compound 1, HCl caused a synergistic growth inhibition (ie, a synergy score higher than 2) of the 13 cell lines tested as a whole (Table 5a). In both cell lines, the synergy effect was marked with a synergy score between 5 and 10. Among the 10 cell lines, the synergistic effect was superior, and a synergy score between 10 and 19.8 was obtained. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations where Compound 3 and Compound 1 themselves do not have antiproliferative effects. For example, in OCI-AML3 cells, the third lowest concentration of compound 3 and compound 1 tested caused growth inhibition of 5% and 1%, respectively, and the corresponding combination of the two compounds achieved 84% growth inhibition (Figure 9A, top left), so it is 79% higher than the additivity calculated based on single agent activity (Figure 9A, top right). In addition, it is worth noting that synergistic effects occur over a wide range of single agent concentrations, which should prove beneficial in vivo with regard to the flexibility of the dosage and arrangement. All in all, the combination of Compound 3 and Compound 1 provided synergistic growth inhibition in all 13 AML cell lines tested. Importantly, superior synergistic growth inhibition was observed in most of the AML cell lines tested (10/13). combination (b). The effects of the combined MCL1 inhibitor compound 3 and the BCL-2 inhibitor ABT-199 on proliferation were analyzed in a group of eight acute myeloid leukemia (AML) cell line groups. Compound 3 as a single agent potently inhibited the growth of most of the eight AML cell lines tested (Table 4a). As a result, 5 cell lines displayed an IC of less than 100 nM₅₀ And 2 additional cell lines show ICs between 100 nM and 1 μM₅₀ . Only 1 cell line exhibits IC greater than 1 μM₅₀ . ABT-199 as a single agent also inhibited the growth of AML cell lines, although less effective (Table 4a). Therefore, only 1 cell line showed an IC of less than 100 nM₅₀ And 2 cell lines show ICs between 100 nM and 1 μM₅₀ . 5 cell lines display ICs greater than 1 μM₅₀ . The combination treatment with MCL1 inhibitor and ABT-199 caused a synergistic growth inhibition (ie a synergy score higher than 2) for the entire group of 8 cell lines tested (Table 5b). In most cell lines, the synergistic effect is superior, obtaining a synergy score between 10 and 17.6. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations where the MCL1 inhibitor and ABT-199 themselves do not have antiproliferative effects. For example, in OCI-AML3 cells, the third lowest concentrations of MCL1 and ABT-199 tested caused 26% and 18% growth inhibition, respectively, and the corresponding combination of the two compounds achieved 91% growth inhibition (Figure 13, top left). In addition, it is worth noting that synergistic effects occur over a wide range of single agent concentrations, which should prove beneficial in vivo with regard to the flexibility of the dosage and arrangement. In summary, the combination of Compound 3 and ABT-199 achieved synergistic growth inhibition for all 8 AML cell lines tested. Importantly, superior synergistic growth inhibition was observed in most of the AML cell lines tested (7/8). combination (c). The effect of the combined MCL1 inhibitor compound 3 and BCL-2 inhibitor compound 4 on proliferation was analyzed in five groups of acute myeloid leukemia (AML) cell lines. Compound 3 as a single agent potently inhibited the growth of the five AML cell lines tested (Table 4b). As a result, all cell lines display ICs less than 200 nM₅₀ . Compound 4, HCl as a single agent also inhibited the growth of 4 of the 5 cell lines tested, with an IC less than or equal to 40 nM₅₀ , A cell line pair with an IC of 10 µM₅₀ Compound 4 is tolerant. The combined treatment of compound 3, compound 4, and HCl caused a synergistic growth inhibition (ie, a synergy score higher than 2) of the five cell lines tested as a whole (Table 5c). In both cell lines, the synergy effect was marked with a synergy score between 5 and 10. In one cell line, the synergistic effect was superior, and a synergy score of 16.5 was obtained. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations where Compound 4, HCl and Compound 3 themselves do not have or have a lower antiproliferative effect. For example, in OCI-AML3 cells, the third lowest concentration of compound 4, HCl and compound 3 tested caused 1% and 40% growth inhibition, respectively, and the corresponding combination of the two compounds achieved 98% growth inhibition (Fig. 1A, left panel; representing two independent experiments); therefore, 53% higher than the additiveity calculated based on single agent activity (Fig. 14A, right panel). In ML-2, the fifth lowest concentration of compound 4, HCl and compound 3 tested caused 18% and 26% growth inhibition, respectively, and the corresponding combination of the two compounds achieved 100% growth inhibition (Figure 14B, left (Figure; represents two independent experiments), and is therefore 51% higher than the calculated additivity based on single agent activity (Figure 15, right panel). In summary, the combination of compound 4 and compound 3 achieved synergistic growth inhibition for all five AML cell lines tested.Examples 9 : combination MCL1 Inhibitors and BCL - 2 Inhibitor 12 Neuroblastoma ( NB ) In vitro effects on proliferation in a cell line group Materials and methods The cell lines were derived from and maintained in FBS-supplemented alkaline cultures as indicated in Table 1. In addition, all cultures contained penicillin (100 IU / ml), streptomycin (100 µg / ml), and L-glutamine (2 mM). Cell lines at 37 ° C containing 5% CO₂ Incubate in a humid atmosphere and expand in a T-150 flask. In all cases, thawed the cells from the frozen stock solution, expanded ≥1 passage with a suitable dilution, counted and analyzed the viability using a CASY cell counter, and then plated 150 μl / well to 96 at the density indicated in Table Hole plate. All cell lines were determined to be free of internal mold contamination. Stock solutions of the compounds were prepared at a concentration of 5 mM in DMSO and stored at -20 ° C. To analyze the activity of a compound as a single agent, cells were seeded and treated with nine 3.16-fold serial dilutions of each compound directly dispensed directly into a cell analysis plate. After 2 or 3 days of incubation (as indicated in Table 6), the effect of compounds on cell survival was analyzed, and the analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 150 μL reagent / well. Two independent experiments were performed, each repeated twice. All experiments were performed in triplicate. Luminescence is quantified on a multi-purpose disk reader. Calculate single-drug IC using standard four-parameter curve fit₅₀ . IC₅₀ It is defined as the concentration of the compound at which the CTG signal is reduced to 50% as measured by the vehicle (DMSO) control. The same experiment was performed to analyze potential synergistic interactions between compound combinations. Analysis of synergy scores based on Loy's additive model using an excess suppression 2D matrix (Lehar et al.,Nat Biotechnol .2009 year July; 27 (7): 659-666). All calculations were performed using Chalice TM bioinformatics software. The doubling times indicated in Table 6 are the average of the doubling times obtained from the different generations (in T-150 flasks) of the implementation in which cells were thawed to 96-well plates. The interpretation of the synergy score is as follows: SS ~ 0 → Additive SS ＞ 1 → Weak synergy SS ＞ 2 → Synergytable 6. Conditions for identification and analysis of 12 neuroblastoma (NB) cell lines in combination experiments. table 7. Single-agent IC indicating compound 3 and compound 1, HCl₅₀ value. The compounds were incubated with the cells over a period of 2 or 3 days. table 8. Synergy scores in combination with compound 3 and compound 1, HCl are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. The compounds were incubated with the cells over a period of 2 or 3 days. result The effect of the combination of MCL1 inhibitor compound 3 and BCL-2 inhibitor compound 1 on proliferation was analyzed in a group of 12 neuroblastoma cell lines. Three of the 12 cell lines tested were sensitive to Compound 3 as a single agent (Table 7). 1 cell line exhibits IC less than 100 nM₅₀ And 2 additional cell lines show ICs between 100 nM and 1 μM₅₀ . All cell lines are tolerant to Compound 1, HCl as a single agent, where all cell lines tested exhibit ICs greater than 1 µM₅₀ . The combined treatment of compound 3 and compound 1 caused a synergistic growth inhibition of 11 of the 12 NB cell lines tested (i.e. a synergy score higher than 2-Lehar et al.,Nat Biotechnol .2009 year July; 27 (7): 659-666) (Table 8). Among the 5 cell lines, the synergistic effect was superior, and a synergy score between 10 and 17.81 was obtained. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations of Compound 3 and Compound 1, HCl itself does not exhibit antiproliferative effects. For example, in LAN-6 cells, Compound 630 and Compound 1, HCl at 630 nM elicited only 12% and 0% growth inhibition, respectively, and the corresponding combination of the two compounds achieved 95% growth inhibition (Figure 10, Top left panel), so it is 76% greater than the calculated additive based on single agent activity (Figure 10, top right panel). All in all, the combination of compound 3 and compound 1 gave strong to superior synergistic growth inhibition for most of the neuroblastoma cell lines tested.Examples 10 : combination MCL1 Inhibitors and BCL - 2 Inhibitor in 8 Each B Cell acute lymphoblastic leukemia ( B - ALL ) and 10 Each T Cell acute lymphoblastic leukemia ( T - ALL ) In vitro effects on proliferation in cell lines. Materials and methods The cell lines were derived from and maintained in FBS-supplemented alkaline cultures as indicated in Table 1. In addition, all cultures contained penicillin (100 IU / ml), streptomycin (100 μg / ml), and L-glutamic acid (2 mM). Cell lines at 37 ° C containing 5% CO₂ Incubate in a humid atmosphere and expand in a T-150 flask. In all cases, thaw cells from frozen stock solution, expand ≥1 passage using appropriate dilutions, count and analyze viability using a CASY cytometer, and then plate 150 μl / well to 96 at the density indicated in Table Hole plate. All cell lines were determined to be free of internal mold contamination. A stock solution of the compound was prepared at a concentration of 5 mM in DMSO and stored at -20 ° C. To analyze the activity of a compound as a single agent, cells were seeded and treated with nine 2-fold serial dilutions of each compound directly administered directly to a cell analysis plate. After 3 days of incubation, the effect of compounds on cell viability was analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 75 μL reagent / well. All conditions were tested in triplicate. Luminescence is quantified on a multi-purpose disk reader. Calculate single-drug IC using standard four-parameter curve fit₅₀ . IC₅₀ It is defined as the concentration of the compound at which the CTG signal is reduced to 50% as measured by the vehicle (DMSO) control. To analyze compound activity in combination, cells were seeded and treated with 7 or 8 3.16-fold serial dilutions of each compound, and each compound was dispensed directly to the cell assay plate individually or in all possible arrangements in a checkerboard fashion. , As indicated in Figure 1. After 3 days of incubation, the effect of a single agent and its checkerboard combination on cell survival was analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 75 μL reagent / well. For B-ALL cell lines, two independent experiments were performed, and each experiment performed was repeated twice. For T-ALL cell lines, one experiment was performed, which was repeated three times. Luminescence is quantified on a multi-purpose disk reader. The potential synergistic interactions between the combinations of compounds were analyzed according to the Loewe additivity model using an excess inhibition 2D matrix and reported as synergy scores (Lehar et al.,Nat Biotechnol . 2009 year July; 27 (7): 659-666). All calculations were performed using Chalice TM bioinformatics software available on the Horizon website. The doubling times indicated in Table 9 are the average of the doubling times obtained from the different generations (in T-150 flasks) of the implementation from the thawing of cells to their inoculation in a 96-well plate. The explanation of the synergy score is as follows: SS ~ 0 → Additive SS ＞ 1 → Weak synergy SS ＞ 2 → Synergytable 9. Conditions for identification and analysis of 8 B-ALL and 10 T-ALL cell lines in a combination experiment. table 10. Single agent IC indicating compound 3 and compound 1, HCl in 8 B-ALL and 10 T-ALL cell lines₅₀ value. The compound was incubated with the cells over a period of 3 days. table 11. Synergy scores for the combination of compound 3, compound 1, and HCl in 8 B-ALL and 10 T-ALL cell lines are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. The standard deviation (sd) of the initial concentration of the compound, the mean of the maximum inhibition, and the synergy score. The compound was incubated with the cells over a period of 3 days. result The effects of the combined MCL1 inhibitor and BCL-2 inhibitor on the proliferation of 8 B-ALL and 10 T-ALL cell line groups were analyzed. MCL1 inhibitors as a single agent strongly inhibited the growth of most ALL cell lines tested (Table 10). As a result, 13 ALL cell lines displayed an IC of less than 100 nM₅₀ And 2 additional ALL cell lines display ICs between 100 nM and 1 μM₅₀ . Only 3 ALL cell lines display ICs greater than 1 μM₅₀ . BCL-2 inhibitors as a single agent also inhibited the growth of several ALL cell lines tested, although they were less effective (Table 10). Therefore, 5 cell lines showed an IC of less than 100 nM₅₀ And 2 cell lines show ICs between 100 nM and 1 μM₅₀ . 11 ALL cell lines display ICs greater than 1 μM₅₀ . The combination treatment of MCL1 inhibitor and BCL-2 inhibitor caused the synergistic growth inhibition of the total 17/18 ALL cell lines tested (i.e. a synergy score higher than 2-Lehar et al.,Nat Biotechnol .2009 year July; 27 (7): 659-666) (Table 11). In 6 cell lines, the synergy effect was marked with a synergy score between 5 and 10. Among the 5 cell lines, the synergistic effect was superior, and a synergy score between 10 and 15.9 was obtained. Importantly, the synergy does not depend on the antiproliferative effect of a single agent, and in fact the synergy is particularly strong at concentrations where the MCL1 inhibitor and BCL-2 inhibitor itself do not have antiproliferative effects. For example, in NALM-6 cells, the fourth lowest concentration of MCL1 inhibitor and BCL-2 inhibitor tested caused growth inhibition of 6% and 8%, respectively, and the corresponding combination of the two compounds obtained 61% Growth inhibition (Figure 11, top left). In addition, it is worth noting that synergistic effects occur over a wide range of single agent concentrations, which should prove beneficial in vivo with regard to the flexibility of the dosage and arrangement. All in all, the combination of MCL1 inhibitor and BCL-2 inhibitor obtained synergistic growth inhibition in most (17/18) ALL cell lines tested. Importantly, superior synergistic growth inhibition was observed in 5/18 ALL cell lines tested.Examples 11 : combination MCL1 Inhibitors and BCL - 2 Inhibitor 5 Mantle cell lymphoma ( MCL ) Effects of Cell Lines on Proliferation in vitro. Materials and methods Cell lines were derived from and maintained in FBS-supplemented alkaline cultures as indicated in Table 12. In addition, all cultures contained penicillin (100 IU / ml), streptomycin (100 µg / ml), and L-glutamine (2 mM). Cell lines at 37 ° C containing 5% CO₂ Incubate in a humid atmosphere and expand in a T-150 flask. In all cases, thawed cells from frozen stock solution, expanded ≥1 passage using appropriate dilutions, counted and analyzed viability using a CASY cytometer, and then spread 150 μl / well to 96 at the density indicated in Table 12. Hole plate. All cell lines were determined to be free of internal mold contamination. Stock solutions of the compounds were prepared at a concentration of 5 mM in DMSO and stored at -20 ° C. In order to analyze the activity of the compounds in a single agent or combination, cells were seeded and treated with 7 or 8 3.16-fold serial dilutions of each compound, and each compound was dosed directly to the cells individually or in all possible permutations Analyze the disk. After 2 days of incubation, the effect of a single agent and its checkerboard combination on cell survival was analyzed. The analysis was performed at 37 ° C / 5% CO₂ The following was performed by using CellTiterGlo to quantify the cellular ATP content at 150 μL reagent / well. All conditions were tested in triplicate. Luminescence is quantified on a multi-purpose disk reader. Potential synergistic interactions between compound combinations were analyzed using the Loewe additivity model using an excess inhibition 2D matrix and reported as a synergy score (Lehar et al., Nat Biotechnol.2009 year July; 27 (7): 659-666). All calculations use Chalice available on the Horizon website^TM Bioinformatics software. Calculate single-drug IC using standard four-parameter curve fit₅₀ . IC₅₀ It is defined as the concentration of the compound at which the CTG signal is reduced to 50% as measured by the vehicle (DMSO) control. The doubling times indicated in Table 12 are the average of the doubling times obtained from the different generations (in T-150 flasks) of the implementation of the cell thawing to its inoculation in a 96-well plate.Synergy score SS ~ 0 → Additive SS ＞ 1 → Weak cooperation SS ＞ 2 → Cooperationtable 12. Conditions for identification and analysis of five sets of cell lymphoma cell lines in combination experiments.table 13. Single agent IC indicating compound 3 and compound 1, HCl in 5 mantle cell lymphoma cell lines₅₀ value. The compound was incubated with the cells over a period of 2 days. table 14. Synergy scores of compound 3, compound 1, and HCl combinations in 5 mantle cell lymphoma cell lines are indicated. When the observed score is ≥ 2.0, the interaction is considered synergistic. Indicates the starting concentration, maximum inhibition, and synergy score of a compound. The compound was incubated with the cells over a period of 2 days. result The in vitro effects of combined MCL1 inhibitors and BCL-2 inhibitors on the proliferation of 5 mantle cell lymphoma cell line groups were analyzed. As a single agent, MCL1 inhibitors exhibit superior activity over BCL-2 inhibitors. Therefore, 3 cell lines against MCL1 inhibitors exhibited ICs of less than 100 nM₅₀ However, only one cell line against BCL-2 inhibitors showed an IC of less than 100 nM₅₀ (Table 13). The combination treatment of MCL1 inhibitor and BCL-2 inhibitor caused synergistic growth inhibition of all tested cell lines (Table 14) (i.e. a synergy score higher than 2-Lehar et al.,Nat Biotechnol .2009 year July; 27 (7): 659-666), as exemplified in Figure 12. It is important that synergy effects are marked with synergy scores higher than 5 in 4/5 cell lines.Examples 12 : combination MCL1 Inhibitors and BCL - 2 Inhibitor 5 Small cell lung cancer ( SCLC ) Effects of Cell Lines on Proliferation in vitro. All cell lines were obtained from ATCC. RPMI1640 (Invitrogen) -containing culture supplemented with 10% FBS (Hyclone) for COR-L95, NCI-H146, NCI-H211, SHP-77, SW1271, NCI-H1339, NCI -H1963 and NCI-H889. Waymouth's MB 752/1 (Inverlogen) -containing culture with 10% FBS was used for DMS-273. 5% FBS with DMEM / F12 (Inverogan) supplemented with 0.005 mg / ml insulin, 0.01 mg / ml transferrin and 30 nM sodium selenite solution (Inverogen), 10 nM hydrogen cortex A culture of ketone (Sigma), 10 nM β-estradiol (Sigma), and 2 mM L-glutamate (sea clone) was used for NCI-H1105. At 37 ℃ and 5% CO₂ Cell lines were grown in incubators and expanded in T-75 flasks. In all cases, cells were thawed from the frozen stock solution, ≥1 passage was expanded using a 1: 3 dilution, counted and analyzed for viability using a ViCell counter (Beckman-Coulter), and then plated in 384-well plates. To isolate and expand cell lines, cells were removed from flasks using 0.25% trypsin-EDTA (GIBCO). All cell lines were determined to be free of mycelial contamination as determined by PCR detection method performed in Idexx Radil (Columbia, MO, USA) and properly confirmed by SNP panel detection. Cell proliferation was measured in a 72-hour CellTiter-Glo ™ (CTG) analysis (Promega G7571), and all results shown are the results of at least three replicate measurements. For CellTiter-Glo ™ analysis, cells were dispensed into tissue culture-treated 384-well dishes (Corning 3707) with a final volume of 35 μL of culture and a density of 5000 cells per well. After 24 hours of plating, 5 μL of each compound dilution group was transferred to a cell-containing plate, resulting in a compound concentration in the range of 0 to 10 μM and a final DMSO (Sigma D8418) concentration of 0.16%. Incubate the dish for 72 hours and use CellTiter-Glo^TM Luminescent cell survival analysis (Promega G7571) and Envision disk reader (Perkin Elmer) were used to determine the effect of compounds on cell proliferation. CellTiter-Glo® Luminous Cell Survival Analysis is a homogeneous method for determining the number of living cells in culture based on the amount of ATP present, which indicates the presence of metabolically active cells. This method is described in detail in Technical Bulletin, TB288 Promega. Briefly, cells were plated in opaque wall multiwell plates in cultures as described above. Control wells containing culture without cells were also prepared to obtain background luminescence values. 15 μL of CellTiter-Glo® reagent was then added and the contents were mixed on an orbital shaker for 10 minutes to induce the cells to break down. Luminescence was then recorded using a disc reader. Chalice software (CombinatoRx, Cambridge MA) was used to analyze growth inhibition and percentage of excessive inhibition. The percentage of growth inhibition relative to DMSO is shown in plated inhibition, and the amount of inhibition exceeds the expected amount in plated ADD excess inhibition (Figure 15 (a) to Figure 15 (e)). The concentration of Compound 1, HCl is shown along the bottom column from left to right and the increased concentration of Compound 3 is shown along the leftmost row from bottom to top. All remaining points in the grid display are generated by a combination of two inhibitors corresponding to a single agent concentration indicated on two axes. Data analysis using cell proliferation was described in Lehar et al.,Nat Biotechnol .2009 year Implemented by Chalice Analyser in July; 27 (7): 659-666. The Loewe synergy model was used to calculate the excess inhibition, and its effect on growth was measured relative to the expected growth when the two drugs were presented in a single dose. Positive numbers indicate areas where synergy is increased.Synergy score SS ~ 0 → Dose additive SS ＞ 2 → Synergy SS ＞ 1 → Weak synergy result The combined treatment of compound 1 and compound 3 caused a synergistic growth inhibition (ie, a synergy score higher than 2) of 8/10 small cell lung cancer cell lines. It is important that synergy effects are marked with a synergy score higher than 6 in 6 cell lines.Examples 13 : MCL1 Inhibitor ( Compound 3 ) and BCL - 2 Inhibitor ( Compound 1 , HCl or ABT - 199 ) Patient-derived primary AML model HAMLX5343 In vivo efficacy Materials and methods material animal Prior to manipulation, female mice with immunodeficiency gamma (NOD scid gamma; NSG) weighing 17 to 27 grams (Jackson Laboratories) were allowed to freely access food and water for 3 days to adapt to the new environment.Primary tumor model carryKRAS Mutated patient-derived primary AML model HAMLX5343 and wild typeFLT3 Obtained from the Dana Farber Cancer Institute.Test compound , Formulation Compound 1, HCl was formulated as a solution in 5% ethanol, 20% Dexolve-7 for intravenous administration, or in PEG300 / EtOH / water (40/10/50) for oral administration. ABT-199 is formulated in PEG300 / EtOH / water (40/10/50) for oral administration. All of them are stable for at least one week at 4 ° C. Compound 3 was formulated as a solution in a lipid formulation for intravenous formulation, which formulation was stable at 4 ° C for 3 weeks. Vehicle and compound administration solutions are prepared as needed. All animals were administered Compound 1 (expressed as free base) or ABT-199 at 10 mL / kg, or Compound 3 at 5 mL / kg.method Research design Eight treatment groups were used in the study 7844HAMLX5343-XEF, as outlined in Table 15. When the average tumor burden (% of CD-45 positive cells) is between 8% and 15%, all treatments are initiated. In this study, as a single agent, Compound 1 was administered by oral gavage (po) or intravenously at 50 mg / kg once a week, and ABT-199 was administered by oral gavage (po) at 25 mg / kg It was administered once a week, or Compound 3 was administered once a week at 12.5 mg / kg for 18 days. Both Compound 1 (expressed as free base) and ABT-199 were administered at 10 mL / kg. Compound 3 was administered at 5 mL / kg. The dose is adjusted according to body weight. Body weight was recorded twice a week and tumor burden was recorded once a week. Table 15. Dose * and dose schedule for 7844HAMLX5343-XEF * Free base Primary AML model For this experiment, 32 mice were implanted with the primary AML strain HAMLX5343. Mice were injected intravenously with 2.0 million leukemia cells. When the tumor burden was between 8% and 15%, the animals were randomly distributed into 8 groups of 4 mice each, each for vehicle, compound 1 (po), compound 1 (iv), ABT-199, Compound 3 or combination therapy. After 18 days of treatment, the study was terminated when the tumor load reached 99%. Tumor burden was measured by FACS analysis.Animal monitoring Monitor animal health and behavior twice daily, including trimming and movement. Mice were monitored for overall health and mortality was recorded daily. Kill any dying animal.Tumor measurement Mice draw blood via tail trimming once a week. The blood was divided into IgG control wells and CD33 / CD45 wells in a 96-well plate. Blood was lysed twice with 200 µl of RBC lysis buffer at room temperature and then washed once with FACS buffer (5% FBS in PBS). Subsequently, the samples were incubated in 100 µl of blocking buffer (5% mouse Fc block + 5% human Fc block + 90% FACS buffer) at 4 ° C for 10 to 30 minutes. Add 20 µl IgG control mixture (2.5 µl mouse igG1 K isotype control-PE + 2.5 µl mouse igG1 K isotype control-APC + 15 µl FACS buffer) to IgG control wells and 20 µl CD33 / CD45 mixture (2.5 µl Mouse anti-human CD33-PE + 2.5 µl mouse anti-human CD45-APC + 15 µl FACS buffer). Prior to analysis, samples were incubated at 4 ° C for 30 to 60 minutes and then washed twice. The samples were run on Canto with FACSDiva software. Analysis was performed using FloJo software. The percentage of CD45-positive living single cells is reported as tumor burden.ANALYSE information The treatment / control (T / C) percentage value is calculated using the following formula:% T / C = 100 ´ DT / DC if DT> 0% regression = 100 ´ DT / T_initial , If DT <0 where: T = mean tumor load of the drug treatment group on the last study day; DT = mean tumor load of the drug treatment group on the last study day-average tumor load of the drug treatment group on the initial administration day; T_initial = Average tumor burden of the drug treatment group on the day of initial administration; C = average tumor burden of the control group on the last study day; and DC = average tumor load of the control group on the last study day-average of the control group on the initial administration day Tumor burden. All data are presented as mean ± SEM. △ Tumor load and weight were used for statistical analysis. Comparisons between groups of final measurements were performed using the ANOVA of the Duke's test. GraphPad Prism was used for statistical analysis.Statistical Analysis All data are presented as mean ± standard error of the mean (SEM). △ Tumor volume and weight were used for statistical analysis. Kruskal-Wallis ANOVA was used for comparison between groups, followed by post hoc Dunn's test or Tukey's test. For all statistical evaluations, the significance level was set at p <0.05. Unless otherwise stated, the significance compared to the vehicle control group is reported. Standard protocols for pharmacological studies do not predetermine efficacy to demonstrate the statistically significant superiority of the combination over the corresponding single agent treatment. Statistical power is often limited by effective single agent response and / or model variation. However, p-values are provided for combination versus single agent treatments. result Of combination MCL1 and BCL - 2 Synergistic antitumor effect In the 7844HAMLX5343-XEF study, once a week at 50 mg / kg (oral oriv ), 25 mg / kg (oral) or 12.5 mg / kg (iv ) When administered, only Compound 1, ABT-199 or Compound 3 is carryingKRAS The mutant HAMLX5343 model did not show antitumor activity (98%, 92%, 98%, or 99% T / C%, respectively, p> 0.05). In this model, compound 3 (12.5 mg / kg) was compounded with 50 mg / kg of compound 1 or 25 mg / kg of ABT-199 once a week.iv ) Oral administration leads to tumor stasis (T / C% of 3% or 6%, p <0.05). On the other hand, the intravenous administration of the combination of Compound 1 and Compound 3 caused almost complete regression of the tumor (100% regression), which was significantly different from a single agent (p <0.05) or Compound 1 / Compound 3 po /iv combination. The average tumor burden of each treatment group was plotted against time for the 18-day treatment period, as shown in FIG. 1. Changes in tumor burden, T / C%, or% regression are presented in Table 16 and Figures 16 (a) to 16 (b).table 16. Overview of Antitumor Effects in 7844HAMLX5343-XEF Studies * p ＜ 0.05 compared with vehicle and single agent (ANOVA, Tukey's test) ** p ＜ 0.05 comparedpo / iv Combination (ANOVA, Duke's Test) in conclusion AML is an aggressive and heterogeneous malignant hematological disease caused by the transformation of hematopoietic progenitor cells obtained by genetic modification (Patel et al.,New England Journal of Medicine 2012 366: 1079-1089). The 5-year survival rate of AML is lower due to the lack of effective therapies. Apoptosis escape is characteristic of cancer (Hanahan et al.Cell 2000 100: 57-70) One of the main means by which cancer cells escape from apoptosis is to promote the survival of BCL-2 family proteins, such as BCL-2, BCL-xL, and MCL1. The MCL1 gene is the most commonly amplified gene in cancer patients. (Beroukhim et al., Nature 2010 463: 899-905). In addition, both BCL-2 and MCL1 are highly expressed in AML. Therefore, the combination of compound 1 (BCL-2i) and compound 3 (MCL1) can provide synergy as a universal mechanism against AML by enhancing pro-apoptotic signals. Here we show that BCL-2 inhibitor compound 1 or ABT-199 binding compound 3 (MCL1 inhibitor) has a significant synergistic effect in the treatment of AML in an AML xenograft model with a KRAS mutation (wt FLT3).iv / iv Compound 1 / Compound 3 combination is better than the same dosepo / iv Combination therapy. The results indicate that the combination of BCL-2 and MCL1 inhibitors will be an effective therapy for AML.

Figure 1. The performance of BCL - 2 and MCL1 is common in AML . Immune dot blot method was performed on 7 AML cell lines with> 70% mother cells and 13 primary AML samples, which showed the major expression of BCL-2 and MCL1 proteins, and in a lower proportion of samples The performance of BCL-XL contrasts. Figure 2. The combined BCL - 2 / MCL1 targeting has synergistic activity against AML in vitro and in vivo. (A) 54 primary AML samples with compound 1 (hydrochloride), compound 2 in a 6 logarithmic concentration range or incubate for 48 hours at 1: 1 concentration in RPMI / 15% FCS and determine LC ₅₀ Four groups of mice were transplanted with MV4; 11 cells expressing luciferase. Tumor transplantation was verified on day 10 (baseline), and then Compound 1, HCl was administered orally (as free base) at 100 mg / d on weekdays or Compound 2 was administered twice a week at 25 mg / kg IV For 4 weeks. The effect of Compound 2 and the combination with Compound 1 was demonstrated by a decrease in luciferase volume, and an increase in overall survival, 14 and 28 days after initiation of treatment (C). Figure 3. Toxicity assay of combined BCL - 2 / MCL1 targeting normal CD34 + cells or leukemia blasts from normal donors . Classified normal CD34 + or leukemia blasts were plated and treated with Compound 1, HCl and Compound 2 at a 1: 1 ratio of the specified concentration. The combined compound 1 + compound 2 is toxic to leukemia but non-toxic to normal CD34 + progenitor cells. 4. In FIG DB cells (A) and Toledo (Toledo) cells (B), and compound 3 from compound 1 HCl The obtained cell growth (left), and inhibition Loewe (Loewe) inhibition excess (right) cells Growth inhibition effect and synergistic combination matrix. The value of the effect matrix ranges from 0 (no inhibition) to 100 (complete inhibition). The values of the synergy matrix represent the extent to which growth inhibition exceeds the theoretical additiveness calculated based on the single agent activity of the tested concentrations of Compound 3 and Compound 1, HCl. Synergistic effects occur across a wide range of single agent concentrations. Figure 5. Antitumor effects of compound 1 , HCl , compound 3, and compound 1 , HCl + compound 3 in a rat lymphoma Karpass422 xenograft model . Figure 6. Changes in body weight of animals treated with a combination of Compound 1 , HCl , Compound 3, and Compound 1 , HCl + Compound 3 in a rat lymphoma Karpass422 xenograft model . Figure 7. Antitumor effects of compound 1 , HCl , compound 3, and compound 1 , HCl + compound 3 in a mouse DLBCL Toledo xenograft model. Figure 8. Body weight changes in animals treated with a combination of Compound 1 , HCl , Compound 3, and Compound 1 , HCl + Compound 3 in a mouse DLBCL Toledo xenograft model . FIG. 9 (A) and (B) of the two independent experiments, in the AML cell lines OCI -. AML3 by Compound 3 (MCL1 inhibitor) and Compound 1, HCl - to obtain the (BCL 2 inhibitors) Cell Growth ( Left ) Cell growth inhibitory effects and synergistic combination matrices of inhibitory and Loy overinhibition ( right ) . The value of the effect matrix ranges from 0 (no inhibition) to 100 (complete inhibition). The values of the synergy matrix represent the extent to which growth inhibition exceeds the theoretical additiveness calculated based on the single agent activity of the tested concentrations of Compound 3 and Compound 1, HCl. Synergistic effects occur across a wide range of single agent concentrations. FIG 10 (A) and (B) of the two independent experiments, the cell line NB LAN -. 6 from the compound 3 (MCL1 inhibitor) and Compound 1, HCl - to obtain the (BCL 2 inhibitors) Cell Growth ( Left ) Inhibition and synergistic combination matrices of inhibitory and Roy over-inhibition ( right ) ( N1 : upper picture ; N2 : lower picture ) . The value of the effect matrix ranges from 0 (no inhibition) to 100 (complete inhibition). The values of the synergy matrix represent the extent to which growth inhibition exceeds the theoretical additiveness calculated based on the single agent activity of the tested concentrations of Compound 3 and Compound 1, HCl. 11. In FIG two independent experiments, the B - ALL cell lines NALM - 6 from Compound 3 (MCL1 inhibitor) and Compound 1, HCl (BCL - 2 inhibitor) to obtain the cell growth (left) and Los inhibition excess inhibition Yi (right) and a synergistic cytostatic effect of combining matrix (N1: figure; N2: lower panel). Figure 12. Cell growth ( left ) and Loy excess inhibition ( right ) of cell growth obtained from compound 3 ( MCL1 inhibitor ) and compound 1 , HCl ( BCL - 2 inhibitor ) in MCL cell line Z - 138 Inhibition effect and synergistic combination matrix. Figure 13. In two independent experiments , cell growth ( left ) and Loy excess inhibition obtained from compound 3 ( MCL1 inhibitor ) and ABT - 199 ( BCL - 2 inhibitor ) in AML cell line OCI - AML3 ( Right ) Cell growth inhibition effect and synergistic combination matrix ( N1 : upper picture ; N2 : lower picture ) . 14. FIG AML cell lines by compounds 3 (MCL1 inhibitor) and the compound 4, HCl (BCL - 2 inhibitors) to obtain the growth of cells (left) and Loy inhibiting excessive inhibition (right) Exemplary cytostatic effect and a synergistic combination of a matrix (ML - 2 cells in A and OCI - AML - 3 in B). Figure 15 (a) to (e). Inhibition ( left ) , Loy surplus inhibition ( middle ) obtained from compound 3 ( MCL1 inhibitor ) and compound 1 , HCl ( BCL - 2 inhibitor ) in SCLC cell line group ) And growth inhibition dose matrix. Figures 16 (a) to (b). Combination of compound 1 , HCl , ABT - 199 , compound 3 and compound 1 , HCl or ABT - 199 + compound 3 in a mouse-derived patient-derived primary AML model HAMLX5343 Antitumor effect. FIG 17. AML of BH3 - Analog monotherapy, or a pharmaceutical composition (a 1: 1 ratio test) FIG comparative heat sensitive (LC ₅₀₎ with respect to chemotherapy (doxorubicin Ida after 48 hours of exposure; idarubicin ) . Cell viability of each primary AML sample after 48 hours in DMSO is shown .

Claims (46)

A combination comprising: (a) a BCL-2 inhibitor of formula (I): Among them: X and Y represent a carbon atom or a nitrogen atom, it should be understood that they may not represent two carbon atoms or two nitrogen atoms at the same time. A ₁ and A ₂ together with the atom carrying them form a substituted by 5, 6 or An aromatic or non-aromatic heterocyclic ring Het composed of 7 ring members, in addition to nitrogen represented by X or Y, may also contain 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen. It should be understood The nitrogen in question may be substituted by a group representing a hydrogen atom, a straight or branched (C ₁ -C ₆ ) alkyl group, or a group -C (O) -O-Alk, where Alk is straight or branched (C ₁ -C ₆ ) alkyl, or A ₁ and A ₂ each independently represent a hydrogen atom, straight or branched (C ₁ -C ₆ ) polyhaloalkyl, straight or branched (C ₁ -C ₆ ) Alkyl or cycloalkyl, T represents a hydrogen atom, optionally a straight or branched chain (C ₁ -C ₆ ) alkyl, or a group (C ₁ -C ₄ ) alkane substituted with 1 to 3 halogen atoms A group -NR ₁ R ₂ or a group (C ₁ -C ₄ ) alkyl-OR ₆ , R ₁ and R ₂ each independently represent a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, or R ₁ and R ₂ form with the nitrogen atom which carries the heterocycloalkyl group, R ₃ represents a linear or branched (C ₁ -C ₆₎ Group, a linear or branched (C ₂ -C ₆₎ alkenyl group, a linear or branched (C ₂ -C ₆₎ alkynyl, cycloalkyl, (C ₃ -C ₁₀₎ cycloalkyl - (C ₁ -C ₆ ) alkyl, in which the alkyl moiety is a straight or branched, heterocycloalkyl, aryl, or heteroaryl group, it should be understood that one of the carbon atoms of the foregoing group or the carbon atom of its possible substituents One or more may be deuterated, R ₄ represents aryl, heteroaryl, cycloalkyl or straight or branched (C ₁ -C ₆ ) alkyl, it should be understood that the carbon atom of the foregoing group or its possible substitution One or more of the carbon atoms of the radical may be deuterated, R ₅ represents a hydrogen or halogen atom, a straight or branched (C ₁ -C ₆ ) alkyl or a straight or branched (C ₁ -C ₆ ) alkane An oxygen group, R ₆ represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group, and R _a , R _b , R _c, and R _d each independently represent R ₇ , a halogen atom, a straight chain, or a branch (C ₁ -C ₆ ) alkoxy, hydroxy, straight or branched (C ₁ -C ₆ ) polyhaloalkyl, trifluoromethoxy, -NR ₇ R ₇ ', nitro, R _7- CO- (C ₀ -C ₆ ) alkyl-, R ₇ -CO-NH- (C ₀ -C ₆ ) alkyl-, NR ₇ R ₇ '-CO- (C ₀ -C ₆ ) alkyl-, NR ₇ R ₇ '-CO- (C ₀ -C ₆ ) alkyl -O-, R ₇ -SO ₂ -NH- (C ₀ -C ₆ ) alkyl-, R ₇ -NH-CO-NH- (C ₀ -C ₆ ) alkyl-, R ₇ -O-CO- NH- (C ₀ -C ₆ ) alkyl-, heterocycloalkyl or a substituent of one of (R _a , R _b ), (R _b , R _c ), or (R _c , _Rd ) The carbon atoms carrying it together form a ring composed of 5 to 7 ring members, which may contain 1 to 2 heteroatoms selected from oxygen and sulfur. It should also be understood that one or more carbon atoms of the ring defined above may be Deuterated or substituted with 1 to 3 groups selected from halogen and straight or branched (C ₁ -C ₆ ) alkyl groups, R ₇ and R ₇ 'independently of each other represent hydrogen, straight or branched chain (C _1- C ₆ ) alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, aryl or heteroaryl, or R ₇ and R ₇ 'together with the nitrogen atom carrying it forms a heterocyclic ring composed of 5 to 7 ring members. It should be understood that when the compound of formula (I) contains a hydroxyl group, the latter may optionally be converted into one of the following groups:- OPO (OM) (OM ') , - OPO (OM) (OM 1 +), - OPO (OM 1 +) (OM 2 +), - OPO (O -) (O -) M ₃ ^{2 +} , -OPO (OM) (O [CH ₂ CH ₂ O] _n CH ₃ ) or -OPO (O ^- M ₁ ⁺ ) (O [CH ₂ CH ₂ O] _n CH ₃ ), wherein M and M 'independently of each other represent a hydrogen atom, a straight or branched (C ₁ -C ₆ ) alkyl, a straight or branched (C ₂ -C ₆ ) alkenyl, a straight or branched chain (C ₂ -C ₆ ) alkynyl, cycloalkyl, or heterocycloalkyl, both of which are composed of 5 to 6 ring members, and M ₁ ⁺ and M ₂ ⁺ independently represent a pharmaceutically acceptable monovalent cation , M ₃ ^{2 +} represents a pharmaceutically acceptable divalent cation, and n is an integer of 1 to 5, it should be understood that: "aryl" means phenyl, naphthyl, biphenyl or indenyl, "heteroaryl By `` radical '' is meant any monocyclic or bicyclic radical consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen (including quaternary nitrogen) "Cycloalkyl" means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members, and "heterocycloalkyl" means any consisting of 3 to 10 ring members and containing 1 to 3 A monocyclic or bicyclic non-aromatic condensed group or spiro group of heteroatoms selected from oxygen, sulfur, SO, SO ₂ and nitrogen, such aryl, heteroaryl, cycloalkyl and Heterocycloalkyl, and such groups Alkyl, alkenyl, alkynyl and alkoxy are substituted by 1 to 3 groups selected from the group consisting of hydroxyl, morpholine, 3-3-difluoropiperidine or 3-3-difluoro, as appropriate Pyrrolidine-substituted linear or branched (C ₁ -C ₆ ) alkyl; (C ₃ -C ₆ ) spirocyclic ring; optionally, linear or branched (C ₁ -C ₆ ) alkoxy substituted with morpholine (C ₁ -C ₆ ) alkyl-S-; hydroxyl; pendant oxygen; N -oxide; nitro; cyano; -COOR ';-OCOR';NR'R"; straight or branched (C ₁ -C ₆ ) polyhaloalkyl; trifluoromethoxy; (C ₁ -C ₆ ) alkylsulfonyl; halogen; aryl optionally substituted with one or more halogens; heteroaryl; Aryloxy; arylthio; cycloalkyl; heterocycloalkyl optionally substituted with one or more halogen atoms or alkyl, wherein R 'and R "independently represent each other a hydrogen atom or optionally methoxy A substituted or unbranched (C ₁ -C ₆ ) alkyl group, the Het group as defined in formula (I) may be selected from 1 to 3 straight or branched (C ₁ -C ₆ ) alkanes group, a hydroxyl group, a linear or branched (C ₁ -C ₆₎ alkoxy, NR ₁ 'R ₁ ", and the halo substituted group, it should be understood that R _1' and R _1" as mentioned above on the As defined by equivalent groups R 'and R ", or its enantiomers, diastereomers, or addition salts thereof with pharmaceutically acceptable acids or bases, and (b) MCL1 inhibitors , Simultaneously, sequentially or separately. A combination comprising: (a) a BCL-2 inhibitor and (b) an MCL1 inhibitor of formula (II): Where: A represents a linear or branched (C ₁ -C ₆ ) alkyl, a linear or branched (C ₂ -C ₆ ) alkenyl, a linear or branched (C ₂ -C ₆ ) alkynyl, straight Chain or branched (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, straight or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxyl, cyano, -NW ₁₀ W ₁₀ ', -Cy ₆ or a halogen atom, W ₁ , W ₂ , W ₃ , W ₄ and W ₅ each independently represent a hydrogen atom, a halogen atom, a straight chain or a branched chain (C ₁ -C ₆ ) Alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, straight or branched (C ₁ -C ₆ ) polyhaloalkyl, Hydroxyl, linear or branched (C ₁ -C ₆ ) alkoxy, -S- (C ₁ -C ₆ ) alkyl, cyano, nitro, -alkyl (C ₀ -C ₆ ) -NW ₈ W ₈ ', -O-Cy ₁ , -alkyl (C ₀ -C ₆ ) -Cy ₁ , -alkenyl (C ₂ -C ₆ ) -Cy ₁ , -alkynyl (C ₂ -C ₆ ) -Cy ₁ , -O-alkyl (C ₁ -C ₆ ) -W ₉ , -C (O) -OW ₈ , -OC (O) -W ₈ , -C (O) -NW ₈ W ₈ ', -NW ₈ -C (O) -W ₈ ', -NW ₈ -C (O) -OW ₈ ', -alkyl (C ₁ -C ₆ ) -NW ₈ -C (O) -W ₈ ', -SO ₂ -NW ₈ W ₈ ', -SO ₂ -alkyl (C ₁ -C ₆ ), or when grafted to two adjacent carbon atoms, for (W ₁ , W ₂ ), (W ₂ , W ₃ ), (W ₁ , W ₃ ), (W ₄ , W ₅ ), together with the carbon atom carrying it, form a substituent of 5 to 7 ring members The aromatic or non-aromatic ring formed may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the resulting ring may be selected from linear or branched (C ₁ -C ₆ ) alkyl groups. , -NW ₁₀ W ₁₀ ', -alkyl (C ₀ -C ₆ ) -Cy ₁ or a group substituted with a pendant oxygen group, X' represents a carbon atom or a nitrogen atom, W ₆ represents hydrogen, a straight chain or a branched chain ( C ₁ -C ₈ ) alkyl, aryl, heteroaryl, arylalkyl (C ₁ -C ₆ ) group, heteroarylalkyl (C ₁ -C ₆ ) group, W ₇ represents straight chain Or branched (C ₁ -C ₆ ) alkyl, straight or branched (C ₂ -C ₆ ) alkenyl, straight or branched (C ₂ -C ₆ ) alkynyl, -Cy ₃ , -alkyl (C ₁ -C ₆ ) -Cy ₃ , -alkenyl (C ₂ -C ₆ ) -Cy ₃ , -alkynyl (C ₂ -C ₆ ) -Cy ₃ , -Cy ₃ -Cy ₄ , -alkynyl ( C ₂ -C ₆ ) -O-Cy ₃ , -Cy ₃ -alkyl (C ₀ -C ₆ ) -O-alkyl (C ₀ -C ₆ ) -Cy ₄ , halogen atom, cyano, -C ( O) -W ₁₁ or -C (O) -NW ₁₁ W ₁₁ ′, W ₈ and W ₈ ′ independently of each other represent a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl group or an -alkyl group ( C ₀ -C ₆ ) -Cy ₁ , or (W ₈ , W ₈ ′) together with the nitrogen atom carrying it to form an aromatic or non-aromatic ring composed of 5 to 7 ring members, in addition to the nitrogen atom, it also It may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. It should be understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (C ₁ -C ₆ ) alkyl group, and should It is understood that one or more carbon atoms of possible substituents may be deuterated, and W ₉ represents -Cy ₁ , -Cy ₁ -alkyl (C ₀ -C ₆ ) -Cy ₂ , -Cy ₁ -alkyl (C _0- C ₆ ) -O-alkyl (C ₀ -C ₆ ) -Cy ₂ , -Cy ₁ -alkyl (C ₀ -C ₆ ) -NW ₈ -alkyl (C ₀ -C ₆ ) -Cy ₂ ,- Cy ₁ -Cy ₂ -O-alkyl (C ₀ -C ₆ ) -Cy ₅ , -C (O) -NW ₈ W ₈ ', -NW ₈ W ₈ ', -OW ₈ , -NW ₈ -C ( O) -W ₈ ', -O-alkyl (C ₁ -C ₆ ) -OW ₈ , -SO ₂ -W ₈ , -C (O) -OW ₈ , -NH-C (O) -NH-W ₈ , or It is possible that the ammonium thus defined exists in the form of zwitterions or has a monovalent counter ion, and W ₁₀ , W ₁₀ ′, W ₁₁ and W ₁₁ ′ independently represent hydrogen atoms or optionally substituted straight or branched chains ( C ₁ -C ₆₎ alkyl, W ₁₂ represents hydrogen or hydroxy, W ₁₃ represents a hydrogen atom or a linear or branched (C ₁ -C ₆₎ alkyl, W ₁₄ represents ^{-OP (O) (O -)} ( O ^{-) group, -OP (O) (O -} ) (OW 16) _{group, -OP (O) (OW 16} ) (OW 16 ') groups, -O-SO ₂ -O ^- group, -O-SO ₂ -OW ₁₆ group, -Cy ₇ , -OC (O) -W ₁₅ group, -OC (O) -OW ₁₅ group, or -OC (O) -NW ₁₅ W ₁₅ 'group , W ₁₅ and W ₁₅ 'independently of each other represent a hydrogen atom, a straight or branched (C ₁ -C ₆ ) alkyl group or a straight or branched amine (C ₁ -C ₆ ) alkyl group, W ₁₆ and W ₁₆ 'independently of each other represents a hydrogen atom, a linear or branched (C ₁ -C ₆ ) alkyl or arylalkyl (C ₁ -C ₆ ) group, Cy ₁ , Cy ₂ , Cy ₃ , Cy ₄ , Cy ₅ , Cy ₆ and Cy ₇ independently represent cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and n is an integer equal to 0 or 1. It should be understood that “aryl” means phenyl, naphthalene Radical, biphenyl, dihydroindenyl or "Heteroaryl" means any monocyclic or bicyclic group consisting of 5 to 10 ring members, which has at least one aromatic moiety and contains 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, “Cycloalkyl” means any monocyclic or bicyclic non-aromatic carbocyclic group containing 3 to 10 ring members, and “heterocycloalkyl” means any 3 to 10 ring members and 1 to 3 alternatives Monocyclic or bicyclic non-aromatic carbocyclic radicals from heteroatoms of oxygen, sulfur and nitrogen, which may include fused, bridged or spiro ring systems, such aryl, heteroaryl, naphthenes, as may be defined as such And heterocycloalkyl, and the alkyl, alkenyl, alkynyl, and alkoxy groups are substituted by 1 to 4 groups selected from the group consisting of straight or branched (C ₁ -C ₆ ) alkanes Group, which may be substituted by a group representing a linear or branched (C ₁ -C ₆ ) alkoxy group, the linear or branched (C ₁ -C ₆ ) alkoxy group may be substituted by a linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, hydroxyl, halogen, pendant oxygen, -NW'W ", -OC (O) -W 'or -CO -NW'W "substituted; straight or branched (C ₂ -C ₆₎ alkenyl group; a straight-chain or can be represented by points Chain (C ₁ -C ₆₎ alkoxy groups of the substituted straight-chain or branched (C ₂ -C ₆₎ alkynyl; may be represented by a straight-chain or branched (C ₁ -C ₆₎ alkoxy, linear (C ₁ -C ₆ ) polyhaloalkyl, straight or branched (C ₂ -C ₆ ) alkynyl, -NW'W "or hydroxyl-substituted straight or branched chain (C _1- C ₆ ) alkoxy; (C ₁ -C ₆ ) alkyl-S- substituted by a group representing a linear or branched (C ₁ -C ₆ ) alkoxy group; a hydroxyl group; a pendant oxygen group; N -oxide; nitro; cyano; -C (O) -OW '; -OC (O) -W';-CO-NW'W";-NW'W";-(C = NW ') -OW "; linear or branched (C ₁ -C ₆ ) polyhaloalkyl; trifluoromethoxy; or halogen; it should be understood that W 'and W" independently represent a hydrogen atom or can be represented by a linear or branched chain (C ₁ -C ₆₎ alkoxy groups of the substituted straight-chain or branched (C ₁ -C ₆₎ alkyl; and it should be understood that the group may be substituted one or more carbon atoms may be deuterated, Its enantiomers, diastereomers and configuration isomers, and addition salts thereof with pharmaceutically acceptable acids or bases are used simultaneously, sequentially or separately. A combination as claimed in claim 1, wherein the MCL1 inhibitor is a compound of formula (II) as defined in claim 2. The composition of any one of the requested items 1-3, wherein the BCL-2 inhibitor based N - (4- hydroxyphenyl) -3- {6 - [(( 3 S) -3- (4- morpholinyl Methyl) -3,4-dihydro-2 ( 1H ) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5 , 6,7,8-tetrahydro-1-indolinazine formamide. The combination of any one of claims 1 to 3, wherein the BCL-2 inhibitor is 5- (5-chloro-2-{[(3 S ) -3- (morpholin-4-ylmethyl)- 3,4-dihydroisoquinoline-2 (1 H ) -yl] carbonyl} phenyl) -N- (5-cyano-1,2-dimethyl-1 H -pyrrole-3-yl)- N- (4-hydroxyphenyl) -1,2-dimethyl- 1H -pyrrole-3-carboxamide. As in the combination of claim 4, wherein N- (4-hydroxyphenyl) -3- {6-[((3 S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 ( 1H ) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5,6,7,8-tetrahydro-1-indene Indomethacin is in the form of the hydrochloride. As a combination of claim 5, wherein 5- (5-chloro-2-{[(3 S ) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoline-2 (1 H) - yl] carbonyl} phenyl) - N - (5- cyano-1,2-dimethyl -1 H - pyrrole-3-yl) - N - (4- hydroxyphenyl) -1,2,5 -Dimethyl- 1H -pyrrole-3-carboxamide is in the form of the hydrochloride salt. The combination of claim 4 or 6, wherein during the combination therapy, N- (4-hydroxyphenyl) -3- {6-[((3 S ) -3- (4-morpholinylmethyl) -3 , 4-dihydro-2 (1 H ) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5,6,7,8 -The dose of tetrahydro-1-indolinazine formamidine is 50 mg to 1500 mg. The combination of any one of claims 1 to 8, wherein the BCL-2 inhibitor is administered once a week. A combination as claimed in claim 6 or 8, wherein during the combination treatment, N- (4-hydroxyphenyl) -3- {6-[((3 S ) -3- (4-morpholinylmethyl)- 3,4-dihydro-2 ( 1H ) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N -phenyl-5,6,7, 8-tetrahydro-1-indolinazine formamide is administered once a day. The combination of any one of claims 1 to 3, wherein the BCL-2 inhibitor is ABT-199. The combination of any one of claims 1 to 11, wherein the MCL1 inhibitor is ( 2R ) -2-{[ ( 5S _a ) -5- {3-chloro-2-methyl-4- [2- ( 4-methylpiperazin-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. The combination of any one of claims 1 to 11, wherein the MCL1 inhibitor is ( 2R ) -2-{[(( 5S _a ) -5- {3-chloro-2-methyl-4- [2- ( 4-methylpiperazin-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. The combination of any one of claims 1 to 13, wherein the BCL-2 inhibitor and the MCL1 inhibitor are administered orally. The combination of any one of claims 1 to 13, wherein the BCL-2 inhibitor is administered orally and the MCL1 inhibitor is administered intravenously. The combination of any one of claims 1 to 13, wherein the BCL-2 inhibitor and the MCL1 inhibitor are administered intravenously. A combination as claimed in any one of claims 1 to 16 for use in the treatment of cancer. The combination for use as claimed in claim 17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in an amount effective for co-treatment of the cancer treatment. The combination as claimed in claim 17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in an amount effective for synergistic treatment of the cancer treatment. The combination for use as claimed in claim 17, wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in a synergistically effective amount to achieve the required dose reduction of each compound in the cancer treatment, while providing effective cancer treatment, and ultimately Reduce side effects. The combination for use of any one of claims 17 to 20, wherein the cancer is leukemia. A combination as claimed in claim 21, wherein the leukemia is acute myeloid leukemia, T-ALL or B-ALL. The combination for use according to any one of claims 17 to 20, wherein the cancer is a myelodysplastic syndrome or a myeloproliferative disease. The combination for use of any one of claims 17 to 20, wherein the cancer is lymphoma. A combination as claimed in claim 24, wherein the lymphoma is a non-Hodgkin lymphoma. The combination as claimed in claim 25, wherein the non-Hodgkin's lymphoma is a diffuse large B-cell lymphoma or a mantle-cell lymphoma. The combination according to any one of claims 17 to 20, wherein the cancer is multiple myeloma. The combination for use of any one of claims 17 to 20, wherein the cancer is a neuroblastoma. The combination for use according to any one of claims 17 to 20, wherein the cancer is small cell lung cancer. The combination of any one of claims 1 to 16, further comprising one or more excipients. Use of a combination according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment of cancer. The use according to claim 31, wherein the cancer is leukemia. The use according to claim 32, wherein the leukemia is acute myeloid leukemia, T-ALL or B-ALL. The use according to claim 31, wherein the cancer is a myelodysplastic syndrome or a myeloproliferative disease. The use according to claim 31, wherein the cancer is lymphoma. The use according to claim 35, wherein the lymphoma is a non-Hodgkin's lymphoma. The use according to claim 36, wherein the non-Hodgkin's lymphoma is diffuse large B-cell lymphoma or mantle cell lymphoma. The use according to claim 31, wherein the cancer is multiple myeloma. The use according to claim 31, wherein the cancer is a neuroblastoma. The use according to claim 31, wherein the cancer is small cell lung cancer. A drug which contains, separately or together, (a) a BCL-2 inhibitor of formula (I) as defined in claim 1, and (b) an MCL1 inhibitor for simultaneous, sequential or separate administration, And wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in an effective amount for treating cancer. A medicament separately or collectively comprising: (a) a BCL-2 inhibitor, and (b) an MCL1 inhibitor of formula (II) as defined in claim 2, for simultaneous, sequential or separate administration, And wherein the BCL-2 inhibitor and the MCL1 inhibitor are provided in an effective amount for treating cancer. A method for treating cancer, comprising administering to a subject in need thereof a co-therapeutic effective amount of (a) a BCL-2 inhibitor of formula (I) as defined in claim 1, and (b) an MCL1 inhibitor. A method for treating cancer comprising administering to a subject in need thereof a (a) BCL-2 inhibitor, and (b) an MCL1 inhibitor of formula (II) as defined in claim 2 in a co-therapeutic effective amount. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient A co-therapeutic effective amount of (a) a BCL-2 inhibitor of formula (I) as defined in claim 1, and (b) an MCL1 inhibitor. A method for sensitizing a patient who is (i) difficult to treat with at least one chemotherapy or (ii) relapses after treatment with chemotherapy, or (i) and (ii), wherein the method comprises administering to the patient A co-therapeutic effective amount of (a) a BCL-2 inhibitor, and (b) an MCL1 inhibitor of formula (II) as defined in claim 2.