Methods of treating myeloid malignancies using BCL-2 inhibitors

Abstract

The present disclosure provides methods of using Bcl-2 inhibitors, in particular, 2-((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-N-((4-((((1r, 2r, 2r, 2r, 2r, 2r, 2r, 2r, 2r, 2r, 2r, 2r) The present invention relates to a method for treating myeloid malignancies in a subject by using azacitidine or a pharmaceutically acceptable salt thereof, and more particularly, to a method for treating myeloid malignancies in a subject by using azacitidine or a pharmaceutically acceptable salt thereof in combination with azacitidine.

Description

Technical Field

[0001] Disclosed herein are methods for treating myeloid malignancies with a combination of a Bcl-2 inhibitor, particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof and azacitidine. Background Art

[0002] Impaired apoptosis plays a central role in tumor development, tumor maintenance, and therapeutic resistance. Apoptosis can be triggered via two major pathways: the extrinsic or death receptor-mediated pathway, and the intrinsic or mitochondrial pathway (Czabotar et al. 2014). In lymphoid malignancies, the more common perturbation is the intrinsic pathway. Cell death mediated through this pathway is regulated by members of the B-cell lymphoma-2 (Bcl-2)-related protein family, which is thought to contain three subfamilies. The prosurvival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1 / Bfl-1, and possibly Bcl-B) promotes cell survival by inhibiting their proapoptotic relationships. Proapoptotic BAX / BAK-like proteins (including BOK) are important effectors of apoptosis, and BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are initiators of apoptosis (Anderson et al. 2014). In healthy cells, prosurvival Bcl-2 proteins bind and inhibit BAX and BAK (after they are partially activated), thereby impairing the ability of BAX / BAK to oligomerize and form pores to induce mitochondrial outer membrane permeabilization. BH3-only proteins are transcriptionally or post-transcriptionally induced in response to a variety of stresses and initiate apoptosis by binding prosurvival Bcl-2 proteins, thereby releasing BAX / BAK, or by directly activating these effectors of apoptosis. The various Bcl-2 family proteins have different binding specificities for each other, creating a complex but ordered network of interactions that controls cell fate (Roberts 2016).

[0003] Bcl-2 is the first anti-apoptotic protein discovered in the 1980s. It is the result of the t(14;18) chromosomal translocation and is a hallmark of FL. The BCL-2 gene is present on chromosome 18q21.33. The Bcl-2 protein has 239 amino acids and has a molecular weight of 26 kDa (Schenk et al. 2017). Bcl-2 is widely expressed during development and is restricted in the maturation of many tissues (Kondo et al. 2008). Mice lacking Bcl-2 are subject to polycystic kidney disease early in life, which is due to Bcl-2 being essential for the survival of renal epithelial progenitor cells during embryogenesis (Veis et al. 1993). In addition, the number of mature resting B and T lymphocytes in Bcl-2-deficient mice is abnormally reduced, and they age prematurely due to abnormal death of melanocytes (Veis et al. 1993, Yamamura et al. 1996). Although Bcl-2 was originally considered a classic growth-driven oncogene, it was later shown that it instead promotes malignant cell survival by attenuating apoptosis. Transgenic mice with pan-hematopoietic Bcl-2 expression (VavP-BCL-2) preferentially develop follicular lymphomas preceded by florid germinal center hyperplasia (Egle et al. 2004). Mice co-expressing BCL-2 and MYC transgenes develop lymphomas significantly faster than littermates expressing either transgene alone, demonstrating that BCL-2 is an oncogene (Adams and Cory 2007).

[0004] High Bcl-2 expression is almost universal in CLL, FL, MCL, and Waldenstrom's macroglobulinemia (WM); in contrast, Bcl-2 expression levels vary slightly in multiple myeloma (MM) and are very different in DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang 2017). When Bcl-2 is overexpressed, the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family members is disturbed, and apoptotic cell death can be prevented. In addition, Bcl-2 proteins are closely associated with chemoresistance in hematological tumors. Because Bcl-2-mediated resistance to intrinsic apoptosis is considered a key pathogenesis, targeting Bcl-2 can improve apoptosis and overcome resistance to cancer therapies. Therefore, Bcl-2 has become an attractive target in cancer treatment strategies.

[0005] Venetoclax (ABT-199) is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, despite such high clinical activity and a favorable safety profile, patients develop acquired resistance to venetoclax over time with continued treatment. Blombery et al. demonstrated that the Gly101Val mutation (G101V mutation) in BCL-2 confers acquired refractory resistance by reducing the binding affinity of venetoclax without disrupting the binding of proapoptotic proteins to Bcl-2. A novel Gly101Val mutation in Bcl-2 was identified in 7 of 15 patients at progression. This mutation was primarily found in patients with long-term exposure to venetoclax monotherapy (Tausch et al. 2019).

[0006] WO 2019 / 210828A discloses a series of compounds having the following formula (III-B), (III-C), (III-D) or (III-E), or stereoisomers thereof, or pharmaceutically acceptable salts thereof as Bcl-2 inhibitors

[0007] The compounds disclosed in WO 2019 / 210828A are potent and selective Bcl-2 protein inhibitors. Summary of the invention

[0008] The inventors of the present disclosure have discovered that a combination of a Bcl2 inhibitor having formula (III-B), (III-C), (III-D) or (III-E), particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound A) or a pharmaceutically acceptable salt thereof, and azacitidine produces significant tumor growth inhibition in acute myeloid leukemia (AML) compared to the efficacy of each therapeutic agent as a single agent. In addition, the combination therapy demonstrated significant tumor growth inhibition in myeloid malignancies, including acute myeloid leukemia (AML) (treatment naive [TN] or relapsed / refractory [R / R] not amenable to intensive induction chemotherapy), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasms (MPNs).

[0009] In a first aspect, disclosed herein is a method of treating myeloid malignancies with a combination of a Bcl-2 inhibitor and azacitidine, wherein the Bcl-2 inhibitor is a compound represented by the following formula (III-B), (III-C), (III-D) or (III-E), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in, R 2 is independently selected at each occurrence from the group consisting of hydrogen, halogen, or -C 1-8 alkyl; R 1d is independently at each occurrence a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR Ba 、-SO2R Ba 、-COR Ba 、-CO2R Ba 、-CONR Ba R Bb 、-C(=NR Ba )NR Bb R Bc 、-NR Ba R Bb 、-NR Ba COR Bb 、-NR Ba CONR Bb R Bc 、-NR Ba CO2R Bb 、-NR Ba SONR Bb R Bc 、-NR Ba SO2NR Bb R Bc , or -NR Ba S02R Bb ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently optionally substituted by 1 to 4 substituents R Bd replace; R Ba , R Bb and R Bc are independently hydrogen, -C 1-8 Alkyl, -C2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -NH2, or -N(C 1-6 Alkyl)2, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Bd is independently at each occurrence hydrogen, halogen, oxo, -CN, -NO2, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R 5 Yes – L 5 -CyC, Where L 5 Is a direct key, -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)O-、-NR a C(O)NR b -、-SO2NRa -、-NR a SO2-、-NR a S(O)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO-, or -C(=NR a )NR b -, where t and v are independently a number from 1 to 7 at each occurrence, and -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -One or both CR a R b The part is not replaced or is selected from O, S, SO, SO2, C(O) and NR a Replacement of one or more parts of; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or two substituents R 5a replace; R 5a is independently selected at each occurrence from: hydrogen, halogen, cyano, oxo, -NO2, -OR 5b 、-SR 5b 、-NR 5b R 5c 、-COR 5b 、-SO2R 5b 、-C(=O)OR 5b 、-C(=O)NR 5b R 5c 、-C(=NR 5b )NR 5c R 5d 、-N(R 5b )C(=O)R 5c 、-N(R 5b )C(=O)OR 5c 、-N(R5b )C(O)NR 5c R 5d 、-N(R 5b )S(O)NR 5c R 5d 、-N(R 5b )S(O)2NR 5c R 5d 、-NR 5b S02R 5c , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with one or two substituents R 5e replace; Where R 5b , R 5c and R 5d are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, C 2-8 Each of the alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with one or two substituents R 5e replace; R 5e is independently selected at each occurrence from: hydrogen, halogen, cyano, oxo, -NO2, -OR 5f 、-SR 5f 、-NR 5f R 5g 、-COR 5f 、-SO2R 5f 、-C(=O)OR 5f 、-C(=O)NR 5f R 5g 、-C(=NR 5f )NR 5g R 5h 、-N(R 5f )C(=O)R 5g 、-N(R 5f )C(=O)OR 5g 、-N(R 5f )C(O)NR 5g R 5h、-N(R 5f )S(O)NR 5g R 5h 、-N(R 5f )S(O)2NR 5g R 5h 、-NR 5f S02R 5g , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5f , R 5g and R 5h are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two adjacent R 5 Together with the phenyl ring, a benzo ring is formed, which is optionally substituted by: halogen, oxo, cyano, -NO2, -OR 5i 、-SR 5i 、-NR 5i R 5j 、-COR 5i 、-SO2R 5i 、-C(=O)OR 5i 、-C(=O)NR 5i R 5j 、-C(=NR 5i )NR 5j R 5k 、-N(R 5i )C(=O)R 5j 、-N(R 5i )C(=O)OR 5j 、-N(R 5i )C(O)NR 5j R 5k 、-N(R 5i )S(O)NR 5j R 5k 、-N(R 5i )S(O)2NR 5j R 5k 、-NR 5i S02R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5i , R5j and R 5k are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxyl, or -C 1-8 Alkoxy substitution; R a , R b , R c and R d is independently at each occurrence hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each independently substituted by: -CN, halogen, -NO2, -NR e R f , oxo, -OR e , or –SR e ;and Where R e and R f are independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0010] In a second aspect, disclosed herein is a combination of a Bcl-2 inhibitor having formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and azacitidine for use in treating myeloid malignancies.

[0011] In a third aspect, disclosed herein is a method of treating a myeloid malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor having Formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of azacitidine.

[0012] In a fourth aspect, disclosed herein is the use of a pharmaceutical composition in the manufacture of a medicament for treating myeloid malignancies, wherein the pharmaceutical combination comprises a Bcl-2 inhibitor having formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof and azacitidine.

[0013] In an embodiment of each of the above aspects, the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0014] In one embodiment of each of the above aspects, the myeloid malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasms (MPN). In some preferred embodiments, acute myeloid leukemia (AML) is treatment naive (TN) or relapsed / refractory (R / R) not suitable for intensive induction chemotherapy.

[0015] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is orally administered at a dose of 40 to 160 mg once daily. In some embodiments, the Bcl-2 inhibitor is orally administered at a dose of 40 mg, 80 mg, or 160 mg daily.

[0016] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is orally administered in two cycles comprising a ramp-up schedule (Cycle 1) and a subsequent cycle (Cycle 2). In one embodiment of each of the above aspects, the Bcl-2 inhibitor is orally administered in two cycles comprising a 4-day ramp-up schedule (Cycle 1) and a subsequent cycle (Cycle 2).

[0017] In some embodiments, each of the 4-day ramp-up schedule (Period 1) and the subsequent period (Period 2) is a 10-day period, a 21-day period, or a 28-day period.

[0018] In some embodiments, each of the 4-day ascending schedule (Period 1) is a 10-day cycle, a 21-day cycle, or a 28-day cycle, and the subsequent cycle (Period 2) is a 10-day cycle, a 21-day cycle, or a 28-day cycle.

[0019] In some preferred embodiments, each of the 4 day ramp-up schedules (Cycle 1) is a 10 day cycle, and the following cycle (Cycle 2) is a 10 day cycle. In some preferred embodiments, each of the 4 day ramp-up schedules (Cycle 1) is a 28 day cycle, and the following cycle (Cycle 2) is a 28 day cycle. In some preferred embodiments, each of the 4 day ramp-up schedules (Cycle 1) is a 21 day cycle, and the following cycle (Cycle 2) is a 21 day cycle.

[0020] In some embodiments, a 4-day ascending schedule (cycle 1) of administration of the Bcl-2 inhibitor comprises a first dose on day 1, a second dose on day 2, a third dose on day 3, and a recommended dose on day 4 and thereafter, wherein the recommended dose on day 4 and thereafter is higher than the second dose on day 3, the third dose on day 3 is higher than the second dose on day 2, and the second dose on day 2 is higher than the second dose on day 1. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, or 160 mg per day, and the Bcl-2 inhibitor is orally administered according to a 4-day ascending schedule comprising a first dose on day 1 that is 12.5% ​​of the recommended dose, a second dose on day 2 that is 25% of the recommended dose, a third dose on day 3 that is 50% of the recommended dose, and a daily dose on day 4 and thereafter that is 100% of the recommended dose. In some more preferred embodiments, the first dose on day 1 is about 5, 10 or 20 mg / day, the second dose on day 2 is about 10, 20 or 40 mg / day, the third dose on day 3 is about 20, 40 or 80 mg / day, and the daily dose on day 4 and thereafter is about 40, 80 or 160 mg / day.

[0021] In some more preferred embodiments, the first dose on day 1 is about 5 mg / day, the second dose on day 2 is about 10 mg / day, the third dose on day 3 is about 20 mg / day, and the daily dose on day 4 and thereafter is about 40 mg / day. In some more preferred embodiments, the first dose on day 1 is about 10 mg / day, the second dose on day 2 is about 20 mg / day, the third dose on day 3 is about 40 mg / day, and the daily dose on day 4 and thereafter is about 80 mg / day. In some more preferred embodiments, the first dose on day 1 is about 20 mg / day, the second dose on day 2 is about 40 mg / day, the third dose on day 3 is about 80 mg / day, and the daily dose on day 4 and thereafter is about 160 mg / day.

[0022] In some embodiments, the dose of the subsequent cycle (Cycle 2) of the Bcl-2 inhibitor administration is the recommended dose without escalation from Day 1. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, or 160 mg per day.

[0023] In some embodiments, in cycle 1, azacitidine is administered 1 day prior to administration of the Bcl-2 inhibitor (designated day 0).

[0024] In some embodiments, azacitidine is administered concurrently with the Bcl-2 inhibitor in Cycle 2 (designated Day 1).

[0025] In one embodiment of each of the above aspects, once daily (QD) at 75 mg / m 2 Azacitidine is administered intravenously or subcutaneously in doses of

[0026] In one embodiment of each of the above aspects, azacitidine is administered for 7 days in Cycle 1 and Cycle 2.

[0027] In one embodiment of each of the above aspects, the Bcl-2 is administered orally once daily (QD). BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 : Part 1 Dosing regimens in AML.

[0029] Figure 2 : Summary of complete responses in patients with AML.

[0030] Figure 3 : Best overall response in patients with AML.

[0031] Figure 4 : Best change from baseline in bone marrow blasts in patients with AML. definition

[0032] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0033] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0034] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or".

[0035] As used herein, the term "anti-cancer agent" refers to any agent useful for treating a cell proliferative disorder such as cancer, including but not limited to cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0036] The terms "administration, administering" and "treating, treatment" herein, when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids, mean that an exogenous drug, therapeutic, diagnostic agent or composition is in contact with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. The treatment of cells covers the contact of an agent with a cell and the contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatments, for example, cells are treated by an agent, a diagnostic agent, a binding compound or by another cell. The term "subject" herein includes any organism, preferably an animal, more preferably a mammal (e.g., a rat, a mouse, a dog, a cat, a rabbit), and most preferably a human. On the one hand, treating any disease or disorder refers to improving the disease or disorder (i.e., slowing down or preventing or reducing the development of a disease or at least one clinical symptom thereof). On the other hand, "treat / treating / treatment" refers to alleviating or improving at least one physical parameter, including those that the patient may not be able to discern. In yet another aspect, "treat / treating / treatment" refers to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In yet another aspect, "treat / treating / treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.

[0037] In the context of the present disclosure, the term "subject" is a mammal, e.g., a primate, preferably a higher primate, such as a human (e.g., a patient suffering from or at risk of suffering from a disorder described herein). In some embodiments, the subject is a human or a patient.

[0038] The term "cancer" or "tumor" herein has the broadest meaning as understood in the art, and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of this disclosure, cancer is not limited to a certain type or location.

[0039] As used herein, the term "therapeutically effective amount" refers to an amount of a Bcl-2 inhibitor that, when administered to a subject to treat a disease, or at least one clinical symptom of a disease or disorder, is sufficient to affect the treatment of the disease, disorder, or symptom. The "therapeutically effective amount" may vary depending on factors such as the agent, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case may be apparent to one skilled in the art or may be determined by routine experimentation. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combined subject used to effectively treat the disease, disorder, or condition.

[0040] As used herein, the term "ascending regimen" or "ascending schedule" refers to a dosing regimen or schedule in which the active ingredient of interest is administered in doses that increase periodically (such as daily or weekly) for a specified period of time, such as several days or several weeks, and then is administered to the recommended dose (daily or weekly). DETAILED DESCRIPTION

[0041] The present disclosure provides methods of treating a myeloid malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of azacitidine. Bcl-2 inhibitors

[0042] The Bcl-2 inhibitor in the present disclosure is a compound represented by the following formula (III-B), (III-C), (III-D) or (III-E), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in, R 2 is independently selected at each occurrence from the group consisting of hydrogen, halogen, or -C 1-8 alkyl; R 1d is independently at each occurrence a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR Ba 、-SO2R Ba 、-COR Ba 、-CO2R Ba 、-CONR Ba R Bb 、-C(=NRBa )NR Bb R Bc 、-NR Ba R Bb 、-NR Ba COR Bb 、-NR Ba CONR Bb R Bc 、-NR Ba CO2R Bb 、-NR Ba SONR Bb R Bc 、-NR Ba SO2NR Bb R Bc , or -NR Ba S02R Bb ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently optionally substituted by 1 to 4 substituents R Bd replace; R Ba , R Bb and R Bc are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -NH2, or -N(C 1-6 Alkyl)2, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Bd is independently at each occurrence hydrogen, halogen, oxo, -CN, -NO2, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R5 Yes – L 5 -CyC, Where L 5 Is a direct key, -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)O-、-NR a C(O)NR b -、-SO2NR a -、-NR a SO2-、-NR a S(O)2NR b -、-NR a S(O)NR b -、-C(O)NR a SO2-、-C(O)NR a SO-, or -C(=NR a )NR b -, where t and v are independently a number from 1 to 7 at each occurrence, and -(CR a R b ) t -、-(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -、-(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1-One or both CR a R b The part is not replaced or is selected from O, S, SO, SO2, C(O) and NR a Replacement of one or more parts of; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted by one or two substituents R 5a replace; R 5a is independently selected at each occurrence from: hydrogen, halogen, cyano, oxo, -NO2, -OR 5b 、-SR 5b 、-NR 5b R 5c 、-COR 5b 、-SO2R 5b 、-C(=O)OR 5b 、-C(=O)NR 5b R 5c 、-C(=NR 5b )NR 5c R 5d 、-N(R 5b )C(=O)R 5c 、-N(R 5b )C(=O)OR 5c 、-N(R 5b )C(O)NR 5c R 5d 、-N(R 5b )S(O)NR 5c R 5d 、-N(R 5b )S(O)2NR 5c R 5d 、-NR 5b S02R 5c , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with one or two substituents R 5e replace; Where R 5b , R 5c and R 5d are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, C 2-8 Each of the alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with one or two substituents R 5e replace; R 5e is independently selected at each occurrence from: hydrogen, halogen, cyano, oxo, -NO2, -OR 5f 、-SR 5f 、-NR 5f R 5g 、-COR 5f 、-SO2R 5f 、-C(=O)OR 5f 、-C(=O)NR 5f R 5g 、-C(=NR 5f )NR 5g R 5h 、-N(R 5f )C(=O)R 5g 、-N(R 5f )C(=O)OR 5g 、-N(R 5f )C(O)NR 5g R 5h 、-N(R 5f )S(O)NR 5g R 5h 、-N(R 5f )S(O)2NR 5g R 5h 、-NR 5f S02R 5g , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5f , R 5g and R 5h are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or two adjacent R 5 Together with the phenyl ring, a benzo ring is formed, which is optionally substituted by: halogen, oxo, cyano, -NO2, -OR 5i 、-SR 5i 、-NR 5i R 5j、-COR 5i 、-SO2R 5i 、-C(=O)OR 5i 、-C(=O)NR 5i R 5j 、-C(=NR 5i )NR 5j R 5k 、-N(R 5i )C(=O)R 5j 、-N(R 5i )C(=O)OR 5j 、-N(R 5i )C(O)NR 5j R 5k 、-N(R 5i )S(O)NR 5j R 5k 、-N(R 5i )S(O)2NR 5j R 5k 、-NR 5i S02R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5i , R 5j and R 5k are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with halogen, hydroxyl, or -C 1-8 Alkoxy substitution; R a , R b , R c and R d is independently at each occurrence hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are each independently substituted by: -CN, halogen, -NO2, -NR e R f, oxo, -OR e , or –SR e ;and Where R e and R f are independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0043] In some embodiments, R 2 It's hydrogen.

[0044] In some embodiments, when substituted on the phenyl group at position 2 of Ring B (including aziridine-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl, or azocyclooctan-1-yl, preferably a pyrrolidin-1-yl group), R 1d are independently halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba 、-SO2R Ba 、-CONR Ba R Bb 、-NO2、-NR Ba R Bb 、-NR Ba COR Bb , or -NR Ba S02R Bb ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 The alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently optionally substituted by 1 to 4 substituents R Bd (as defined by formula (III-B), (III-C), (III-D) or (III-E)), preferably substituted with 1 or 2 substituents R Bd (as defined by formula (III-B), (III-C), (III-D) or (III-E)). In another aspect, one R 1d At position 2 of ring B at position 2 of the phenyl ring.

[0045] In some embodiments, R 1dIt is methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyl groups at the phenyl ring positions; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0046] In some embodiments, the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety in Formula (III-B), (III-C), (III-D), or (III-E) is selected from the group consisting of:

[0047] In some embodiments, m is 1; and L 5 Is a direct key, -(CR a R b ) t -or-NR a -, where t is a number from 1 to 7, and -(CR a R b ) t -One or both CR a R b Part is not replaced or is selected from O and NR a One or more parts of R a and R b Defined by formula (III-B), (III-C), (III-D) or (III-E).

[0048] In some embodiments, L 5 Is a direct key, -(CR a R b ) 1-4 -、-O-(CR a R b ) 1-3 -、-NH-(CR a R b ) 1-3 , or -NH-, where R a and R b As defined by formula (III-B), (III-C), (III-D) or (III-E), therefore –L 5 -CyC parts are CyC, -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b )1-3 -CyC, or -NH-CyC. More preferably, L 5 Is a direct bond, -(CH2) 1-4 -、-O-(CH2) 1-3 -、-NH-(CR a R b )-(CH2)2-, or -NH-, where R a is hydrogen, and R b is C optionally substituted by phenyl-S- 1-8 Alkyl, so –L 5 -CyC parts are CyC, -(CH2) 1-4 -CyC, -O-(CH2) 1-3 -CyC, -NH-(CR a R b )-(CH2)2-CyC, or -NH-CyC. More preferably, L 5 is a direct bond, -CH2-, -O-CH2-, -NH-CH2-, or -NH-, so –L 5 The -CyC moiety is CyC, -CH2-CyC, -O-CH2-CyC, -NH-CH2-CyC, or -NH-CyC, respectively.

[0049] In some embodiments, CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two substituents R 5a replace; R 5a are independently selected from hydrogen, halogen, cyano, oxo, -OR 5b 、-NR 5b R 5c 、-COR 5b 、-SO2R 5b , -C 1-8 Alkyl, -C 2-8 Alkynyl, -cycloalkyl, or heterocyclic group, the -C 1-8 Each of the alkyl and heterocyclic groups is optionally substituted by one or two substituents R 5e Substituted, the substituent is selected from: hydrogen, halogen, cyano, -OR 5f , -C 1-8 Alkyl, -cycloalkyl, or heterocyclyl; Where R 5b and R 5c are independently hydrogen, -C 1-8 Alkyl or heterocyclic group, the -C 1-8 The alkyl group is optionally substituted by one or two substituents R 5e Substituted, the substituent being hydrogen, -NR 5f R 5gor -cycloalkyl; R 5f and R 5g are independently hydrogen or -C 1-8 alkyl; or two adjacent R 5 Together with the phenyl ring, a benzo ring is formed, which is optionally substituted by heteroaryl.

[0050] In some embodiments, CyC is selected from monocyclic C 3-8 Cycloalkyl or bridged cycloalkyl (each of which is optionally substituted by one or two substituents R 5a Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted by one or two substituents R 5a replace.

[0051] In some embodiments, CyC is a heterocyclyl selected from: a) monocyclic 4- to 9-membered heterocyclyl groups which contain one nitrogen, oxygen or sulfur heteroatom as a ring member; b) monocyclic 4- to 9-membered heterocyclyl groups which contain two heteroatoms selected from oxygen, sulfur and nitrogen as ring members; and c) a 5- to 20-membered spiroheterocyclyl group which contains one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members, Each of which is optionally replaced by one or two R 5a replace.

[0052] In some embodiments, CyC is a monocyclic 4- to 6-membered heterocyclyl group containing one nitrogen or oxygen or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetane, tetrahydrofuran, tetrahydropyran, azetidinyl, pyrrolidinyl and piperidinyl. Even more preferably, CyC is selected from oxetane-2-yl, oxetane-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

[0053] In some embodiments, CyC is a monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is dioxanyl, morpholino, morpholinyl, or piperazinyl. Even more preferably, it is 1,3-dioxane-2-yl, 1,3-dioxane-4-yl, 1,4-dioxane-2-yl, morpholine-1-yl, morpholine-2-yl, or morpholine-3-yl.

[0054] In some embodiments, R 5a are independently selected from hydrogen, halogen, cyano, oxo, -OR 5b 、-NR 5b R 5c 、-COR 5b 、-SO2R 5b , -C 1-8 Alkyl, -C 2-8 Alkynyl, monocyclic C 3-8 Cycloalkyl, or a monocyclic 4- to 9-membered heterocyclyl group (containing one or two heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms as ring members), the -C 1-8 Each of the alkyl and monocyclic 4- to 9-membered heterocyclyl groups is optionally substituted by one or two substituents R 5e Substituted; preferably, as R 5a The cycloalkyl group is C 3-6 Cycloalkyl; more preferably cyclopropyl; preferably, as R 5a The heterocyclyl radicals of R are 4- to 6-membered heterocyclyl radicals containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members; more preferably, as R 5a The heterocyclic group as R is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, or morpholinyl; even more preferably, 5a The heterocyclic group is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morphin-4-yl.

[0055] In some embodiments, as R 5e The heterocyclyl radical is a monocyclic 4- to 9-membered heterocyclyl radical which contains one or two heteroatoms selected from nitrogen or oxygen or sulphur heteroatoms as ring members.

[0056] In some embodiments, as R 5e The heterocyclyl group is tetrahydro-pyran-4-yl.

[0057] In some embodiments, R 5a Yes - NR 5b R 5c , where R 5b is hydrogen, and R 5c It is a heterocyclic group.

[0058] In some embodiments, R 5a Yes - NR 5b R 5c , where R 5b is hydrogen, and R 5c It is tetrahydro-pyran-4-yl.

[0059] In some embodiments, R 5a Yes - NR 5bR 5c , where R 5b and R 5c are each independently hydrogen or -C substituted by cycloalkyl 1-6 Alkyl, preferably monocyclic C 3-8 Cycloalkyl-substituted –C 1-6 alkyl.

[0060] In some embodiments, R 5a Yes-OR 5b or-SO2R 5b , where R 5b is hydrogen or C 1-8 The alkyl group is preferably a methyl group.

[0061] In some embodiments, R 5a Yes-COR 5b , where R 5b is hydrogen or optionally substituted by -NR 5f R 5g Substituted C 1-8 Alkyl, where R 5f and R 5g are independently hydrogen or C 1-8 The alkyl group is preferably a methyl group.

[0062] In some embodiments, two adjacent R 5 Together with the phenyl ring it forms an indazolyl group substituted with a tetrahydropyranyl group.

[0063] In some embodiments, m is 1, and R 5 is selected from the group consisting of -L 5 -CyC, the group consists of:

[0064] In some embodiments, m is 1, and R 5 yes

[0065] In some embodiments, the Bcl-2 inhibitors of the present disclosure are selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.5]decan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(dimethylamino)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2-(dimethylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(oxo)-16-sulfanediyl)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanediylidene)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(3-oxomorpholino)ethyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octan-6-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((cis or trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((trans or cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0066] In some embodiments, the Bcl-2 inhibitor of the present disclosure is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound A) or a pharmaceutically acceptable salt thereof. Preparation of Bcl-2 inhibitors

[0067] All Bcl-2 inhibitors having formula (III-B), (III-C), (III-D) or (III-E), including 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide (Compound A) can be prepared by the method disclosed in International Publication WO 2019 / 210828A1. Preparation of Compound A

[0068] Step 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane hydrochloride

[0069] At room temperature, to the solution of tert-butyl 2-oxo-7-azaspiro [3.5] nonane-7-formate (500g, 2.09mol) in MeOH (750mL) and EA (750mL), concentrated HCl (350mL, 4.18mol) is added and stirred for 4 hours. After concentrating in a vacuum, MeOH (750mL) is added to the residue, and then the resulting mixture is concentrated in a vacuum (repeating this process twice). The brown residue is suspended in EA (1250mL), and stirred for 1 hour. The solid precipitate is filtered and dried in a vacuum to obtain the title product (350g, yield: 76.0%) in an off-white powder. 1 H NMR (400MHz, DMSO-d6) δppm: 3.03 (s, 6H), 2.96-2.89 (m, 4H), 1.93 (s, 4H), 1.74-1.67 (m, 4H). MS(ESI,m / e)[M+1] + 186.0.

[0070] Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7- Aza Spiro[3.5]nonan-7-yl)benzoate

[0071] A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (100 g), 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (116 g, 1.5 eq.) and DBU (160 g, 3.0 eq.) in NMP (500 mL) was stirred for 16 hours at 85 ° C. After the reaction was completed, the mixture was cooled to 50 ° C ± 5 ° C, and an aqueous solution of citric acid (2%, 5 L) was added dropwise to the system under stirring. After filtration, the filter cake was collected and dissolved with DCM (1.5 L). The solution of the crude product was washed with an aqueous solution of citric acid (2%, 1.5 L), a saturated aqueous solution of NaHCO3 (1.5 L), and a 15% aqueous solution of NaCl (1.5 L), and then dried over anhydrous Na2SO4. Silica gel (100 g) was added to the solution of the crude product under stirring, and then filtered. The filtrate was concentrated to 300 mL. MTBE (500 mL) was poured into the system. After stirring for 2 hours, the filter cake was collected after filtration and dried in vacuum to give an off-white solid (192 g, yield: 72.1%). 1H NMR (400MHz, DMSO-d6) δppm: 11.63 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.76 (d, J = 9.2Hz, 1H), 7.47 (t, J = 3.2Hz, 1H), 7.42 (d, J = 2.4Hz, 1H) ), 6.79 (dd, J = 2.4Hz, J = 9.2Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). MS(ESI,m / e)[M+1] + 451.9.

[0072] Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro [3.5] Nonane-7-yl)benzoate

[0073] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonane-7-yl)benzoate (176 g, 0.39 mol) in DCM (2 L) was added dilute HCl (1 M, 1.5 L) and stirred overnight. After the reaction was complete, the mixture was cooled to 10 ° C and adjusted to pH=8-9 with an aqueous NaOH solution (4 M) under stirring. The organic phase was separated and washed with a 15% aqueous NaCl solution (1 L) and then with H2O (1 L). After the organic phase was concentrated to 500 mL, MTBE (1 L) was poured into the solution, and the system was then concentrated to 500 mL (this treatment was repeated 3 times). The resulting system was stirred for 0.5 hours. After filtration, the filter cake was collected and then dried in a vacuum to obtain the title product (152 g, yield: 96.23%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δppm: 11.64 (s, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.78 (d, J = 9.2Hz, 1H), 7.47 (t, J = 3.2Hz, 1H), 7.44 (d, J = 2.4Hz, 1H), 6. 83(dd,J=2.4Hz,J=9.2Hz,1H),6.43(d,J=2.4Hz,1H),6.38-6.36(m,1H),3.65(s,3H),3.24-3.21(m,4H),2.80(s,4H),1.70-1.67(m,4H). MS(ESI,m / e)[M+1] + 405.9.

[0074] Step 4: (S)-tert-Butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0075] To a mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in dioxane (500 mL) and H2O (50 mL) was added Cs2CO3 (100 g, 305 mmol) and Pd(dppf)Cl2 (6.6 g, 7.5 mmol). The mixture was stirred at 100°C for 8 hours. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v) = 100 / 1 to 10 / 1) to obtain (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude product). The crude product was used directly in the next step.

[0076] Step 5: (S)-tert-Butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0077] To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd / C (10 g, 10%) and the mixture was stirred at 20° C. under H (15 Psi) for 12 hours. TLC showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to give (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude product), which was used in the next step without further purification. 1 HNMR (400MHz, CDCl3) δppm:7.39-6.90(m,4H),5.36-5.04(m,1H),3.77-3.52(m,2H),3.20-3.17( m,1H),2.47-2.24(m,1H),1.96-1.65(m,3H),1.54-1.38(m,2H),1.31-1.22(m,8H),1.17(s,7H).

[0078] Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0079] At room temperature, HCl in 1,4-dioxane (4M, 142 mL, 570 mmol) was added dropwise to a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was slurried with EA (100 mL), then filtered and dried in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR(400MHz,DMSO-d6)δppm:9.93(s,1H),8.81(s,1H),7.63-7.57(m,1H),7.41-7.34(m,2H),7.32-7.24(m,1H),4.91-4.75(m, 1H),3.47-3.35(m,1H),3.31-3.25(m,1H),2.40-2.21(m,1H),2.19-1.86(m,3H),1.25(d,J=6.7Hz,3H),1.17(d,J=6.7Hz,3H). MS(ESI,m / e)[M+1] + 190.0.

[0080] Step 7: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-isopropyl)- benzene 1-Azaspiro[3.5]nonan-7-yl)benzoate

[0081] A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mole) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonane-7-yl)benzoate (218 g, 0.509 mole) in DCM (2.2 L) was charged into a reactor. The temperature was controlled below 30°C, and NaBH(OAc)3 (216 g, 1.018 mole) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After complete consumption of the starting material ketone, the mixture was adjusted to pH=4 to 5 with dilute HCl (0.5 M). The separated organic phase was washed with H2O (600 mL×2), then with NaHCO3 aqueous solution (600 mL×2), and NaCl saturated aqueous solution (600 mL). The organic phase was collected, then dried over anhydrous Na2SO4 and concentrated. 256 g of off-white solid was obtained as a crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0082] Step 8: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0083] To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). It was stirred at room temperature overnight. After THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. At room temperature, with stirring, the resulting mixture was adjusted to pH=5 to 6 with 3N HCl. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%). 1 H NMR (400MHz, DMSO-d6) δppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.56-7.40 (m, 2H), 7.35 (s, 1H), 7.27-7.04 (m,3H),6.68(d,J=8.0Hz,1H),6.32(s,2H),3.62(s,1H),3.32-3.26(m,1H),3.10-3.04(m,4H),2.35-2.30(m,1H),2.9-2.15(m,1H),1.74 -1.64(m,4H),1.52-1.37(m,6H),1.28-1.06(m,6H). MS(ESI,m / e)[M+1] + 564.9.

[0084] Step 9: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4- (methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl) 1-Azaspiro[3.5]nonan-7-yl)benzamide

[0085] A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol) and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After the starting material (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid was completely consumed, the reaction mixture was heated to about 35° C. and N 1 ,N 1 -dimethylethane-1,2-diamine (17.2g, 195mmol). The reaction was stirred for another 12 hours. The mixture was washed twice with 10wt% AcOH aqueous solution (300mL×2), and then washed with NaHCO3 saturated aqueous solution (300mL×2). The organic layer was collected and concentrated to about 90mL. 22g silica gel was added and stirred for 2 hours. After filtering, 180mL EA was added to the filtrate under reflux and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered, and then the wet cake was washed twice with EA (180mL). At 80°C-90°C, after drying in vacuum, the desired compound (48g, yield: 69.5%) was obtained. 1 H NMR(DMSO-d6)δppm:11.65(s,1H),11.11(br,1H),8.58-8.39(m,2H),8.00(d,J=2.8Hz,1H),7.74 (d,J=8.8Hz,1H),7.57-7.37(m,4H),7.30-7.10(m,3H),7.00(d,J=9.2Hz,1H),6.65(d,J=1.2Hz, 1H),6.35(s,1H),6.17(s,1H),4.24(s,1H),3.39-3.20(m,5H),3.04-2.88(m,4H),2.23(s,1H),1 .94-1.47(m,11H),1.44-1.26(m,7H),1.19(d,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H),1.10(s,4H). MS(ESI,m / e)[M+1] +889.9. Treatment

[0086] In one aspect, the disclosure provides a method of treating cancer. In certain aspects, the method comprises administering to a patient a therapeutically effective amount of Compound A in combination with a therapeutically effective amount of azacitidine. The cancer is a myeloid malignancy selected from the group consisting of acute myeloid leukemia (AML).

[0087] Compound A can be administered by any suitable means, including oral administration, parenteral administration, intrapulmonary administration, and intranasal administration, and if local treatment is required, by intralesional administration. Administration can be by any suitable route. Various dosing regimens are contemplated herein, including but not limited to single administration or multiple administrations at different time points, push injection administration, and pulse infusion.

[0088] Compound A will be formulated, dosed and applied in a manner consistent with good medical practice. Factors to be considered at this point include the specific disorder of treatment, the specific mammal of treatment, the clinical condition of individual patients, the cause of the disorder, the delivery site of the agent, the method of administration, the administration regimen and other factors known to medical practitioners. Compound A is optionally formulated with one or more agents currently used to prevent or treat the disorder studied. The effective amount of such other agents depends on the amount of Compound A in the preparation, the type of disorder or treatment and other factors discussed above.

[0089] For the prevention or treatment of disease, the appropriate dose of Compound A will depend on the type of disease to be treated, the severity and course of the disease, whether Compound A is being administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to Compound A, and the judgment of the attending physician. Compound A is appropriately administered to the patient at one time or over a series of treatments. Examples

[0090] The invention is further illustrated by the following examples which illustrate the invention but are not limited to these examples. Example 1: Clinical research 1. Methods Study design / objectives

[0091] A clinical study was conducted to evaluate the combination of Compound A and azacitidine in patients with myeloid malignancies, including acute myeloid leukemia (AML) (treatment naive [TN] or relapsed / refractory [R / R] not suitable for intensive induction chemotherapy), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasms (MPN). Patients with AML (treatment naive or relapsed / refractory not suitable for intensive chemotherapy) were recruited to the AML cohort; and patients with myelodysplastic syndrome (MDS) or MDS / myeloproliferative neoplasms (MPN) (treatment naive or relapsed / refractory with high-risk disease) were recruited to the MDS cohort. AML Cohort:

[0092] The AML cohort enrolled patients with treatment-naïve (TN) AML and relapsed / refractory (R / R) AML who were not suitable for intensive chemotherapy. All AML cohorts were treated for 28 days unless otherwise recommended by the Safety Monitoring Committee (SMC).

[0093] Part 1 AML (dose finding; N≈18 to 36, i.e., minimum 6 and maximum 12 per cohort) investigated different dose regimens of Compound A compared with 75 mg / m 2 The safety and tolerability of the fixed dose of azacitidine combination for 7 days. After 3 patients completed the dose-limiting toxicity (DLT) window period, the SMC reviewed all available data and considered the probability of a DLT rate > 20%, and recommended whether to recruit additional patients (i.e., up to 12). If additional patients are not needed, the SMC will recommend whether to open the subsequent dose regimen in Part 1 and whether to open the dose regimen for Part 2 expansion.

[0094] Each cohort had a 4-day ramp-up of Compound A in Cycle 1 only, with 12.5% ​​of the target dose on Day 1, 25% on Day 2, 50% on Day 3, and 100% on Day 4. The window for assessing dose-limiting toxicities (DLTs) ended on Day 28 (for non-hematologic toxicities) and Day 42 or the start of Cycle 2 (for hematologic toxicities).

[0095] The AML Part 1 dose regimen discovery cohorts are as follows: A) Compound A 40 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 5 mg, 10 mg, 20 mg, 40 mg) B) Compound A 80 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 10 mg, 20 mg, 40 mg, 80 mg) C) Compound A 160 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, 160 mg) D) Compound A 160 mg daily x 28 days with azacitidine (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, 160 mg) E) Compound A 320 mg daily x 21 days with azacitidine (ascending dosing of Compound A: 40 mg, 80 mg, 160 mg, and 320 mg) F) Compound A 320 mg daily x 28 days with azacitidine (ascending dosing of Compound A: 40 mg, 80 mg, 160 mg, and 320 mg) In all Part 1 AML cohorts and Part 2 cohorts receiving a 28-day dosing schedule, the initial dose of azacitidine was given 1 day prior to Compound A administration (designated Day 0) to compare baseline PK samples of azacitidine monotherapy and the combination of azacitidine and Compound A starting on Day 1. In subsequent cycles and all remaining cohorts, concurrent administration of azacitidine with Compound A was initiated on Day 1. Figure 1 The dosing regimen in Part I AML is shown.

[0096] Part 2 AML (safety extension; N≈60) Cohorts consisting of up to approximately 10 patients per cohort were treated with the dose regimen defined as in Part 1 and recommended by the SMC to enter Part 2. Part 2 of the study determined the safety and anti-leukemic activity of more patients who were followed longer at the dose regimen that was declared tolerable and had early signs of activity in Part 1. At a given time, multiple dose regimens may be approved for expansion in Part 2; however, only a single Part 2 AML cohort will be offered to potential participants. If applicable, priority will be given to recruiting patients into any open Part 1 cohort. Each Part 2 cohort will continue to recruit up to 10 patients; this will include any additional patients recruited in Part 1, but an initial SMC safety review for that cohort will not be required. Based on the SMC's recommendation, the cohort may be closed before recruiting 10 patients, or expanded to recruit an additional 10 patients to collect additional data for a specific dose regimen. After completing recruitment of all Part 2 AML cohorts, the SMC will determine the recommended dose based on safety, tolerability, and PK.

[0097] Unless another tested dosing regimen appears superior based on SMC assessment, compound A (160 mg once daily for 10 days) versus azacitidine (75 mg / m 2 ) as the recommended dose for Part 3.

[0098] Part 3 AML (efficacy extension; N ≈ 40) treated approximately 20 patients with the recommended dose determined in the part 2 AML cohort. All AML patients were enrolled in a single part 3 AML cohort; however, based on differences in safety and tolerability among AML patients, the AML cohort could be divided into 2 separate cohorts: TN AML patients who were not suitable for intensive chemotherapy and R / R AML patients.

[0099] A subset of the AML cohort in Part 3 will receive a modified second cycle of treatment to explore DDI with posaconazole (a strong cytochrome P450 (CYP) 3A4 inhibitor). The schedule for the second cycle will depend on whether a 10-day or 28-day regimen is selected as the recommended dose for AML. If a 10-day dosing regimen is selected, patients will be treated at the recommended dose for the first 10 days of cycle 2. Then, patients will receive compound A at one-eighth of the recommended dose from day 11 to day 20. Posaconazole will be given at 300 mg twice daily (BID) on day 13, and then at 300 mg once daily with food on days 14 to 20 (30 minutes before compound A administration). If a 28-day compound A course is selected, one-eighth of the recommended dose of compound A will be given from day 11 to day 28 of cycle 2, as well as posaconazole from day 13 to day 20. PK sampling will be performed on days 12 to 13 and 20 to 21 of cycle 2. Normal dosing will continue from cycle 3.

[0100] The AML monotherapy part (N≈10) studies the safety and tolerability of compound A as a monotherapy in patients with R / R. After 3 patients complete the dose-limiting toxicity (DLT) window period, the SMC will review all available data and consider the probability of a DLT rate >20%, and will recommend whether to recruit additional patients. The SMC will also recommend whether the dose level needs to be modified.

[0101] The monotherapy cohort had 4 days of ramp-up of Compound A in the first cycle only, with day 1 at 12.5% ​​of the target dose, day 2 at 25%, day 3 at 50%, and day 4 at 100%.

[0102] The R / R AML monotherapy cohorts are as follows: Compound A 160 mg daily x 28 days (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, and 160 mg) The target dose is 160 mg daily x 28 days unless the SMC selects another dose level as the dose.

[0103] The monotherapy cohort received Compound A once daily for 28 days at a target dose of 160 mg (selected by the SMC as the recommended dose). Inclusion criteria

[0104] Each patient eligible to participate in this study must meet all applicable criteria: 1. Aged 18 or above 2. According to the 2016 World Health Organization criteria, the confirmed diagnosis is one of the following: a. AML, non-acute promyelocytic leukemia Eastern Cooperative Oncology Group (ECOG) performance status of 3.0 to 2. 4. Adequate organ function, defined as: a. Creatinine clearance ≥45 mL / min (or between 30 and 45 mL / min in the unsuitable AML cohort) b. Adequate liver function 5. Life expectancy > 12 weeks 6. Ability to comply with the requirements of the study Exclusion criteria

[0105] Each patient eligible to participate in this study must not meet any of the following exclusion criteria: 1. Diagnosis of acute promyelocytic leukemia 2. Previous malignant tumors within the past 2 years, except for cured local skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ, or prostate cancer with a local Gleason score of ≤6 3. Previous MPN (including myelofibrosis, essential thrombocythemia, polycythemia vera) or chronic myeloid leukemia (with or without BCR-ABL1 translocation) and AML (with BCR-ABL1 translocation) 4. Known involvement of the central nervous system due to leukemia 5. Prior therapy with Bcl-2 inhibitors or azacytidine MDS cohort:

[0106] The MDS cohort enrolled patients with TN MDS and TN MDS / MPN or R / R MDS and R / R MDS / MPN who had received at least 1 prior systemic therapy. In the MDS cohort, treatment cycles were 28 days unless modified by the SMC.

[0107] Part 1 MDS (dose regimen finding, N≈12 to 24) treated a minimum of 3 and a maximum of 6 MDS patients / cohort at each dose regimen of Compound A with 75 mg / m 2 Azacitidine combination for 7 days.

[0108] Each cohort will have a 4-day ramp-up of Compound A in the first cycle only, with Day 1 at 12.5% ​​of the target dose, Day 2 at 25%, Day 3 at 50%, and Day 4 at 100%.

[0109] The MDS Part 1 dose regimen discovery cohorts are as follows: A) Compound A 40 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 5 mg, 10 mg, 20 mg, and 40 mg) B) Compound A 80 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 10 mg, 20 mg, 40 mg, and 80 mg) C) Compound A 160 mg daily x 10 days with azacitidine (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, and 160 mg) D) Compound A 160 mg daily x 21 days with azacitidine (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, and 160 mg)

[0110] A combination of Compound A (once daily, target dose of 160 mg for 10 days) with azacitidine. This cohort will be opened after the SMC reviews the safety data of the first 2 cohorts of AML patients recruited in Part 1 and no safety issues are found. Compound A in Cycle 1 will be given in 4-day ascending doses (20 mg, 40 mg, 80 mg, 160 mg). It is expected that a single dose regimen will be tested in Part 1 MDS, although the SMC may choose to test another dose regimen after reviewing data from this MDS or AML cohort or subsequent MDS or AML cohorts. After 3 patients in the cohort complete one cycle of treatment, the SMC will review all available data before opening subsequent cohorts (if any). The SMC may recommend treating additional patients in the cohort before confirming tolerability.

[0111] Part 2 MDS (safety extension, N≈40), up to 10 patients were treated with one or more dose regimens selected in Part 1 MDS. At any given time, a single Part 2 MDS cohort will be open for recruitment. After completing recruitment of all Part 2 MDS cohorts, the SMC will determine the recommended dose based on the safety, tolerability, and PK data from these Part 2 cohorts, as well as any available active data and / or exploratory data.

[0112] Compound A (160 mg once daily for 10 days) and azacitidine (75 mg / m 2 ) as the recommended dose for Part 3.

[0113] Part 3 MDS (efficacy extension, N ≈ 40) treated approximately 20 patients at the MDS dose determined in Part 2 MDS. Enrollment in Part 3 will open after the Part 2 cohort completes enrollment and the SMC recommendation is obtained after review of all available data.

[0114] All Part 1, 2, and 3 cohorts are evaluated for DLT. The DLT window will begin with the first dose of study drug and continue until Day 28 for non-hematologic toxicity and until Day 42 of Cycle 1 or the start of Cycle 2 for hematologic toxicity.

[0115] The MDS monotherapy part (N≈10) studies the safety and tolerability of compound A as a monotherapy in patients with MDS or MDS / MPN. After 3 patients complete the DLT window period, the SMC will review all available data and consider the probability of a DLT rate >20%, and will recommend whether to recruit additional patients. The SMC will also recommend whether the dose level needs to be modified. The monotherapy cohort will have a 4-day ramp-up of Compound A in the first cycle only, with Day 1 at 12.5% ​​of the target dose, Day 2 at 25%, Day 3 at 50%, and Day 4 at 100%. The MDS and MDS / MPN monotherapy cohorts are as follows: Compound A 160 mg daily x 28 days (ascending dosing of Compound A: 20 mg, 40 mg, 80 mg, and 160 mg) The target dose is 160 mg daily x 28 days unless the SMC selects another dose level as the dose.

[0116] Unless another dosing regimen is considered to be superior in terms of toxicity or efficacy, the compound (160 mg once daily for 10 days) may be given in combination with azacitidine (75 mg / m 2 ) as the recommended dose for Part 3. 2. Results and Conclusions Security

[0117] As of February 04, 2023, 97 patients have been enrolled, including 66 patients with AML and 31 patients with MDS or MDS / MPN. SMC has completed evaluation of the 10-day regimen of the combination of Compound A and azacitidine at 40, 80, and 160 mg and the 28-day regimen of the combination of Compound A and azacitidine at 160 mg in the Part 1 AML cohort, and has also opened enrollment for the corresponding Part 2 expansion cohort. Enrollment is also open for the 21-day regimen of Compound A at 320 mg in Part 1.

[0118] In MDS or MDS / MPN, the SMC has completed the evaluation of the Part 1 cohort of a 10-day regimen of 40, 80, and 160 mg of Compound A in combination with azacitidine and has also opened recruitment for the corresponding Part 2 expansion cohort.

[0119] Safety analysis showed that the combination of Compound A and azacitidine for the treatment of AML or MDS or MDS / MPN was well tolerated and safe. effect

[0120] At the time of data cutoff (September 05, 2022), 57 patients with AML (31 TN and 26 R / R AML) were treated with azacitidine in combination with Compound A (40 mg x 10 days [n=16]; 80 mg x 10 days [n=17], 160 mg x 10 days later [n=16], and 160 mg x 28 days [n=8]). In the overall population, the median duration of treatment was 3 months (range: 0.1-15.4). Twenty-four (42%) patients had adverse cytogenetics, and 23 (40%) patients had bone marrow blasts ≥50% at study entry.

[0121] 65% of TN unfit AML patients and 50% of patients with R / R AML achieved CR / CRh; most CR+CRh in TN AML (15 of 20) were achieved by the end of cycle 1. Figure 2 is a summary of complete responses in patients with AML. The 80 mg x 10 day cohort (n=17) had the longest duration of treatment with a median of 7 cycles ( Figure 3 ); CR+CRh was seen in 73% and 67% of TN and R / R patients, respectively; and CR was seen in 73% and 50% of TN and R / R patients, respectively. Figure 4 A reduction in bone marrow blasts is shown.

[0122] The foregoing examples and descriptions of certain embodiments should be considered illustrative, rather than limiting, of the present invention as defined by the claims. As will be readily appreciated, many variations and combinations of the above features may be used without departing from the present invention as set forth in the claims. All of these variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entirety. References Adams,JM,and Cory,S.(2007)The Bcl-2apoptotic switch in cancer development and therapy.Oncogene 26,1324-1337 Anderson,M.A.,Huang,D.,and Roberts,A.(2014)Targeting BCL2 for thetreatment of lymphoid malignancies.Semin Hematol 51,219-227 Czabotar,P.E.,Lessene,G.,Strasser,A.,and Adams,J.M.(2014)Controlofapoptosis by the BCL-2 protein family:implications for physiology andtherapy.Nat RevMol Cell Biol 15,49-63 Egle,A.,Harris,A.W.,Bath,M.L.,O'Reilly,L.,and Cory,S.(2004)VavP-Bcl2transgenic mice develop follicular lymphoma preceded by germinal centerhyperplasia.Blood 103,2276-2283 Kondo,S.,Oakes,M.G.,and Sorenson,C.M.(2008)Rescue of renal hypoplasiaandcystic dysplasia in Bcl-2- / -mice expressing Bcl-2 in ureteric bud derivedepithelia.DevDyn 237,2450-2459 Roberts,A.W.(2016)Targeting apoptotic pathways to treat lymphoidmalignancies.Rinsho Ketsueki 57,2054-2058 Roberts,A.W.,and Huang,D.(2017)Targeting BCL2 With BH3 Mimetics:BasicScience and Clinical Application of Venetoclax in Chronic LymphocyticLeukemia andRelated B Cell Malignancies.Clin Pharmacol Ther 101,89-98 Schenk,R.L.,Strasser,A.,and Dewson,G.(2017)BCL-2:Long and windingpathfrom discovery to therapeutic target.Biochem Biophys Res Commun 482,459-469 Tausch,E.,Close,W.,Dolnik,A.,Bloehdorn,J.,Chyla,B.,Bullinger,L.,Dohner,H.,Mertens,D.,and Stilgenbauer,S.(2019)Venetoclax resistance andacquired BCL2mutations in chronic lymphocytic leukemia.Haematologica 104,e434-e437. Veis,D.J.,Sorenson,C.M.,Shutter,J.R.and Korsmeyer,S.J.(1993)Bcl-2-deficientmice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,andhypopigmentedhair.Cell,75,229–240. Yamamura,K.,Kamada,S.,Ito,S.,Nakagawa,K.,Ichihashi,M.,and Tsujimoto,Y.(1996)Accelerated disappearance of melanocytes in bcl-2-deficientmice.Cancer Res 56,3546-3550.

Claims

1. A method of treating a myeloid malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor in combination with a therapeutically effective amount of azacitidine, wherein the myeloid malignancies are acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN); and The Bcl-2 inhibitor is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.5]decan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(dimethylamino)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2-(dimethylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(oxo)-16-sulfanediyl)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanediylidene)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(3-oxomorpholino)ethyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octan-6-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((cis or trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((trans or cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. The method of claim 1, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 or 2, wherein the acute myeloid leukemia (AML) is treatment naive (TN) or relapsed / refractory (R / R) not suitable for intensive induction chemotherapy.

4. The method of claim 1 or 2, comprising orally administering to the patient the Bcl-2 inhibitor in increasing doses once daily, wherein the increasing doses comprise an initial dose of 5, 10, 20, or 40 mg of the Bcl-2 inhibitor per day.

5. The method of claim 4, wherein the Bcl-2 inhibitor is orally administered in two cycles comprising a 4-day ascending schedule (Cycle 1) and a subsequent cycle (Cycle 2).

6. A method as claimed in claim 5, wherein each of the 4-day ascending schedule (Period 1) is a 10-day cycle, a 21-day cycle, or a 28-day cycle; and the subsequent cycles (Period 2) are 10-day cycles, 21-day cycles, or 28-day cycles.

7. The method of claim 6, wherein the 4-day ascending schedule (cycle 1) of administration of the Bcl-2 inhibitor comprises a first dose on day 1, a second dose on day 2, a third dose on day 3, and a recommended dose on day 4 and later, wherein the recommended dose on day 4 and later is higher than the second dose on day 3, the third dose on day 3 is higher than the second dose on day 2, and the second dose on day 2 is higher than the second dose on day 1.

8. The method of claim 7, wherein the 4-day ascending schedule (cycle 1) of administration of the Bcl-2 inhibitor comprises a first dose on day 1 that is 12.5% ​​of the recommended dose, a second dose on day 2 that is 25% of the recommended dose, a third dose on day 3 that is 50% of the recommended dose, and daily doses on day 4 and thereafter that are 100% of the recommended dose.

9. The method of claim 8, wherein the dose of the subsequent cycle (Cycle 2) of the Bcl-2 inhibitor is administered at the recommended dose from Day 1 without escalation.

10. The method of claim 9, wherein in cycle 1, azacitidine is administered 1 day prior to administration of the Bcl-2 inhibitor (designated day 0).

11. The method of claim 10, wherein in cycle 2, azacitidine is administered concurrently with the Bcl-2 inhibitor.

12. The method of claim 11, wherein once daily (QD) at 75 mg / m 2 Azacitidine is administered intravenously or subcutaneously at a dose of 13. The method of claim 12, wherein the recommended dose of the Bcl-2 inhibitor is 160 mg once daily (QD).

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