Methods for Treating Myeloid Malignancies Using BCL-2 Inhibitors

Abstract

The present disclosure provides a method of treating a myeloid malignancy in a subject with 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, in combination with azacitidine, or a pharma- ceutical acceptable salt thereof.

Description

[Technical field]

[0001] Disclosed herein is a method for treating myeloid malignancies with 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, in combination with azacitidine, or a pharma- ceutical acceptable salt thereof. [Background technology]

[0002] Impaired apoptosis plays a central role in tumor initiation, tumor maintenance, and therapeutic resistance. Apoptosis can be induced through two major pathways: the extrinsic or death receptor-mediated pathway and the intrinsic or mitochondrial pathway (Czabotar et al. 2014). It is the intrinsic pathway that is more commonly perturbed in malignant lymphomas. Cell death mediated through this pathway is regulated by members of the family of proteins related to B-cell lymphoma-2 (Bcl-2), which is thought to comprise three subfamilies. The pro-survival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1 / Bfl-1, and possibly Bcl-B) promotes cell survival by inhibiting their pro-apoptotic relatives. Proapoptotic BAX / BAK-like proteins, including BOK, are essential effectors of apoptosis, while BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are initiators of apoptosis (Anderson et al. 2014). In healthy cells, pro-survival Bcl-2 proteins bind and inhibit BAX and BAK after they are partially activated, impairing the ability of BAX / BAK to oligomerize, form pores, and induce mitochondrial outer membrane permeabilization. BH3-only proteins are transcriptionally or post-transcriptionally induced in response to various stresses and initiate apoptosis by releasing BAX / BAK by binding to pro-survival Bcl-2 proteins or by directly activating these effectors of apoptosis. Various Bcl-2 family proteins have distinct binding specificities with each other, resulting in a complex but ordered network of interactions that govern cell fate (Roberts 2016).

[0003] Bcl-2 was the first anti-apoptotic protein discovered in the 1980s as a result of the t(14;18) chromosomal translocation and a hallmark of FL. The BCL-2 gene resides on chromosome 18q21.33. The Bcl-2 protein has 239 amino acids and a molecular weight of 26 kDa (Schenk et al., 2017). Bcl-2 is widely expressed during development and becomes restricted during maturation in many tissues (Kondon et al., 2008). Mice lacking Bcl-2 suffer from polycystic kidney disease early in life, as Bcl-2 is essential for the survival of renal epithelial progenitor cells during embryogenesis (Veis et al., 1993). Bcl-2-deficient mice also have abnormally reduced numbers of mature lymphocytes, resting B lymphocytes, and T lymphocytes, and are prematurely gray due to abnormal death of melanocytes (Veis et al., 1993, Yamara et al., 1996). Initially thought to act as a classical growth-promoting oncogene, Bcl-2 was later shown to instead promote the survival of malignant cells by attenuating apoptosis. Transgenic mice with pan-hematopoietic Bcl-2 expression (VavP-BCL-2) preferentially develop follicular lymphomas, which are preceded by florid germinal center hyperplasia (Egle et al. 2004). Mice co-expressing BCL-2 and MYC transgenes developed lymphomas significantly faster than littermates expressing either transgene alone, validating BCL-2 as an oncogene (Adams and Cory 2007).

[0004] High Bcl-2 expression is nearly universal in CLL, FL, MCL, and Waldenström's macroglobulinemia (WM). In contrast, Bcl-2 expression levels are somewhat more variable among multiple myeloma (MM) and substantially more variable among DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang 2017). Overexpression of Bcl-2 can perturb the ratio of pro- to anti-apoptotic Bcl-2 family members and block apoptotic cell death. In addition, Bcl-2 protein is closely related to chemoresistance in hematological tumors. Bcl-2-mediated resistance to intrinsic apoptosis is considered key to pathogenesis, so targeting Bcl-2 may improve apoptosis and overcome drug resistance to cancer therapy. Thus, Bcl-2 has become an attractive target for therapeutic strategies in cancer.

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

[0006] WO2019 / 210828A disclosed a series of compounds having the following formula (III-B), (III-C), (III-D), or (III-E), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, as Bcl-2 inhibitors: [ka]

[0007] The compounds disclosed in WO2019 / 210828A are potent and selective Bcl-2 protein inhibitors. Summary of the Invention

[0008] The inventors of the present disclosure have demonstrated that a Bcl2 inhibitor having formula (III-B), (III-C), (III-D) or (III-E), in particular 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 pharma- ceutical acceptable salt thereof, in combination with azacitidine, resulted in significant inhibition of tumor growth in acute myeloid leukemia (AML) compared to the efficacy of each therapeutic agent as a single agent. Additionally, the combination therapy demonstrates significant inhibition of tumor growth in myeloid malignancies, including acute myeloid leukemia (AML) (either treatment-naïve [TN] or relapsed / refractory [R / R] unsuitable for intensive induction chemotherapy), myelodysplastic syndromes (MDS), or MDS / myeloproliferative neoplasms (MPN).

[0009] In a first aspect, disclosed herein is a method of treating a myeloid malignancy with a Bcl-2 inhibitor in combination with azacitidine, the Bcl-2 inhibitor being a compound represented by the following formula (III-B), (III-C), (III-D), or (III-E): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof; During the ceremony, R 2 each independently represents hydrogen, halogen, or -C optionally substituted with halogen1-8 is selected from the group consisting of alkyl, R 1d are each independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR Ba , -SO 2 R Ba , -COR Ba , -CO 2 R 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 CO 2 R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO 2 NR Bb R Bc , or -NR Ba SO 2 R Bb and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently have 1 to 4 substituents R Bd is optionally replaced by; R Ba , R Bb , and R Bc are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl,1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -NH 2 Or -N(C 1-6 Alkyl) 2 , -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Bd are each independently hydrogen, halogen, oxo, -CN, -NO 2 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R 5 -L 5 -CyC, In the formula, L 5 is a direct bond, -(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)-, -SO 2-, -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 -, -SO 2 NR a -, -NR a SO 2 -, -NR a S(O) 2 NR b -, -NR a S(O)NR b -, -C(O)NR a SO 2 -, -C(O)NR a SO-, or -C(=NR a )NR b -, wherein each of t and v is independently a number from 1 to 7; -(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 two CRs in a R b The moiety is either unsubstituted or O, S, SO, SO 2 , C(O), and NR a is replaced by one or more moieties selected from; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may contain one or two substituents R 5a is optionally replaced by; R 5a are each independently hydrogen, halogen, cyano, oxo, -NO 2, -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 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) 2 NR 5c R 5d , -NR 5b SO 2 R 5c , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may have one or two substituents R 5e is optionally replaced by; R 5b , R 5c , and R 5d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may have one or two substituents R 5e is optionally replaced by; R 5e are each independently hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO 2 R 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) 2 NR 5g R 5h , -NR 5f SO 2 R 5g , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5f , R 5g , and R 5h are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or, two adjacent R on a phenyl ring 5together with the phenyl ring to form a benzo ring, said ring being free of halogen, oxo, cyano, -NO 2 , -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO 2 R 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) 2 NR 5j R 5k , -NR 5i SO 2 R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 optionally substituted with 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, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, or -C 1-8 optionally substituted with alkyloxy; R a , R b , R c , and R d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or -SR e is optionally replaced by; R e and R f are each independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, C 2-8 It is alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0010] In a second aspect, disclosed herein is a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D), or (III-E), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, in combination with azacitidine, for use in the treatment of a myeloid malignancy.

[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 of 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 use in treating a myeloid malignancy, wherein the pharmaceutical combination comprises a Bcl-2 inhibitor of Formula (III-B), (III-C), (III-D), or (III-E), or a stereoisomer thereof, or a pharmaceutical 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 pharma- ceutical acceptable salt thereof.

[0014] In one embodiment of each of the above aspects, the malignant myeloid neoplasm is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN). In some preferred embodiments, the acute myeloid leukemia (AML) is either untreated (TN) or relapsed / refractory (R / R) for intensive induction chemotherapy.

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

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

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

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

[0020] In some embodiments, the 4 day ramp-up schedule (Cycle 1) of Bcl-2 inhibitor administration comprises a first dose on day 1, a second dose on day 2, a third dose on day 3, and a recommended dose on days 4 and beyond, where the recommended dose on days 4 and beyond is greater than the second dose on day 3, the third dose on day 3 is greater than the second dose on day 2, and the second dose on day 2 is greater 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 administered orally on a 4 day ramp-up 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 daily doses on days 4 and beyond that are 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 doses on days 4 and thereafter are 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 days 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 days 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 days 4 and thereafter is about 160 mg / day.

[0022] In some embodiments, the subsequent cycle (Cycle 2) of administration of the Bcl-2 inhibitor is at the recommended dose from day 1 with no ramp-up. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, or 160 mg daily.

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

[0024] In some embodiments, the azacitidine in cycle 2 is administered simultaneously with the Bcl-2 inhibitor (referred to as day 1).

[0025] In one embodiment of each of the above aspects, azacitidine is administered at 75 mg / m 2 is administered intravenously or subcutaneously once daily (QD) at a dose 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, Bcl-2 is administered orally once daily (QD). [Brief description of the drawings]

[0028] [Figure 1] Part 1 Dosing schema in AML. [Diagram 2] Overview of complete responses in patients with AML. [Diagram 3] Best overall response in a patient with AML. [Figure 4] Best change from baseline in bone marrow blasts in patients with AML. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] definition Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art.

[0030] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0031] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0032] As used herein, the term "anti-cancer agent" refers to any agent that can be used to treat a cell proliferative disorder, such as cancer, including, but not limited to, cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapy agents, targeted anti-cancer agents, and immunotherapy agents.

[0033] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to an animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell includes contact of a reagent to the cell, as well as contact of a reagent to a fluid where the fluid is in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, for example, with a reagent, diagnostic, binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human. Treating any disease or disorder, in one aspect, refers to ameliorating the disease or disorder (i.e., slowing, preventing, or alleviating at least one of the disease or its clinical symptoms). In another aspect, "treat", "treating", or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another aspect, "treat", "treating", or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another aspect, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.

[0034] The term "subject" in the context of this disclosure refers to a mammal, such as a primate, preferably a higher primate, such as a human (e.g., a patient having or at risk of having a disorder described herein). In some embodiments, the subject is a human or a patient.

[0035] The term "cancer" or "tumor" as used herein has the broadest meaning as understood in the art and refers to a physiological condition in mammals that is typically characterized by unregulated cell proliferation. In the context of this disclosure, cancer is not limited to a particular type or location.

[0036] 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 effect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on 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 being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of skill in the art or can be determined by routine experimentation. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination for effective treatment of a disease, disorder, or condition.

[0037] As used herein, the term "ramp-up scheme" or "ramp-up schedule" refers to a regimen in which an active ingredient of interest is administered in increasing doses on a regular basis, such as daily or weekly, over a specified period of time (days or weeks), and then administered up to the recommended dose (daily or weekly).

[0038] The present disclosure provides a method of treating a myeloid malignancy in a subject, comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of azacitidine.

[0039] Bcl-2 inhibitors The Bcl-2 inhibitors of the present disclosure are compounds represented by the following formula (III-B), (III-C), (III-D), or (III-E): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof; During the ceremony, R 2 each independently represents hydrogen, halogen, or -C optionally substituted with halogen 1-8 is selected from the group consisting of alkyl, R 1d are each independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -OR Ba , -SO 2 R Ba , -COR Ba , -CO 2 R 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 CO 2 R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO 2 NR Bb R Bc , or -NR Ba SO 2 R Bb and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently have 1 to 4 substituents R Bd is optionally replaced by; R Ba , R Bb , and R Bcare each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -NH 2 Or -N(C 1-6 Alkyl) 2 , -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Bd are each independently hydrogen, halogen, oxo, -CN, -NO 2 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R 5 -L 5 -CyC, In the formula, L 5 is a direct bond, -(CR a R b ) t -, -(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -, -(CR a Rb ) t-1 -(C≡C)-(CR a R b ) v-1 -, -O-, -S-, -S(O)-, -SO 2 -, -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 -, -SO 2 NR a -, -NR a SO 2 -, -NR a S(O) 2 NR b -, -NR a S(O)NR b -, -C(O)NR a SO 2 -, -C(O)NR a SO-, or -C(=NR a )NR b -, wherein each of t and v is independently a number from 1 to 7; -(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 two CRs in a R b The moiety is either unsubstituted or O, S, SO, SO 2 , C(O), and NR a is replaced by one or more moieties selected from; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may contain one or two substituents R 5a is optionally replaced by; R 5a are each independently hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 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) 2 NR 5c R 5d , -NR 5b SO 2 R 5c , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may have one or two substituents R 5e is optionally replaced by; R 5b , R 5c , and R 5d are each independently hydrogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may have one or two substituents R 5e is optionally replaced by; R 5e are each independently hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO 2 R 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) 2 NR 5g R 5h , -NR 5f SO 2 R 5g , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5f , R 5g , and R 5h are each independently hydrogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or, two adjacent R on a phenyl ring 5 together with the phenyl ring to form a benzo ring, said ring being free of halogen, oxo, cyano, -NO 2 , -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO 2 R 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) 2 NR 5j R 5k , -NR 5i SO 2 R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 optionally substituted with 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, 1-8Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from halogen, hydroxy, or -C 1-8 optionally substituted with alkyloxy; R a , R b , R c , and R d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or -SR e is optionally replaced by; R e and R f are each independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, C 2-8 It is alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0040] In some embodiments, R 2 is hydrogen.

[0041] In some embodiments, R 1d is substituted on the phenyl group at the 2-position of ring B (containing an aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl, or azocan-1-yl, preferably a pyrrolidin-1-yl group), independently represents a halogen, -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO 2 R Ba , -CONR Ba R Bb , -NO 2 , -NR Ba R Bb , -NR Ba COR Bb , or -NR Ba SO 2 R Bb and 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently represent one to four substituents R as defined in formula (III-B), (III-C), (III-D), or (III-E). Bd and optionally substituted with one or two substituents R as defined in formula (III-B), (III-C), (III-D), or (III-E). Bd In another embodiment, one R 1d is at the 2-position of ring B and the 2-position of the phenyl ring.

[0042] In some embodiments, R 1d is methyl, ethyl, isopropyl, propyl, or methoxymethyl, or two methyls at positions on a phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0043] 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: [ka] [ka] [ka]

[0044] In some embodiments, m is 1; L 5 is a direct bond, -(CR a R b ) t -OR-NR a -, where t is a number from 1 to 7, -(CR a R b ) t -One or two CRs in a R b is unsubstituted or is O and NR a wherein R a and R b is defined by formula (III-B), (III-C), (III-D), or (III-E).

[0045] In some embodiments, L 5 is a direct bond, -(CR a R b ) 1-4 -, -O-(CR a R b ) 1-3 -, -NH-(CR a R b ) 1-3 or -NH-, where R a and R b is defined as in formula (III-B), (III-C), (III-D), or (III-E), so that -L 5 The -CyC portion is CyC, -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b )1-3 More preferably, L is -CyC, or -NH-CyC. 5 is a direct bond, -(CH 2 ) 1-4 -, -O-(CH 2 ) 1-3 -, -NH-(CR a R b )-(CH 2 ) 2 - or -NH-, where R a is hydrogen and R b is C optionally substituted with phenyl-S- 1-8 alkyl, so that -L 5 The -CyC moiety is CyC, -(CH 2 ) 1-4 -CyC, -O-(CH 2 ) 1-3 -CyC, -NH-(CR a R b )-(CH 2 ) 2 More preferably, L is -CyC, or -NH-CyC. 5 is a direct bond, -CH 2 -, -O-CH 2 -, -NH-CH 2- or -NH-, so that -L 5 The -CyC moiety is CyC, -CH 2 -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC, or -NH-CyC.

[0046] In some embodiments, CyC is cycloalkyl, or heterocyclyl, each of which is selected from the group consisting of one or two substituents R 5a is optionally replaced by; R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 Alkyl, -C2-8 alkynyl, -cycloalkyl, or heterocyclyl; 1-8 Each of alkyl and heterocyclyl is selected from hydrogen, halogen, cyano, -OR 5f , -C 1-8 one or two substituents R selected from alkyl, -cycloalkyl, or heterocyclyl; 5e is optionally replaced by; In the formula, R 5b and R 5c are each independently hydrogen, -C 1-8 alkyl or heterocyclyl, 1-8 Alkyl is hydrogen, -NR 5f R 5g or one or two substituents R which are -cycloalkyl 5e is optionally replaced by; R 5f and R 5g are each independently hydrogen or -C 1-8 is alkyl; Or, two adjacent R on a phenyl ring 5 taken together with the phenyl ring forms a benzo ring, which is optionally substituted with heteroaryl.

[0047] In some embodiments, CyC is a monocyclic C 3-8 Cycloalkyl or bridged cycloalkyl ( [ka] ), each of which is selected from one or two substituents R 5a Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two substituents R 5a is optionally replaced by

[0048] In some embodiments, CyC is a heterocyclyl selected from: a) a monocyclic 4- to 9-membered heterocyclyl group containing one nitrogen, oxygen or sulfur heteroatom as a ring member; b) a monocyclic 4- to 9-membered heterocyclyl group containing two heteroatoms selected from oxygen, sulfur, and nitrogen as ring members, and c) 5-20 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur, and oxygen as ring members. (Each of these has one or two R 5a (optionally replaced by ).

[0049] In some embodiments, CyC is a monocyclic 4-6 membered heterocyclyl group containing one nitrogen or oxygen or sulfur heteroatom as a ring member. More preferably, CyC is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 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.

[0050] 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 piperidinyl. Even more preferably, CyC is 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl.

[0051] In some embodiments, R 5a are independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R5c , -COR 5b , -SO 2 R 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 a nitrogen, oxygen, or sulfur heteroatom as ring members, 1-8 Each of the alkyl and monocyclic 4- to 9-membered heterocyclyl groups may have one or two substituents R 5e and optionally substituted with; preferably, R 5a Cycloalkyl as C 3-6 is cycloalkyl; more preferably, cyclopropyl; preferably, R 5a Heterocyclyl as R is a 4- to 6-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen or sulfur heteroatoms as ring members; more preferably, R 5a Heterocyclyl as R is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or morpholinyl; even more preferably, R 5a Heterocyclyl as is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morphin-4-yl.

[0052] In some embodiments, R 5e Heterocyclyl as is a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members.

[0053] In some embodiments, R 5e Heterocyclyl as is tetrahydro-pyran-4-yl.

[0054] In some embodiments, R 5a -NR 5b R 5c where R 5bis hydrogen and R 5c is heterocyclyl.

[0055] In some embodiments, R 5a -NR 5b R 5c where R 5b is hydrogen and R 5c is tetrahydro-pyran-4-yl.

[0056] In some embodiments, R 5a -NR 5b R 5c where R 5b and R 5c each independently represents hydrogen or a -C substituted with cycloalkyl; 1-6 Alkyl, preferably monocyclic C 3-8 Cycloalkyl-substituted -C 1-6 It is an alkyl.

[0057] In some embodiments, R 5a -OR 5b OR -SO 2 R 5b where R 5b is hydrogen or C 1-8 It is alkyl, preferably methyl.

[0058] In some embodiments, R 5a HA-COR 5b where R 5b is hydrogen or -NR 5f R 5g C optionally replaced with 1-8 is alkyl, R 5f and R 5g are each independently hydrogen or C 1-8 It is alkyl, preferably methyl.

[0059] In some embodiments, two adjacent R on the phenyl ring 5 together with the phenyl ring forms an indazolyl substituted with tetrahydropyranyl.

[0060] In some embodiments, m is 1 and R 5 is selected from the group consisting of: 5 -CyC: [ka] [ka]

[0061] In some embodiments, m is 1 and R 5 teeth, [ka] It is.

[0062] In some embodiments, the Bcl-2 inhibitor of the present disclosure is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]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]undecan-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]undecan-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]heptan-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]heptan-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-sulfanylidene)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-sulfanylidene)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]heptan-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]heptan-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]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-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]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-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]heptan-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 pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0063] 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 pharma- ceutical acceptable salt thereof.

[0064] Preparation of Bcl-2 inhibitors 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]nonan-7-yl)benzamide (Compound A), may be prepared by the methods disclosed in International Publication WO2019 / 210828A1.

[0065] Preparation of Compound A Step 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane hydrochloride

[0066] To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 g, 2.09 mol) in MeOH (750 mL) and EA (750 mL) was added concentrated HCl acid (350 mL, 4.18 mol) at room temperature and stirred for 4 h. After concentration in vacuum, MeOH (750 mL) was added into the residue and then the resulting mixture was concentrated in vacuum (this workup was repeated twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 h. The solid precipitate was filtered and dried in vacuum to give the title product as an off-white powder (350 g, yield: 76.0%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 3.03 (s, 6 H), 2.96-2.89 (m, 4 H), 1.93 (s, 4 H), 1.74-1.67 (m, 4 H). MS (ESI, m / e) [M+1] + 186.0.

[0067] Step 2: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate methyl

[0068] 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 equiv.), and DBU (160 g, 3.0 equiv.) in NMP (500 mL) was stirred at 85° C. for 16 h. After the reaction was completed, the mixture was cooled to 50±5° C., and aqueous citric acid (2%, 5 L) was added dropwise into the system with stirring. After filtration, the cake was collected and dissolved in DCM (1.5 L). The crude product solution was diluted with aqueous citric acid (2%, 1.5 L), saturated NaHCO 3aqueous solution (1.5 L) and 15% NaCl aqueous solution (1.5 L), then washed with anhydrous Na 2 SO 4 The crude product was dried over 100 ml. Silica gel (100 g) was added to the solution with 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 cake was collected after filtration and dried in vacuum to give an off-white solid (192 g, yield: 72.1%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.63 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.79 (dd, J MS (ESI, m / e) [M+1]+ 451.9.

[0069] Step 3: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate methyl

[0070] To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate (176 g, 0.39 mol) in DCM (2 L) was added diluted HCl acid (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 aqueous NaOH (4 M) while stirring. The organic phase was separated, washed with 15% aqueous NaCl (1 L) and then diluted with H 2The organic phase was concentrated to 500 mL, and then MTBE (1 L) was poured into the solution, and the system was then concentrated to 500 mL (this workup was repeated three times). The resulting system was stirred for 0.5 h. After filtration, the cake was collected and then dried in vacuum to give the title product as a white solid (152 g, yield: 96.23%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm: 11.64 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.38-6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H). MS (ESI, m / e) [M+1]+ 405.9.

[0071] Step 4: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0072] Dioxane (500 mL) and H 2 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 200 (50 mL) was added Cs 2 CO 3 (100 g, 305 mmol) and Pd(dppf)Cl 2(6.6 g, 7.5 mmol) was added. The mixture was stirred at 100° C. for 8 h. TLC showed 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 give (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.

[0073] Step 5: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0074] 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), Pd / C (10 g, 10%) was added and the mixture was heated at 20 °C for 30 min. 2 The mixture was stirred under (15 psi) for 12 h. 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), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H).

[0075] Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0076] To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) dropwise at room temperature. 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 (400 MHz, DMSO-d 6 ) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, MS (ESI, m / e) [M+1]+ 190.0.

[0077] Step 7: (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)benzoate methyl

[0078] A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) was charged to the reactor. The temperature was controlled below 30° C., and NaBH(OAc) 3(216 g, 1.018 mol) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature overnight and monitored by TLC. After the starting ketone was completely consumed, the mixture was adjusted to pH=4-5 with dilute HCl acid (0.5 M). The separated organic phase was diluted with H 2 Wash with O (600 mL × 2) and then with NaHCO 3 The organic phase was collected and then washed with anhydrous NaCl (600 mL x 2). 2 SO 4 It was dried over and concentrated to give 256 g of an off-white solid as crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0079] Step 8: (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

[0080] To a solution of (S)-methyl 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)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). The mixture was stirred at room temperature overnight. After removing THF and MeOH in vacuum, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH=5-6 with 3N HCl acid while stirring at room temperature. The precipitate was filtered and dried in vacuum to give the product as a white solid (102.4 g, yield: 99%). 1 HNMR (400 MHz, DMSO-d 6) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.35 (s, 1H), 7.27 - 7.04 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 - 3.26 (m, 1H), 3.10 - 3.04 (m, 4H), 2.35-2.30 (m, 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.

[0081] 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)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide

[0082] 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 at room temperature overnight. The reaction was monitored by HPLC. After complete consumption of the (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 starting material, the reaction mixture was heated to about 35° C. and N 1 ,N 1 -Dimethylethane-1,2-diamine (17.2 g, 195 mmol) was added in one portion. The reaction was stirred for an additional 12 h. The mixture was washed twice with 10 wt% aqueous AcOH (300 mL x 2) and then saturated NaHCO 3 The mixture was cooled to room temperature, and the precipitate was filtered, and then the wet cake was washed twice with EA (180 mL). After drying under vacuum at 80-90°C, the desired compound was obtained (48 g, yield: 69.5%). 1 HNMR (DMSO-d 6) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, MS (ESI, m / e) [M+1]+ 889.9.

[0083] Treatment method In one embodiment, the present disclosure provides a method for treating cancer.In certain embodiments, 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).

[0084] Compound A can be administered by any suitable means, including oral, parenteral, intrapulmonary, and intranasal, and can be administered intralesionally if localized treatment is required. Administration can be by any suitable route. Various administration schedules are contemplated herein, including, but not limited to, single or multiple administrations over various time periods, bolus administration, and pulse infusion.

[0085] Compound A will be formulated, dispensed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular injury being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the injury, the site of delivery of the agent, the method of administration, the dosing schedule, 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 in question. The effective amount of such other agents will depend on the amount of Compound A in the formulation, the type of injury or treatment, and other factors described above.

[0086] For the prevention or treatment of disease, the appropriate dosage of Compound A will depend on the type of disease being treated, the severity and course of the disease, whether Compound A is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's medical history and response to Compound A, and the discretion of the attending physician. Compound A is suitably administered to the patient at one time or over a series of treatments. EXAMPLES

[0087] The present invention is further illustrated by the following examples which illustrate the invention but are not limited thereto.

[0088] Example 1: Clinical Study 1. Method Research design / purpose This clinical trial was conducted to evaluate the combination of Compound A and azacitidine in patients with myeloid malignancies, including acute myeloid leukemia (AML) (either treatment-naïve [TN] or relapsed / refractory [R / R] ineligible for intensive induction chemotherapy), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN). Patients with AML who were treatment-naïve and ineligible for intensive chemotherapy or who were relapsed / refractory were enrolled in the AML cohort. Patients with myelodysplastic syndrome (MDS) or MDS / myeloproliferative neoplasm (MPN) who had high-risk disease and were treatment-naïve or who were relapsed / refractory were enrolled in the MDS cohort.

[0089] AML cohort: The AML cohort will enroll patients with treatment-naïve (TN) AML and relapsed / refractory (R / R) AML who are unsuitable for intensive chemotherapy. Treatment cycles will be 28 days for all AML cohorts unless otherwise recommended by the Safety Monitoring Committee (SMC).

[0090] Part 1 AML (dosing regimen setting; N ≈ 18–36, i.e., min 6, max 12 / cohort) was administered at 75 mg / m 2 The safety and tolerability of different dose regimens of Compound A in combination with a fixed dose of azacitidine was tested. After three patients completed the dose-limiting toxicity (DLT) window, the SMC reviewed all available data and, considering the possibility of a DLT rate >20%, recommended whether to enroll additional patients (i.e., up to 12 patients). If no additional patients were required, the SMC would recommend whether to initiate a subsequent dose regimen in part 1 and whether to initiate a dose regimen in an expansion in part 2.

[0091] In each cohort, Compound A was ramped up for 4 days in cycle 1 only: 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 evaluating dose-limiting toxicities (DLTs) was until day 28 for non-hematologic toxicities and until day 42 or the start of cycle 2 for hematologic toxicities.

[0092] The dosing cohorts for AML Part 1 are as follows: A) Compound A was administered at 40 mg per day for 10 days together with azacitidine (ramp-up doses of Compound A: 5 mg, 10 mg, 20 mg, 40 mg). B) Compound A was administered at 80 mg per day for 10 days with azacitidine (ramp-up doses of Compound A: 10 mg, 20 mg, 40 mg, 80 mg). C) Compound A 160mg per day for 10 days, administered with azacitidine (ramp-up doses of Compound A: 20mg, 40mg, 80mg, 160mg) D) Compound A 160mg per day for 28 days, administered with azacitidine (ramp-up doses of Compound A: 20mg, 40mg, 80mg, 160mg) E) Compound A 320 mg / day x 21 days with azacitidine (compound A ramp-up doses: 40 mg, 80 mg, 160 mg, and 320 mg) F) Compound A 320 mg / day x 28 days with azacitidine (ramp-up doses of Compound A: 40 mg, 80 mg, 160 mg, and 320 mg) In all Part 1 AML cohorts receiving the 28-day dosing regimen and in Part 2 cohorts, the first dose of azacitidine was administered 1 day prior to administration of Compound A (referred to as Day 0) to compare baseline PK samples of azacitidine monotherapy with azacitidine in combination with Compound A beginning on Day 1. In subsequent cycles and all remaining cohorts, administration of azacitidine begins simultaneously with Compound A on Day 1. The dosing schema for Part 1 AML is shown in Figure 1.

[0093] Part 2 AML (safety expansion, N≈60) was treated up to cohorts of approximately 10 patients each with the dose regimen defined in part 1 and recommended by the SMC for progression to part 2. Part 2 of the study involved longer follow-up to determine safety and antileukemic activity in a larger number of patients with dose regimens that showed early signs of activity and were deemed tolerable in part 1. At a given time point, multiple dose regimens may be approved for expansion in part 2, but prospective participants were to be offered only a single part 2 AML cohort. Patients were preferentially enrolled in any open part 1 cohort, if applicable. Each of the second cohorts continued to enroll up to 10 patients. This includes additional patients who were enrolled in part 1 but were not required for the initial SMC safety review of that cohort. Based on SMC recommendations, cohorts may be closed before enrolling 10 patients or may be expanded to enroll an additional 10 patients and collect additional data at a particular dose regimen. Once enrollment in all Part 2 AML cohorts is complete, the recommended dose will be determined by the SMC based on safety, tolerability, and PK.

[0094] Azacitidine 75 mg / m 2 The dose regimen of 160 mg once daily of Compound A with 0.1% CI 0.01 to 0.15 for 10 days may be selected as the recommended dose for Part 3, unless another tested dose regimen is deemed superior based on the SMC evaluation.

[0095] Part 3 AML (efficacy expansion, N≈40) treated approximately 20 patients with the recommended dose determined in the Part 2 AML cohort. All AML patients will be enrolled in a single Part 3 AML cohort. However, based on differences in safety and tolerability in AML patients, the AML cohort may be split into two separate cohorts: TN AML patients who are unsuitable for intensive chemotherapy and R / R AML patients.

[0096] A subset of the Part 3 AML cohort will undergo a modified second treatment cycle to explore DDIs with posaconazole, a potent cytochrome P450 (CYP) 3A4 inhibitor. The schedule of 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. Patients will then receive Compound A at one-eighth the recommended dose from days 11-20. Posaconazole will be administered at 300 mg twice daily (BID) on day 13, then 300 mg once daily with food (30 min prior to Compound A administration) from days 14-20. If a 28-day Compound A course is selected, Compound A at 1 / 8 the recommended dose will be administered on days 11-28 of cycle 2 with posaconazole on days 13-20. PK sampling will be performed on days 12-13 and 20-21 of cycle 2. Regular dosing will resume from cycle 3 onwards.

[0097] In the AML monotherapy part (N≈10), the safety and tolerability of Compound A as monotherapy in R / R patients was tested. After three patients have completed the dose-limiting toxicity (DLT) window, the SMC will review all available data and, considering the possibility of a DLT rate >20%, recommend whether to enroll additional patients. The SMC will also recommend whether the dose level needs to be modified.

[0098] In the monotherapy cohort, there was a 4-day ramp-up of Compound A in the first cycle only, with 12.5% ​​of the target dose on day 1, 25% on day 2, 50% on day 3, and 100% on day 4.

[0099] The R / R AML monotherapy cohorts were as follows: Compound A was administered at 160mg per day for 28 days (ramp-up doses of Compound A: 20mg, 40mg, 80mg, and 160mg) The target dose is 160 mg daily for 28 days unless another dose level is selected for dosing by the SMC.

[0100] The monotherapy cohort received Compound A at a target dose of 160 mg (selected by SMC as the recommended dose) once daily for 28 days.

[0101] Selection Criteria Each patient eligible to participate in this study must meet all of the following eligibility criteria: 1. Age 18 or older 2. Confirmed diagnosis according to the 2016 World Health Organization criteria: a. AML, non-acute promyelocytic leukemia 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 4. Adequate organ function defined as: Creatinine clearance ≥ 45 mL / min (or 30-45 mL / min in the unmatched AML cohort) b. Liver function is adequate 5. Life expectancy of more than 12 weeks 6. Ability to comply with exam requirements Exclusion criteria

[0102] Each patient eligible to participate in this study must not meet any of the following exclusion criteria: 1. Diagnosis of Acute Promyelocytic Leukemia 2. Have had a malignancy within the past 2 years, except for localized skin cancer that has been treated with medical therapy, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score of 6 or less for prostate cancer. 3. Antecedent MPN including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation 4. Known central nervous system involvement by leukemia 5. Pretreatment with Bcl-2 inhibitors or azacytidine

[0103] MDS cohort: 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 one systemic therapy. In the MDS cohort, the dosing cycle was 28 days unless changed by SMC.

[0104] Part 1 MDS (dosing regimen setting, N≒12-24) will consist of a minimum of 3 and a maximum of 6 MDS patients / cohort, with 75 mg / m 2 The patients were treated with the respective dose regimens of Compound A in combination with azacitidine.

[0105] In each cohort, there was a 4-day ramp-up of Compound A in the first cycle only, with 12.5% ​​of the target dose on day 1, 25% on day 2, 50% on day 3, and 100% on day 4.

[0106] The dose-setting cohorts for MDS Part 1 were as follows: A) Compound A was administered at 40 mg per day for 10 days with azacitidine (ramp-up doses of Compound A: 5 mg, 10 mg, 20 mg, and 40 mg). B) Compound A 80 mg / day x 10 days with azacitidine (ramp-up doses of Compound A: 10 mg, 20 mg, 40 mg, and 80 mg) C) Compound A 160mg / day x 10 days with azacitidine (ramp-up doses of Compound A: 20mg, 40mg, 80mg, and 160mg) D) Compound A 160 mg / day x 21 days with azacitidine (compound A ramp-up doses: 20 mg, 40 mg, 80 mg, and 160 mg)

[0107] Compound A was administered in combination with azacitidine at a target dose of 160 mg once daily for 10 days. This cohort was initiated after safety data from the first two cohorts of AML patients enrolled in Part 1 were reviewed by the SMC and no safety concerns were identified. Compound A in cycle 1 will be administered with a 4-day ramp-up: 20 mg, 40 mg, 80 mg, 160 mg. Although it is expected that a single dose regimen will be tested in Part 1 MDS, the SMC may choose to test alternative dose regimens after reviewing this data or data from subsequent MDS or AML cohorts. After three patients in a cohort have completed one cycle of treatment, the SMC will review all available data before initiating a subsequent cohort, if applicable. The SMC may recommend treating additional patients in a cohort before confirming tolerability.

[0108] In Part 2 MDS (safety expansion, N≈40), up to 10 patients are treated with the dose regimen(s) selected in Part 1 MDS. At any time, a single Part 2 MDS cohort may be enrolled. After completion of enrollment into all Part 2 MDS cohorts, the recommended dose may be determined by the SMC based on safety, tolerability, and PK data from these Part 2 cohorts, as well as any available activity and / or exploratory data.

[0109] Azacitidine 75 mg / m 2 A dose regimen of Compound A 160 mg once daily for 10 days with

[0110] In Part 3 MDS (efficacy expansion, N≈40), approximately 20 patients were treated with the MDS dose determined in Part 2 MDS. Enrollment into Part 3 will begin once the Part 2 cohort has completed enrollment and an SMC recommendation has been received after review of all available data.

[0111] All cohorts in Part 1, Part 2, and Part 3 were evaluated for DLTs. The DLT window began with the first dose of study drug and continued until Day 28 for non-hematologic toxicities and until Day 42 of Cycle 1 or the start of Cycle 2 for hematologic toxicities.

[0112] The MDS monotherapy part (N≈10) tested the safety and tolerability of Compound A as monotherapy in patients with MDS or MDS / MPN. After three patients completed the DLT window, the SMC reviewed all available data and, considering the possibility of a DLT rate >20%, recommended whether to enroll additional patients. The SMC also recommended whether dose levels should be modified. In the monotherapy cohort, there was a 4-day ramp-up of Compound A in the first cycle 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 MDS and MDS / MPN monotherapy cohorts are as follows: Compound A was administered at 160mg per day for 28 days (ramp-up doses of Compound A: 20mg, 40mg, 80mg, and 160mg) The target dose is 160 mg daily for 28 days unless another dose level is selected for dosing by the SMC.

[0113] Azacitidine 75 mg / m 2 A dose regimen of 160 mg of the compound once daily for 10 days with may be selected as the recommended dose for part 3 unless an alternative dose regimen is deemed likely to be superior in terms of toxicity or efficacy.

[0114] 2. Results and Conclusions safety As of February 4, 2023, 97 patients have been enrolled, of which 66 have AML and 31 have MDS or MDS / MPN. Evaluation of the part 1 AML cohort for the 10-day regimens of 40 mg, 80 mg, and 160 mg Compound A, as well as the 28-day regimen of 160 mg in combination with azacitidine, has been completed by SMC, and the respective part 2 expansion cohorts have also begun enrollment. The 21-day regimen of 320 mg Compound A has also begun enrollment in part 1.

[0115] Evaluation of part 1 cohorts for 10-day regimens of 40 mg, 80 mg, and 160 mg Compound A in combination with azacitidine in MDS or MDS / MPN has been completed by SMC, and respective part 2 expansion cohorts have also begun enrolling.

[0116] Safety analyses demonstrated that the use of Compound A in combination with azacitidine in the treatment of AML or MDS or MDS / MPN was well tolerated and safe.

[0117] Effectiveness At the time of data cutoff (September 5, 2022), 57 patients with AML (31 TN, 26 R / R AML) were being treated with azacitidine in combination with Compound A (40 mg × 10 days [n = 16]; 80 mg × 10 days [n = 17], 160 mg × 10 days [n = 16], and 160 mg × 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%) had ≥ 50% bone marrow blasts at study entry.

[0118] CR / CRh was achieved in 65% of TN-mismatched AML and 50% of R / R AML patients; most CR+CRh in TN AML (15 of 20) were achieved by the end of cycle 1. Figure 2 summarizes the complete responses in AML patients. The 80 mg x 10 days cohort (n=17) had the longest treatment duration, with a median of 7 cycles (Figure 3); CR+CRh was seen in 73% and 67% of TN and R / R patients, respectively; CR was seen in 73% and 50% of TN and R / R patients, respectively. The reduction in bone marrow blasts is shown in Figure 4.

[0119] The foregoing examples and descriptions of specific embodiments should be construed as illustrative rather than limiting the invention defined by the claims. As will be readily understood, numerous variations and combinations of the features described above can be utilized without departing from the invention as defined by the claims. All such 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-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324-1337 Anderson, MA, Huang, D., and Roberts, A. (2014) Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol 51, 219-227 Czabotar, PE, Lessene, G., Strasser, A., and Adams, JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49-63 Egle, A., Harris, A. W., Bath, M. L., O’Reilly, L., and Cory, S. (2004) VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276- 2283 Kondo, S., Oakes, M. G., and Sorenson, C. M. (2008) Rescue of renal hypoplasia and cystic dysplasia in Bcl-2 - / - mice expressing Bcl-2 in ureteric bud derived epithelia. Dev Dyn 237, 2450-2459 Roberts, A. W. (2016) Targeting apoptotic pathways to treat lymphoid malignancies. Rinsho Ketsueki 57, 2054-2058 Roberts, A. W., and Huang, D. (2017) Targeting BCL2 With BH3 Mimetics: Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies. Clin Pharmacol Ther 101, 89-98 Schenk, R. L., Strasser, A., and Dewson, G. (2017) BCL-2: Long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482, 459-469 Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Dohner, H., Mertens, D., and Stilgenbauer, S. (2019) Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434-e437. Veis, D.J., Sorenson, C.M., Shutter, J.R. and Korsmeyer, S.J. (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75, 229-240. Yamamura, K., Kamada, S., Ito, S., Nakagawa, K., Ichihashi, M., and Tsujimoto, Y. (1996) Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res 56, 3546-3550.

Claims

1. 1. A method of treating a myeloid malignancy in a subject, 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 malignancy is acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or MDS / myeloproliferative neoplasm (MPN); The method, wherein 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]undecan-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]undecan-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]heptan-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]heptan-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-sulfanylidene)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-sulfanylidene)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]heptan-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]heptan-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]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-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]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-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]heptan-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 pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

2. 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. 3. The method of claim 1 or 2, wherein the acute myeloid leukemia (AML) is either untreated (TN) or relapsed / refractory (R / R) unsuitable for intensive induction chemotherapy.

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

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

6. 6. The method of claim 5, wherein each of the four day ramp-up schedules (cycle 1) is a 10 day cycle, a 21 day cycle, or a 28 day cycle, and the subsequent cycle (cycle 2) is a 10 day cycle, a 21 day cycle, or a 28 day cycle.

7. 7. The method of claim 6, wherein the 4 day ramp-up 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 days 4 and beyond, wherein the recommended dose on days 4 and beyond is greater than the second dose on day 3, which is greater than the second dose on day 2, and which is greater than the second dose on day 1.

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

9. 9. The method of claim 8, wherein the subsequent cycle (Cycle 2) of administration of the Bcl-2 inhibitor is at the recommended dose with no ramp-up from day 1.

10. 10. The method of claim 9, wherein cycle 1 azacitidine is administered one day (referred to as day 0) prior to said administration of said Bcl-2 inhibitor.

11. 11. The method of claim 10, wherein cycle 2 azacitidine is administered simultaneously with said Bcl-2 inhibitor.

12. The azacitidine is administered at a dose of 75 mg / m ２ 12. The method of claim 11 , wherein the compound is administered intravenously or subcutaneously once daily (QD) at a dose of

13. 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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