Methods of treating multiple myeloma using BCL-2 inhibitors

Abstract

The present disclosure provides methods of treating multiple myeloma 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 or a pharmaceutically acceptable salt thereof, or in combination with dexamethasone.

Description

[Technical Field]

[0001] Disclosed herein are methods of treating multiple myeloma 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 or a pharmaceutically acceptable salt thereof, or in combination with dexamethasone. [Background technology]

[0002] Multiple myeloma (MM) is a malignant tumor containing terminally differentiated plasma cells that accumulate in the bone marrow, resulting in bone destruction and bone marrow failure. Myeloma displays a typical multistep transformation process with an early premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), which exhibits numerous recurrent cytogenetic abnormalities in addition to altered gene expression. The most common cytogenetic abnormalities include hyperdiploidy, del(13), hypodiploidy, t(11;14), pseudodiploidy, t(4;14), and del(17). (Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genetics. 2011;204(1):P3-12). The molecular subgroup of t(11;14) MM is associated with high levels of B-cell lymphoma-2 (Bcl-2) and myeloid leukemia cell differentiation protein-1 (MCL-1) / Bcl-extra large (XL) expression (Touzeau C, Maciag P, Amiot M, et al. Targeting Bcl-2 for the treatment of multiple myeloma. Leukemia. 2018;32(9):1899-1907.).

[0003] The Bcl-2 family consists of a number of pro- and anti-apoptotic proteins, including Bcl-2, Bcl-XL, MCL-1, Bcl-W, and Bcl-2-related protein A1 (Bfl-1). Specifically, pro-apoptotic proteins bind to the hydrophobic groove of anti-apoptotic proteins via their Bcl-2 homology 3 (BH3) domains and then neutralize activator BH3 pro-apoptotic proteins, thereby shifting the balance of anti- and pro-apoptotic proteins in favor of anti-apoptosis, providing MM cells with a survival advantage (Gong JN, Khong T, Segal D, et al. Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1. Blood. 2016;128(14):1834-44.; Gupta VA, Ackley J, Kaufman JL, et al. BCL2 family inhibitors in the biology and treatment of multiple myeloma. Blood Lymph Cancer: Targets Ther. 2021;11:11-24).

[0004] Venetoclax (ABT-199) is a Bcl-2 inhibitor approved for treating patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). It is also a first-in-class, bioavailable, oral, Bcl-2-selective BH3 mimetic and has demonstrated potent clinical activity against MM cell lines, either alone or in combination with other drugs. An early phase 1 study in patients with relapsed / refractory (R / R) MM treated with venetoclax monotherapy demonstrated a 21% overall response rate (ORR) (14 of 66 patients), with 15% (10 of 66 patients) achieving a very good partial response (VGPR) or better. In a subgroup analysis of patients with t(11;14), the ORR was 40% (Kumar S, Kaufman JL, Gasparetto C, et al. Efficacy of venetoclax as targeted therapy for relapsed / refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401-09). The addition of venetoclax to bortezomib and dexamethasone significantly improved response rate and progression-free survival (PFS), but overall survival (OS) favored the placebo group, indicating an unfavorable risk-benefit ratio in unselected patients with multiple myeloma (Kumar S, Harrison SJ, Cavo M, et al. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomized, double-blinded, multicentre, phase 3 trail. Lancet Oncol. 2020b;21(12):1630-42.).At the 2020 meeting of the American Society of Clinical Oncology, updated results from the BELLINI trial were presented, showing that median OS in all patients was 33.5 months vs. not reached in the venetoclax and placebo arms, respectively (hazard ratio [HR] = 1.46 (0.91, 2.34)). Median OS in the t(11;14) or BCL-2 high subgroup was not reached in either arm (HR = 0.97 (0.43, 2.17)). (Kumar S, Harrison SJ, Cavo M, et al. Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed / refractory multiple myeloma. J Clin Oncol. 2020a;38(15_suppl):8509). These findings led the Food and Drug Administration (FDA) to issue a safety warning. Interim trial results showed an increased risk of death in patients receiving venetoclax compared with the control group. A phase III trial comparing venetoclax / dexamethasone / bortezomib with placebo / dexamethasone / bortezomib demonstrated a median progression-free survival (PFS) of 22.4 vs. 11.5 months (p=0.010, hazard ratio [HR]=0.630, 95% CI: 0.443-0.897) (Multiple Myeloma Hub. EHA 2019|Results of the phase III BELLINI trial:VenBd for RRMM. https: / / multiplemyelomahub.com / medical-information / eha-2019-or-results-of-the-phase-iiibellini-trial-venbd-for-rrmm.). 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 pharmaceutically acceptable salt thereof, as Bcl-2 inhibitors. The compounds disclosed in WO2019 / 210828A are potent and selective Bcl-2 protein inhibitors. [ka] [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Sawyer JR.The prognostic significance of cytogenetics and molecular profiling in multiple myeloma.Cancer Genetics.2011;204(1):P3-12 [Non-patent document 2] MCL-1) / Bcl-extra large (XL) expression (Touzeau C, Maciag P, Amiot M, et al.Targeting Bcl-2 for the treatment of multiple myeloma.Leukemia.2018;32(9):1899-1907. [Non-patent document 3] Gong JN, Khong T, Segal D, et al.Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma:pivotal role of MCL1.Blood.2016;128(14):1834-44. [Non-patent document 4] Gupta VA, Ackley J, Kaufman JL, et al.BCL2 family inhibitors in the biology and treatment of multiple myeloma.Blood Lymph Cancer:Targets Ther.2021;11:11-24 [Non-Patent Document 5] Kumar S, Kaufman JL, Gasparetto C, et al.Efficacy of venetoclax as targeted therapy for relapsed / refractory t(11;14) multiple myeloma.Blood.2017;130(22):2401-09 [Non-patent document 6] Kumar S, Harrison SJ, Cavo M, et al.Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma(BELLINI): a randomized, double-blinded, multicentre, phase 3 trail. Lancet Oncol.2020b;21(12):1630-42. [Non-Patent Document 7] Kumar S,Harrison SJ,Cavo M,et al.Updated results from BELLINI,a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed / refractory multiple myeloma.J Clin Oncol.2020a;38(15_suppl):8509 Summary of the Invention [Means for solving the problem]

[0006] The inventors of the present disclosure have discovered that a Bcl2 inhibitor having Formula (III-B), (III-C), (III-D), or (III-E), particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1) or a pharmaceutically acceptable salt thereof, in combination with dexamethasone resulted in significant inhibition of tumor growth in multiple myeloma (MM) when compared to the efficacy of each therapeutic agent as a single agent. Furthermore, the combination therapy demonstrated potential safety and efficacy.

[0007] In a first aspect, disclosed herein is a method of treating multiple myeloma (MM) with a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is a compound represented by the following formula (III-B), (III-C), (III-D) or (III-E): [ka] or a pharmaceutically 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, -NO2, -OR Ba , -SO2R Ba , -COR Ba , -CO2R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb RBc , -NR Ba R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc , -NR Ba CO2R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO2NR Bb R Bc , or -NR Ba SO2R Bb and -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, and said -C 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 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, -NO2, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1-8 Alkyl, -C2-8 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)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -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 -,-(CRa 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 may be unsubstituted or may be O, S, SO, SO2, 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, -NO2, -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C(=O)OR 5b , -C(=O)NR 5b R 5c , -C(=NR 5b )NR 5c R 5d , -N(R 5b )C(=O)R 5c , -N(R 5b )C(=O)OR 5c , -N(R 5b )C(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -NR 5b SO2R 5c , -C 1-8 Alkyl, -C2-8 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 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, and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from one or two substituents R 5e is optionally replaced by; R 5e are each independently hydrogen, halogen, cyano, oxo, -NO2, -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO2R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR 5g R 5h , -N(R 5f )S(O)NR 5g R 5h , -N(R 5f)S(O)NR 5g R 5h , -NR 5f SO2R 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 is 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, and said ring is not substituted with any of halogen, oxo, cyano, -NO2, -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO2R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR 5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -NR 5i SO2R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8optionally 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, and said -C 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, and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO, -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.

[0008] In a second aspect, disclosed herein is a method of treating multiple myeloma (MM) with a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is a compound represented by the following formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with dexamethasone.

[0009] In a third aspect, disclosed herein is a method of treating multiple myeloma (MM) with a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is a compound represented by the following formula (III-B), (III-C), (III-D), or (III-E), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with a proteasome inhibitor and dexamethasone.

[0010] In a fourth 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 pharmaceutically acceptable salt thereof, or in combination with dexamethasone, or in combination with a proteasome inhibitor and dexamethasone, for use in the treatment of multiple myeloma.

[0011] In a fifth aspect, disclosed herein is a method of treating multiple myeloma 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, for use in treating multiple myeloma, or in combination with dexamethasone, or in combination with a proteasome inhibitor and dexamethasone.

[0012] In a sixth aspect, disclosed herein is the use of a pharmaceutical composition in the manufacture of a medicament for use in the treatment of multiple myeloma, 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 pharmaceutically acceptable salt thereof, and dexamethasone.

[0013] In a seventh aspect, disclosed herein is the use of a pharmaceutical composition in the manufacture of a medicament for use in the treatment of multiple myeloma, 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 pharmaceutically acceptable salt thereof, a proteasome inhibitor, and dexamethasone.

[0014] 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 1) or a pharmaceutically acceptable salt thereof.

[0015] In embodiments of each of the above aspects, the proteasome inhibitor is carfilzomib or bortezomib.

[0016] In one embodiment of each of the above aspects, the multiple myeloma is relapsed / refractory multiple myeloma (R / R MM).

[0017] In one embodiment of each of the above aspects, the multiple myeloma exhibits cytogenetic abnormalities and / or gene expression alterations. In some embodiments, the multiple myeloma is t(11;14)-positive multiple myeloma.

[0018] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally. In some embodiments, the Bcl-2 inhibitor is administered daily in a 21-day cycle in combination with dexamethasone. In some embodiments, the Bcl-2 inhibitor is administered in a 28-day cycle in combination with dexamethasone and carfilzomib.

[0019] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally once daily (QD) at a dose of 40 to 640 mg. In some embodiments, the Bcl-2 inhibitor is administered at a dose of 40 mg QD, 80 mg QD, 160 mg QD, 320 mg QD, or 640 mg QD.

[0020] In some embodiments, dexamethasone is administered at a dose of 40 mg / m2 once a week. In some embodiments, dexamethasone is administered simultaneously with a Bcl-2 inhibitor.

[0021] In some embodiments, carfilzomib is administered once a week at a dose of 56 mg / m2 or 70 mg / m2. In some embodiments, carfilzomib is administered simultaneously with a Bcl-2 inhibitor.

[0022] definition Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those of ordinary skill in the art.

[0023] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural referents unless the content clearly dictates otherwise.

[0024] The term "or" is used to mean, and is used interchangeably with, the term "and / or," unless the context clearly dictates otherwise.

[0025] The term "anti-cancer agent," as used herein, refers to any agent that can be used to treat a cell proliferative disorder, such as cancer, and includes, but is not limited to, cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0026] As used herein, the terms "administration," "administering," "treating," and "treatment," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to contacting an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell includes contacting a reagent with the cell, as well as contacting a reagent with a fluid in contact with the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment of a cell, e.g., 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., a rat, mouse, dog, cat, rabbit), and most preferably a human. In one aspect, treating any disease or disorder refers to alleviating the disease or disorder (i.e., delaying, preventing, or reducing the onset of the disease or at least one of 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., stabilizing a discernible symptom), physiologically (e.g., stabilizing 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.

[0027] The term "subject," in the context of this disclosure, refers to a mammal, e.g., a primate, preferably a higher primate, e.g., 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.

[0028] The terms "cancer" or "tumor" herein have the broadest meaning as understood in the art and refer to a physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of this disclosure, cancer is not limited to a particular type or location.

[0029] The term "therapeutically effective amount," as used herein, refers to the 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 to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled 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 combined agents intended to effectively treat the disease, disorder, or condition. [Brief explanation of the drawings]

[0030] [Figure 1A] The effects of Compound 1 and dexamethasone at 0.1 mg / kg, alone and in combination, are shown. [Figure 1B] The effects of Compound 1 and dexamethasone at 1 mg / kg, alone and in combination, are shown. [Figure 2] PK characterization of compound 1 in the KMS-12-PE human MM subcutaneous xenograft model. [Figure 3] Effect of Compound 1 in combination with dexamethasone on body weight in the KMS-12-PE human MM subcutaneous xenograft model. [Figure 4] Initial results in patients with R / R multiple myeloma harboring the t(11,14) mutation; ORR: overall response rate, sCR: stringent complete response, CR: complete response, VGPR: very good partial response, MR: minimal response, PR: partial response, DLT: dose-limiting toxicity, TEAE: treatment-emergent adverse event. DETAILED DESCRIPTION OF THE INVENTION

[0031] Disclosed herein are methods of treating multiple myeloma 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 or a pharmaceutically acceptable salt thereof, or in combination with dexamethasone, or in combination with a proteasome inhibitor and dexamethasone.

[0032] Bcl-2 inhibitors Bcl-2 inhibitors according to the present disclosure include compounds represented by the following formula (III-B), (III-C), (III-D), or (III-E): [ka] or a pharmaceutically 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, -NO2, -OR Ba , -SO2R Ba , -COR Ba , -CO2R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb R Bc, -NR Ba R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc , -NR Ba CO2R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO2NR Bb R Bc , or -NR Ba SO2R Bb and -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, and said -C 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 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, -NO2, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and said -C 1-8 Alkyl, -C 2-8Alkenyl, -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)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -,-SO2NR a -, -NR a SO2-, -NR a S(O)NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -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 Rb ) 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 may be unsubstituted or may be O, S, SO, SO2, 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, -NO2, -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C(=O)OR 5b , -C(=O)NR 5b R 5c , -C(=NR 5b )NR 5c R 5d , -N(R 5b )C(=O)R 5c , -N(R 5b )C(=O)OR 5c , -N(R 5b )C(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -NR 5b SO2R 5c , -C 1-8 Alkyl, -C 2-8Alkenyl, -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 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, and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be selected from one or two substituents R 5e is optionally replaced by; R 5e are each independently hydrogen, halogen, cyano, oxo, -NO2, -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO2R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR 5g R 5h , -N(R 5f )S(O)NR 5g R 5h , -N(R 5f )S(O)NR5g R 5h , -NR 5f SO2R 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 is 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, and said ring is not substituted with any of halogen, oxo, cyano, -NO2, -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO2R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR 5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -NR 5i SO2R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8optionally 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, and said -C 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, and said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO, -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.

[0033] In some embodiments, R2 is hydrogen.

[0034] 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, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO2R Ba , -CONR Ba R Bb , -NO2, -NR Ba R Bb , -NR Ba COR Bb , or -NR Ba SO2R Bb and -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each independently contain one to four substituents R as defined in formula (III-B), (III-C), (III-D), or (III-E). Bd and preferably 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.

[0035] In some embodiments, R 1dis methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyls in position on the phenyl ring, or propenyl, or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or ethoxy or isopropoxy, or amino or dimethylamino.

[0036] In some embodiments, the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety of Formula (III-B), (III-C), (III-D), or (III-E) is selected from the group consisting of: [ka] [ka]

[0037] 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 O and NR a wherein R a and R b is defined by formula (III-B), (III-C), (III-D), or (III-E).

[0038] 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 ) 1-3or -NH-, wherein R a and R b is defined similarly to formula (III-B), (III-C), (III-D), or (III-E), so that -L 5 The -CyC moiety is CyC, -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b ) 1-3 -CyC, or -NH-CyC. More preferably, L 5 is a direct bond, -(CH2) 1-4 -, -O-(CH2) 1-3 -, -NH-(CR a R b )-(CH2)2-, or -NH-, wherein 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, -(CH2), respectively. 1-4 -CyC, -O-(CH2) 1-3 -CyC, -NH-(CR a R b )-(CH2)2-CyC, or -NH-CyC. More preferably, L 5 is a direct bond, -CH2-, -O-CH2-, -NH-CH 2- , or -NH-, resulting in -L 5 The -CyC moiety is CyC, -CH2-CyC, -O-CH2-CyC, -NH-CH2-CyC, or -NH-CyC, respectively.

[0039] In some embodiments, CyC is cycloalkyl, or heterocyclyl, each of which is substituted with 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 , -SO2R 5b , -C 1-8 Alkyl, -C 2-8 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 to form a benzo ring, said ring being optionally substituted with heteroaryl.

[0040] 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

[0041] 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) a 5- to 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 ).

[0042] In some embodiments, CyC is a monocyclic 4- to 6-membered heterocyclyl group containing one nitrogen, 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.

[0043] 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.

[0044] In some embodiments, R 5aare independently hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C 1-8 Alkyl, -C 2-8 Alkynyl, monocyclic C 3-8 cycloalkyl, or a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members, 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.

[0045] 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.

[0046] In some embodiments, R 5e Heterocyclyl as is tetrahydro-pyran-4-yl.

[0047] In some embodiments, R 5a is -NR5b R 5c where R 5b is hydrogen and R 5c is heterocyclyl.

[0048] In some embodiments, R 5a is -NR 5b R 5c where R 5b is hydrogen and R 5c is tetrahydro-pyran-4-yl.

[0049] In some embodiments, R 5a Ha-NR 5b R 5c where R 5b and R 5c are each independently hydrogen or a cycloalkyl-substituted -C 1-6 Alkyl, preferably monocyclic C 3-8 Cycloalkyl-substituted -C 1-6 It is alkyl.

[0050] In some embodiments, R 5a -OR 5b or -SO2R 5b where R 5b is hydrogen or C 1-8 It is alkyl, preferably methyl.

[0051] In some embodiments, R 5a HA-COR 5b where R 5b is hydrogen, or -NR 5f R 5g C optionally replaced with 1-8 alkyl, and R 5f and R 5g are each independently hydrogen or C 1-8 It is alkyl, preferably methyl.

[0052] In some embodiments, two adjacent R on the phenyl ring 5taken together with the phenyl ring to form an indazolyl substituted with tetrahydropyranyl.

[0053] In some embodiments, m is 1 and R 5 is selected from the group consisting of: 5 -CyC: [ka] [ka]

[0054] In some embodiments, m is 1 and R 5 teeth, [ka] is.

[0055] 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 pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0056] In some embodiments, the Bcl-2 inhibitor of the present disclosure is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound A) or a pharmaceutically acceptable salt thereof.

[0057] Preparation of Bcl-2 inhibitors All of the 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 1), can be prepared by the methods disclosed in International Publication WO 2019 / 210828 A1.

[0058] Preparation of Compound 1 Step 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane Hydrochloride

[0059] 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), concentrated HCl (350 mL, 4.18 mol) was added at room temperature and stirred for 4 hours. After concentration in vacuo, MeOH (750 mL) was added to the residue, and the resulting mixture was then concentrated in vacuo (this workup was repeated twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 hour. The solid precipitate was filtered and dried in vacuo to give the title product as an off-white powder (350 g, yield: 76.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 3.03 (s, 6 H), 2.96-2.89 (m, 4 H), 1.93 (s, 4 H), 1.74-1.67 (m, 4 H). MS (ESI, m / e) [M+1] + 186.0.

[0060] Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate

[0061] 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 equivalents), and DBU (160 g, 3.0 equivalents) in NMP (500 mL) was stirred at 85° C. for 16 hours. After the reaction was completed, the mixture was cooled to 50±5° C., and an aqueous citric acid solution (2%, 5 L) was added dropwise to the system with stirring. After filtration, the cake was collected and dissolved in DCM (1.5 L). The crude product solution was washed with an aqueous citric acid solution (2%, 1.5 L), saturated aqueous NaHCO (1.5 L), and 15% aqueous NaCl (1.5 L), and then dried over anhydrous NaSO. Silica gel (100 g) was added to the crude product solution with stirring, followed by filtration. 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 vacuo to give an off-white solid (192 g, yield: 72.1%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.63 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). MS (ESI, m / e) [M+1] + 451.9.

[0062] Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0063] 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), diluted HCl acid (1 M, 1.5 L) was added 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 and washed with 15% aqueous NaCl (1 L) and then with HO (1 L). After concentrating the organic phase to 500 mL, 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 vacuo to give the title product as a white solid (152 g, yield: 96.23%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.64 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 6.38-6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H).MS (ESI, m / e) [M+1] + 405.9.

[0064] Step 4: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0065] To a mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in dioxane (500 mL) and HO (50 mL) was added CsCO (100 g, 305 mmol) and Pd(dppf)Cl (6.6 g, 7.5 mmol). The mixture was stirred at 100 °C for 8 h. TLC indicated 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.

[0066] Step 5: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0067] To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd / C (10 g, 10%), and the mixture was stirred at 20 °C under H (15 psi) for 12 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, CDCl3) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H).

[0068] Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0069] To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) 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 evaporated to dryness in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.25 (m, 1H), 2.40-2.21 (m, 1H), 2.19-1.86 (m, 3H), 1.25 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.7 Hz, 3H).MS (ESI, m / e) [M+1] + 190.0.

[0070] 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

[0071] 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 into a reactor. The temperature was controlled below 30 °C, and NaBH(OAc) (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 washed with H2O (600 mL x 2), then with aqueous NaHCO3 (600 mL x 2), and saturated aqueous NaCl (600 mL). The organic phase was collected, then dried over anhydrous Na2SO4, and concentrated. 256 g of an off-white solid was obtained as crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0072] 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

[0073] 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 THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH 5-6 with 3 N HCl acid while stirring at room temperature. The precipitate was filtered and evaporated to dryness to give the product as a white solid (102.4 g, yield: 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.35 (s, 1H), 7.27 - 7.04 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 - 3.26 (m, 1H), 3.10 - 3.04 (m, 4H), 2.35-2.30 (m, 1 H), 2.9-2.15 (m, 1 H), 1.74 -1.64 (m, 4H), 1.52-1.37 (m, 6H), 1.28 - 1.06 (m, 6H). MS (ESI, m / e) [M+1] + 564.9.

[0074] 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

[0075] 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 17.2 g (195 mmol) of 1,2-dimethylethane-1,2-diamine was added in one portion. The reaction mixture was stirred for an additional 12 h. The mixture was washed twice with 10 wt% aqueous AcOH (300 mL × 2) and then with saturated aqueous NaHCO3 (300 mL × 2). The organic layer was collected and concentrated to approximately 90 mL. 22 g of silica gel was added and stirred for 2 h. After filtration, 180 mL of EA was added to the refluxing filtrate and stirred for an additional 5 h. After cooling the mixture to room temperature, the precipitate was filtered, and 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%). 1H NMR (DMSO-d6) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.44-1.26 (m, 7H), 1.19 (d, J = 8.0 Hz, 3H), 1.14 (d, J = 8.0 Hz, 3H), 1.10 (s, 4H). MS (ESI, m / e) [M+1] + 889.9.

[0076] Treatment method In one aspect, the present disclosure provides a method for treating multiple myeloma. In certain aspects, the method comprises administering to a patient a therapeutically effective amount of Compound 1, or in combination with dexamethasone, or in combination with a proteasome inhibitor and dexamethasone.

[0077] Compound 1 can be administered by any suitable means, including oral, parenteral, intrapulmonary, and intranasal administration, and, if desired for localized treatment, intralesional administration. Administration can be by any suitable route. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple administrations over various time periods, bolus administration, and pulse infusion.

[0078] Compound 1 will be formulated, dispensed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to physicians. Compound 1 is optionally formulated with one or more drugs currently used to prevent or treat the disorder in question. The effective amount of such other drugs will depend on the amount of Compound 1 in the formulation, the type of disorder or treatment, and other factors discussed above.

[0079] For the prevention or treatment of disease, the appropriate dosage of Compound 1 will depend on the type of disease being treated, the severity and course of the disease, whether Compound 1 is being administered for prophylactic or therapeutic purposes, previous therapy, the patient's medical history and response to Compound 1, and the discretion of the attending physician. Compound 1 is suitably administered to the patient at one time or over a series of treatments. [Example]

[0080] The present invention is further illustrated by the following examples which are illustrative of the present invention but are not intended to be limiting.

[0081] Example 1: KMS-12-PE xenograft model study 1. Test Materials 1.1 Test substance(s) Dexamethasone (HPLC purity: ≥98%, MW = 392.46).

[0082] 1.1.1 Vehicle Preparation Compound 1 was formulated for oral administration in 60% (v / v) phosal 50 PG, 30% (v / v) PEG 400, and 10% (v / v) ethyl alcohol. The vehicle was prepared according to the following procedure: To make 10 mL of vehicle, 3 mL of PEG 400, 6 mL of phosal 50 PG, and 1 mL of ethyl alcohol were added to a clean tube, vortexed for 1 minute, and then sonicated for 3 minutes to create a clear solution. The solution was stored at 2-8°C until use.

[0083] 1.1.2 Preparation of the test substance Compound 1 was formulated with vehicle for oral dosing at 1.5 mg / mL according to the following procedure: 1) Weigh out the appropriate amount of test article into a clean tube. 2) Use a syringe to add vehicle (approximately 60%-80% of the total volume) to the tube. 3) Vortex the tube for 3 minutes and sonicate it for 10 minutes. 4) Repeat the above procedure until Compound 1 is completely dissolved. 5) Add vehicle to reach the final volume.

[0084] Dexamethasone was initially formulated at 1 mg / mL for oral dosing and diluted to 0.1 mg / mL with saline.

[0085] 1.2 Experimental system Sixty-five female NCG mice were purchased from GemParmatech Co., Ltd. On the day of inoculation, the mice were 6-7 weeks old and weighed between 17.9 and 22.9 g. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions and had free access to food and water. Mice were group-housed in IVC cages under a 12-hour light:dark cycle (lights on at 8:00 AM) with a temperature range of 22.3-24.8°C and a humidity range of 45.2-65.8%. 60 Animals were fed a radiation-sterilized, fully granulated diet.

[0086] 2. Experimental Procedure 2.1 Cell culture The human MM cell line, KMS-12-PE, was obtained from the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, catalog: ACC 606). KMS-12-PE cells were cultured in complete RPMI 1640 medium supplemented with 20% (v / v) fetal bovine serum and 100 μg / mL penicillin and streptomycin. For this study, cells were used within 10 passages after recovery from liquid nitrogen. KMS-12-PE cells were maintained as suspension cultures at 37°C in a 5% CO2 atmosphere, with passages twice a week.

[0087] 2.2 Cell seeding On the day of seeding, the cell suspension was centrifuged at 1,000 rpm for 5 minutes, and the cell pellet was resuspended in an appropriate amount of pre-chilled PBS. Cells were counted with a hemocytometer and their viability was assessed using 0.4% trypan blue. Cells were resuspended at 3 × 10 in pre-chilled PBS. 7 Resuspend at 1.5 x 10 cells / mL and add the same volume of Matrigel. 7 A final concentration of 3 × 10 cells / mL was obtained. The resuspended cells were placed on ice before seeding. Before cell seeding, the right front flank of each mouse was washed with 75% ethanol. Each animal received 3 × 10 cells in 200 μL of cell suspension. 7 Cells were injected subcutaneously into the right anterior flank via a 1 mL LS 25GA syringe.

[0088] 2.3 Animal Classification and Administration Four days after cell inoculation, the animals were monitored for body weight and tumor volume (185.0–223.1 mm). 3 Mice were randomly assigned to six groups with eight mice per group according to the phenotype. Mice were treated once daily (QD) with vehicle, 0.1 or 1 mg / kg dexamethasone, or 1.5 mg / kg Compound 1 for 17 days. Treatments were administered by oral gavage (po) in a volume of 10 mL / kg body weight. Body weight was assessed immediately prior to dosing, and dosage was adjusted accordingly.

[0089] 2.4 Clinical Observations, Body Weight, and Tumor Volume Tumor volumes were measured bidimensionally using calipers twice weekly (measurements were possible from day 4 post-treatment in this study). Body weights were recorded twice weekly. Tumor measurements were performed by a single individual throughout the study. Mice were also monitored daily for clinical signs of toxicity. At the end of the study, mice were euthanized using carbon dioxide.

[0090] 2.5 PK analysis On day 14 after treatment, blood samples (approximately 100 μL per mouse) were collected from the retro-orbital sinus under isoflurane / oxygen anesthesia at 0 hours before dosing with Compound 1 and 0.5, 2, 8, and 24 hours after dosing (three mice per time point, all mice were used for two or three time points). Blood was transferred to EDTA-K2 anticoagulated tubes, and plasma was collected by centrifugation at 5,600 rpm for 7 minutes and stored frozen at -80°C until analysis.

[0091] 3. Data Analysis The two-dimensional diameter of the tumor was determined using calipers. Tumor volume was calculated using the formula: V = 0.5 × (a × b 2 ) (where a and b are the long and short diameters of the tumor, respectively).

[0092] Tumor growth inhibition (TGI) was calculated using the following formula:

number

[0093] In PK analysis, the maximum plasma concentration (C max ) and peak arrival time (T max The area under the plasma concentration-time curve (AUC) from 0 to 24 hours after administration (AUC 0-24h ) was calculated.

[0094] Tumor volumes 17 days after treatment were analyzed using ANOVA on a logarithmic scale in SAS Enterprise Guide version: 7.15 HF3. The following comparisons were made between treatment groups:

[0095] The combination of 1.5 mg / kg Compound 1 with 0.1 mg / kg or 1 mg / kg dexamethasone was compared to the vehicle group using Dunnett's multiple comparison test.

[0096] Combination therapy was compared with the corresponding single agents. A significant combination effect was claimed if the combination therapy showed improved antitumor activity over both single agents (i.e., EOHSA criteria). EOHSA tests were adjusted by Holm's multiple comparison test. #p<0.05, ####p<0.0001.

[0097] An adjusted p<0.05 was considered statistically significant.

[0098] 4.Results In this study, the combined effect of Compound 1 and dexamethasone was evaluated in a KMS-12-PE human MM subcutaneous xenograft model in NCG mice. The results are shown in Figures 1A, 1B, 2, 3, and Tables 1 and 2.

[0099] Figure 1 shows the effect of Compound 1 in combination with dexamethasone on tumor growth in a KMS-12-PE human MM subcutaneous xenograft model. KMS-12-PE tumor cells (3 x 10 7 ) were subcutaneously implanted into female NCG mice. Four days after inoculation, mice were divided into six groups with eight mice per group according to body weight and tumor volume and treated for 17 days as indicated. Tumor volumes were measured twice weekly. Figures 1A and 1B show the effects of compound 1 and dexamethasone at 0.1 mg / kg (A) or 1 mg / kg (B) alone and in combination on tumor growth. Data are presented as the mean tumor volume ± standard error of the mean (SEM) for eight animals in each group. Tumor volumes on day 17 were analyzed on a logarithmic scale using ANOVA. Combination treatments were compared with the vehicle group using Dunnett's multiple comparison test ( ** p<0.01,**** p<0.0001). The effect of the combination was evaluated using Holm's multiple comparison test according to EOHSA criteria (#p<0.05, ####p<0.0001). Abbreviations: po: oral gavage, QD: once daily, TGI: tumor growth inhibition, mpk: mg / kg.

[0100] Figure 4 shows the PK profile of Compound 1 in the KMS-12-PE human MM subcutaneous xenograft model. KMS-12-PE tumor cells (3 x 10 7 ) were subcutaneously implanted into female NCG mice. Four days after inoculation, mice were sorted into six groups with eight mice per group according to body weight and tumor volume and treated for 17 days as indicated. Fourteen days after treatment, blood samples were collected from the retro-orbital sinus under carbon dioxide / oxygen anesthesia at 0, 0.5, 2, 8, and 24 hours after administration of Compound 1. Data are presented as the mean plasma concentration ± SEM of three animals at each time point. Abbreviations: po: oral gavage; QD: once daily; mpk: mg / kg.

[0101] Figure 5 shows the effect of Compound 1 in combination with dexamethasone on body weight in a KMS-12-PE human MM subcutaneous xenograft model. KMS-12-PE tumor cells (3 x 10 7 ) were subcutaneously implanted into female NCG mice. Four days after inoculation, mice were sorted into six groups with eight mice per group according to body weight and tumor volume and treated for 17 days as indicated. Body weights were measured twice weekly from treatment onward. Data are presented as the mean weight ± SEM of eight animals in each group. Abbreviations: po: oral gavage; QD: once daily; mpk: mg / kg.

[0102] Oral administration of 1.5 mg / kg QD compound 1 or 0.1 mg / kg QD dexamethasone as single agents showed little inhibitory effect on tumor growth, with TGI at 17 days post-treatment of 11% and 9%, respectively (Figure 1A and Table 1). Combination treatment with 0.1 mg / kg compound 1 and dexamethasone resulted in a TGI of 45%, demonstrating significant improvement in antitumor activity (adjusted p<0.01). The combination therapy demonstrated significant improvement in antitumor activity compared to both single agents; i.e., the combination effect was significant according to EOHSA criteria (adjusted p<0.05) (Figure 1A and Table 1).

[0103] Oral administration of 1 mg / kg QD dexamethasone demonstrated consistent antitumor activity, with a TGI of 46% on day 17 (Figure 1B and Table 1). Mice treated orally with 1 mg / kg Compound 1 and dexamethasone demonstrated superior efficacy with a TGI of 89% (adjusted p<0.0001). The combined effect was significant according to EOHSA criteria (adjusted p<0.0001) (Figure 1B and Table 1).

[0104] Additionally, the steady-state exposure (AUC 0-24h and C max ) was consistent with the exposure to the combined treatment (Fig. 2, Table 1 and Table ). No clear effect on body weight was observed in any treatment group (Fig. 3).

[0105] In conclusion, all the results indicate that the combination of Compound 1 and dexamethasone exhibited superior antitumor activity to either single agent in the KMS-12-PE xenograft model. [Table 1] [Table 2]

[0106] Example 2: Clinical Trials 1. Method Study design / objectives Part 1 (dose escalation)

[0107] A dose-escalation study will be conducted to evaluate the safety and tolerability of Compound 1 in combination with dexamethasone and dexamethasone plus carfilzomib in patients with relapsed / refractory (R / R) multiple myeloma (MM) and t(11;14). The corresponding maximum tolerated dose (MTD) / maximum assessed dose (MAD), recommended phase 2 dose (RP2D), and pharmacokinetics of Compound 1 in the combination therapy will also be observed.

[0108] Compound 1 and dexamethasone: Patients with R / R MM and t(11;14) will receive escalating doses of Compound 1 once daily, starting at 80 mg once daily, plus 40 mg of dexamethasone weekly to determine safety, tolerability, efficacy, and pharmacokinetics (PK). At the end of the 21-day dose-limiting toxicity (DLT) period, depending on the number of evaluable patients and the observed DLTs, the Compound 1 dose may be tapered to 40 mg once daily, maintained at 80 mg once daily, or escalated to 160 mg once daily. Provided that no DLTs are observed during the DLT period after dose escalation to 160 mg once daily, studies may be conducted to escalate to several higher dose levels (up to 640 mg once daily) or to insert a fixed intermediate dose between 80 mg and 160 mg once daily.

[0109] One analysis will be performed for the Compound 1 plus dexamethasone cohort once all patients in the corresponding dose escalation have completed the DLT observation period. In addition to confirming the RP2D, the analysis for the Compound 1 plus dexamethasone cohort will summarize the safety profile of Compound 1 in combination with dexamethasone based on all available data.

[0110] Compound 1 with Dexamethasone and Carfilzomib: The combination of Compound 1 with dexamethasone and carfilzomib will be evaluated according to the RP2D for Compound 1 in combination with dexamethasone. The initial dose of Compound 1 in combination with dexamethasone and carfilzomib will be one dose level lower than the previously determined RP2D defined for the Compound 1 and dexamethasone cohort. The initial starting dose of carfilzomib will be 56 mg / m² weekly. The dexamethasone dose will remain at 40 mg once weekly. Three combination doses of Compound 1 with carfilzomib and dexamethasone are initially planned, including: 1) Compound 1 at the RP2D-1 dose level plus carfilzomib 56 mg / m² weekly plus dexamethasone; 2) Compound 1 at the RP2D-1 dose level plus carfilzomib at 70 mg / m² weekly plus dexamethasone, and 3) Compound 1 at RP2D + carfilzomib 70 mg / m2 weekly + dexamethasone.

[0111] The RP2D-1 dose level refers to the dosage ladder. For example, 80 mg, 160 mg, 320 mg, and 640 mg are test doses, and the determined RP2D is 320 mg. Then, RP2D-1 is the next dose level below, i.e., 160 mg, and RP2D-2 is 80 mg.

[0112] At the end of the DLT period (28 days), depending on the number of evaluable patients and the observed DLTs, dose escalation and decrementation of Compound 1 in combination with carfilzomib and dexamethasone will be performed using the mTPI-2 methodology. After completion of the dose escalation / decrement process, the MTD of Compound 1 in combination with carfilzomib and dexamethasone will be determined according to the mTPI-2 methodology, and this MTD, along with other outcomes such as overall safety and preliminary efficacy, will be used to determine the final recommended dose of Compound 1 in combination with carfilzomib and dexamethasone in Cohorts 3 and 4 of Part 2.

[0113] Part 2 (Cohort Expansion)

[0114] Cohort expansion will be conducted to evaluate the safety and tolerability of Compound 1 as monotherapy and in combination with dexamethasone at the RP2D, and in combination with dexamethasone and carfilzomib at the recommended combination dose in patients with R / R MM and t(11;14). The study will also be conducted to evaluate the efficacy of Compound 1 as monotherapy, in combination with dexamethasone, and in combination with dexamethasone and carfilzomib in patients with R / R MM and t(11;14), as measured by response or response rate.

[0115] Compound 1 Monotherapy (Cohort 1): Patients will receive compound 1 monotherapy at the same dose level as the RP2D of compound 1 in combination with dexamethasone. Patients in the compound 1 monotherapy cohort (Cohort 1) whose disease progresses according to International Myeloma Working Group (IMWG) criteria may be moved to the combination therapy arm and receive compound 1 plus dexamethasone and carfilzomib at the highest dose being studied in Part 2.

[0116] Compound 1 and dexamethasone (Cohort 2): Patients will receive Compound 1 in combination with dexamethasone (40 mg weekly) at the same dose level as the RP2D of Compound 1 in combination with dexamethasone.

[0117] Compound 1 plus dexamethasone and carfilzomib 70 mg / m² weekly (Cohort 3): Patients will be enrolled in this cohort. If the recommended carfilzomib dose for the combination of Compound 1 and carfilzomib is not determined to be 70 mg / m² weekly, this cohort may not be established.

[0118] Compound 1 plus dexamethasone and carfilzomib 56 mg / m² weekly (Cohort 4): Patients will be enrolled in this cohort. If the RP2D-1 dose level of Compound 1 plus carfilzomib and dexamethasone 56 mg / m² weekly is determined to be intolerable, expansion of the Compound 1 plus dexamethasone and carfilzomib cohorts in Part 2 (Cohorts 3-5) will not occur.

[0119] Compound 1 plus carfilzomib at 70 mg / m² weekly and dexamethasone (Cohort 5): Patients will be enrolled in this cohort. This cohort will serve as a control for Cohort 3 (and / or Cohort 4) to differentiate treatment effects and ensure the safety of Compound 1. If an expansion of the cohort receiving Compound 1 plus dexamethasone and carfilzomib is not performed in Part 2, Cohort 5 will also not be performed. The carfilzomib dose is planned to be 70 mg / m² weekly at the time of Cohort 3 enrollment in Part 2, but will be reduced to 56 mg / m² weekly if Cohort 3 is not enrolled due to intolerance.

[0120] Main selection criteria: Eastern Cooperative Oncology Group (ECOG) performance status of 1.0 to 2 2. Confirmed diagnosis of multiple myeloma (M components must be present in serum and / or urine) 3. Measurable disease defined as: i. M spike ≥ 500 mg / dL, or ii. urinary protein M spike ≥ 200 mg / day, or iii. serum free light chain ≥ 10 mg / dL and an abnormal kappa:lambda ratio 4. Participant has documented recurrent or progressive MM after any regimen or is refractory to the most recent line of therapy. i. Relapsed MM is defined as previously treated MM that has progressed, requiring initiation of salvage therapy, but does not meet the criteria for refractory MM. ii. Refractory MM is defined as disease that is non-responsive (failure to achieve minimal response or development of progressive disease) during first-line or salvage therapy or progresses within 60 days of the last therapy. a. Participants in Part 1 must have failed all other available options, including having received three or more prior lines of therapy, including a proteasome inhibitor, an IMiD agent, and an anti-CD38 monoclonal antibody. b. Part 2 participants must have failed at least one but no more than seven prior lines of therapy and have received prior treatment with both a proteasome inhibitor and an IMiD agent. Note: A line of therapy consists of one or more complete cycles of a single agent, a regimen consisting of several drug combinations, or planned sequential therapy of various regimens. Induction therapy with consolidation and maintenance after stem cell transplantation is considered one line of therapy. c. Prior treatment with carfilzomib is permitted, but patients should not be considered carfilzomib refractory and must not have received carfilzomib within the past 6 months. 5. Positive for t(11;14) by a pre-specified laboratory-validated fluorescent in situ hybridization (FISH) assay a. A fresh bone marrow aspirate must be obtained at the time of screening and sent to a central laboratory for t(11;14) FISH testing. 6. Adequate organ function defined as: Hemoglobin ≥ 8.0 g / dL (within 7 days prior to the first dose of study treatment, independent of growth factor support and transfusions) b. Platelet count ≥ 75,000 / μL (within 7 days prior to the first dose of study treatment, independent of growth factor support and transfusions) c. Absolute neutrophil count (ANC) ≥ 1000 / mm3 [ANC = (% of separated neutrophils + % of separated bands) × total WBC count within 7 days prior to the first dose of study treatment] d. ALT and AST ≤ 3 x upper limit of normal (ULN), and total bilirubin ≤ 2.0 x ULN, serum creatinine ≤ 1.5 x ULN, or creatinine clearance calculated by the MDRD-6 equation ≥ 45 mL / min / 1.73 m2.

[0121] Key exclusion criteria: 1. The participant meets any of the following conditions: a. Non-secretory MM (serum light chain absence <10 mg / dL) b. Solitary plasmacytoma c. Active plasma cell leukemia (i.e., either 20% of peripheral blood leukocytes or circulating plasma cells >2.0 × 109 / L with standard differential) d. Waldenström macroglobulinemia e. Amyloidosis. f. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and cutaneous manifestations (POEMS) syndrome g. Uncontrolled diabetes (HbA1c > 7% or 53mmol / mol at the time of study entry or requiring insulin) h. Chronic respiratory disease requiring continuous oxygen 2. Significant cardiovascular disease (including but not limited to): a. Myocardial infarction within 6 months prior to screening b. Ejection fraction ≦50% c. Unstable angina within 3 months prior to screening d. New York Heart Association Class III or IV congestive heart failure e. History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes) f. Heart rate-corrected QT interval according to the Fridericia formula >480 msec g. History of Mobitz type II second- or third-degree heart block without a permanent pacemaker in place h. Uncontrolled hypertension at screening (defined as systolic blood pressure >170mmHg and diastolic blood pressure >105mmHg on two or more consecutive measurements) 3. Human immunodeficiency virus (HIV) infection discovered 4. Serologic status reflecting active viral hepatitis B (HBV) or viral hepatitis C (HCV) infection, such as: aPresence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Participants with HBcAb present but not HBsAg are eligible if HBV DNA is undetectable (sensitivity limit < 20 IU / mL) and if the participant is willing to undergo monthly monitoring for HBV reactivation. b. Presence of HCV antibodies. Participants with HCV antibodies will be eligible if their HCV RNA is undetectable (sensitivity limit <15 IU / mL).

[0122] 2. Conclusion In a study of the combination of Compound 1 and dexamethasone, Compound 1 and dexamethasone were generally well tolerated at doses up to 640 mg in patients with R / R MM harboring t(11;14), and initial safety and efficacy results were promising. The SMC recommended 640 mg with dexamethasone as the RP2D.

[0123] PK data for Compound 1 in combination with dexamethasone are available from MM patients receiving target doses of 80 to 640 mg in this study. The available PK data demonstrated that the steady-state exposure (Cmax and AUC) of Compound 1 in combination with dexamethasone was comparable to that of Compound 1 monotherapy, indicating a low potential for drug-drug interactions (DDIs) between dexamethasone and Compound 1.

[0124] In this study, no patients experienced treatment-emergent adverse events leading to treatment changes. No dose-limiting toxicities (DLTs) were observed across the four dose levels tested. No TEAEs led to discontinuation. The most common TEAEs were insomnia (42%), fatigue (32%), nausea (26%), arthralgia (21%), and COVID-19 (16%). Toxicity was rare and manageable. The only hematologic toxicity noted was one case of grade 2 neutropenia, which did not lead to dose adjustment or discontinuation. These results suggest that compound 1 in combination with dexamethasone is safe.

[0125] Compound 1 in combination with dexamethasone appeared to be well tolerated in patients with R / R MM harboring t(11;14) at the dose levels tested in four dose-escalation cohorts (80, 160, 320, and 640 mg once daily [QD]). Additionally, based on preliminary efficacy data from 19 patients in four dose-escalation cohorts (3 patients at 80 mg, 3 patients at 160 mg, 3 patients at 320 mg, and 10 patients at 640 mg), compound 1 demonstrated activity at the dose levels tested, with disease control achieved in most patients. At 640 mg, the ORR was 70%, with 40% achieving a VGPR or better (results shown in Figure 4). Competitive data indicated that venetoclax monotherapy in t(11;14) MM resulted in an ODD of 40%, with 27% achieving a VGPR.

[0126] The foregoing examples and descriptions of certain specific embodiments should be construed as illustrative rather than limiting of the invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features described above can be utilized without departing from the invention as defined in the claims. All such variations are intended to be within the scope of the present invention. All references cited are incorporated herein by reference in their entirety.

Claims

1. A pharmaceutical composition for treating multiple myeloma in a subject, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Bcl-2 inhibitor, The aforementioned pharmaceutical composition is characterized by being administered simultaneously, sequentially, or separately in combination with a therapeutically effective amount of dexamethasone. The pharmaceutical composition wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridine-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. The multiple myeloma is relapsed / refractory multiple myeloma; The aforementioned multiple myeloma exhibits cytogenetic abnormalities or altered gene expression; or The pharmaceutical composition according to claim 1, wherein the multiple myeloma is t(11;14)-positive multiple myeloma.

3. The Bcl-2 inhibitor is formulated for oral administration; or The Bcl-2 inhibitor is formulated for use in combination with dexamethasone in a 21-day treatment cycle; or The pharmaceutical composition according to claim 1, wherein the Bcl-2 inhibitor is formulated for oral administration once daily at a dose of 40 to 640 mg.

4. The pharmaceutical composition according to claim 1, wherein the Bcl-2 inhibitor is formulated to be administered once daily in doses of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg.

5. The pharmaceutical composition according to claim 4, wherein dexamethasone is formulated to be administered once a week at a dose of 40 mg.

6. The pharmaceutical composition according to claim 5, wherein the Bcl-2 inhibitor is formulated to be administered once daily in a dose of 160 mg.

7. The pharmaceutical composition according to claim 6, characterized in that the pharmaceutical composition is administered in combination with carfilzomib at a dose of 56 mg / m² once a week or 70 mg / m² once a week.

8. The pharmaceutical composition according to claim 5, wherein the Bcl-2 inhibitor is formulated to be administered once daily in a dose of 320 mg.

9. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutical composition is administered in combination with carfilzomib at a dose of 56 mg / m² once a week or 70 mg / m² once a week.

10. The pharmaceutical composition according to claim 5, wherein the Bcl-2 inhibitor is formulated to be administered once daily at a dose of 640 mg.

11. The pharmaceutical composition according to claim 10, characterized in that the pharmaceutical composition is administered in combination with carfilzomib at a dose of 56 mg / m² once a week or 70 mg / m² once a week.

12. A pharmaceutical composition for treating multiple myeloma, wherein the pharmaceutical composition comprises a therapeutically effective amount of dexamethasone, The pharmaceutical composition is characterized in that it is administered simultaneously, sequentially, or separately in combination with a Bcl-2 inhibitor as defined in any one of claims 1 to 11.

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