WO2021110102A1

WO2021110102A1 - Methods of cancer treatment using bcl-2 inhibitor

Info

Publication number: WO2021110102A1
Application number: PCT/CN2020/133636
Authority: WO
Inventors: Nan HU; Yin GUO; Yunhang GUO; Zhiwei Wang
Original assignee: Beigene Ltd
Current assignee: BeOne Medicines I GmbH
Priority date: 2019-12-02
Filing date: 2020-12-03
Publication date: 2021-06-10
Anticipated expiration: 2022-06-02

Abstract

Provided herein are methods of treating cancer in a subject with a Bcl-2 inhibitor, in 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.

Description

METHODS OF CANCER TREATMENT USING BCL-2 INHIBITOR

FIELD OF THE DISCLOSURE

Disclosed herein are methods of treating cancer with a Bcl-2 inhibitor, in 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.

BACKGROUND OF THE DISCLOSURE

Impaired apoptosis plays a central role in tumor development, tumor maintenance, and therapeutic resistance. Apoptosis can be triggered via two main pathways: the extrinsic or death-receptor-mediated pathway, and the intrinsic or mitochondrial pathway (Czabotar et al 2014) . It is the intrinsic pathway that is more commonly perturbed in lymphoid malignancies. Cell death mediated through this pathway is regulated by members of a family of proteins related to B-cell lymphoma-2 (Bcl-2) , which is considered to contain three subfamilies. The pro-survival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1/Bfl-1, and possibly Bcl-B) promotes cell survival by inhibiting their pro-apoptotic relatives. The pro-apoptotic BAX/BAK-like proteins, including BOK, are the essential effectors of apoptosis, and the BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are the initiators of apoptosis (Anderson et al 2014) . In healthy cells, the pro-survival Bcl-2 proteins bind and inhibit BAX and BAK after they have been partially activated, impairing the ability of BAX/BAK to oligomerize and form pores to induce mitochondrial outer membrane permeabilization. The BH3-only proteins are induced transcriptionally or post-transcriptionally in response to diverse stresses and initiate apoptosis by either binding the pro-survival Bcl-2 proteins, thereby unleashing BAX/BAK, or by directly activating these effectors of apoptosis. The various Bcl-2 family proteins have differential specificity of binding to one another, resulting in a complex but ordered network of interactions governing cell fate (Roberts 2016) .

Bcl-2 was the first anti-apoptotic protein discovered in 1980s as a consequence of t (14; 18) chromosomal translocation and the hallmark of FL. BCL-2 gene resides on chromosome 18q21.33. The Bcl-2 protein has 239 amino acids and a molecular weight of 26 kDA (Schenk et al 2017) . Bcl-2 is widely expressed during development and becomes restricted upon maturation in many tissues (Kondo et al 2008) . Mice lacking Bcl-2 succumb to polycystic kidney disease early in life because Bcl-2 is critical for the survival of renal epithelial progenitor cells during embryogenesis (Veis et al 1993) . The Bcl-2-deficient mice also have abnormally reduced numbers of mature, resting B and T lymphocytes, and gray prematurely because of the aberrant death of melanocytes (Veis et al 1993, Yamamura et al 1996) . Although originally believed to act as a classical growth-driving oncogene, it was later shown that Bcl-2 instead promotes malignant cell survival by attenuating apoptosis. Transgenic mice with pan-hematopoietic Bcl-2 expression (VavP-BCL-2) preferentially develop follicular lymphoma, preceded by florid germinal center hyperplasia (Egle et al 2004) . Mice co-expressing BCL-2 and MYC transgenes developed lymphomas markedly faster than littermates expressing either transgene alone, validating BCL-2 as an oncogene (Adams and Cory 2007) .

High Bcl-2 expression is almost universal in CLL, FL, MCL, and Waldenstrom macroglobulinemia (WM) ; in contrast, the levels of Bcl-2 expression are somewhat more variable among multiple myeloma (MM) and substantially more variable among DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang 2017) . When Bcl-2 is overexpressed, the ratio of pro-and anti-apoptotic Bcl-2 family members is disturbed and apoptotic cell death can be prevented. Moreover, Bcl-2 protein is closely related to chemoresistance in hematological tumors. As Bcl-2-mediated resistance to intrinsic apoptosis is considered as a key to pathogenesis, targeting Bcl-2 can improve apoptosis and overcome drug resistance to cancer therapy. Thus, Bcl-2 has become an attractive target for therapeutic strategy in cancer.

Venetoclax (ABT-199) was approved for treating patients with chronic lymphocytic leukemia (CLL) and acute myeloblastic leukemia (AML) . However, despite this high clinical activity and favorable safety profile, patients can develop acquired resistance to venetoclax over time with continuous treatment. Blombery et al demonstrated that the Gly101Val mutation (G101V mutation) in BCL-2 confers acquired refractoriness by reducing the binding affinity of venetoclax without disrupting the binding of pro-apoptotic proteins to Bcl-2. The novel Gly101Val mutation in Bcl-2 was identified at progression in 7 of 15 patients. This mutation is mainly found in patients after long-term exposure to venetoclax monotherapy (Tausch et al 2019) .

WO2019/210828A disclosed a series of compounds having following Formulas (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 inhibitor.

SUMMARY OF THE DISCLOSURE

The inventors of the present disclosure have found that a Bcl2 inhibitor having Formulas (III-B) , (III-C) , (III-D) or (III-E) , in 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, exhibited potent cell killing activity against a variety of lymphoma and leukemia cell lines, including MV4-11 (acute myeloid leukemias, AML) , OCI-LY10 (B-cell non-Hodgkin's lymphoma, B-NHL) , Toledo (diffuse large B-cell lymphomas, DLBCL) , DOHH2 (follicular lymphomas, FL) , DHL-4 (Germinal center B-cell like diffuse large B-cell lymphomas, GCB-DLBCL) and MAVER-1 (mantle cell lymphomas, MCL) . And, the IC ₅₀ values were found ranging from 0.6 nM to 13 nM.

The inventors of the present disclosure have also found that a Bcl2 inhibitor having Formulas (III-B) , (III-C) , (III-D) or (III-E) , in particularly Compound 1 or a pharmaceutically acceptable salt thereof, demonstrated significant inhibition of tumor growth in cancer with high safety, including B-cell malignancies selected from acute lymphoblastic leukemia (ALL) , mantle cell lymphomas (MCL) and diffuse large B-cell lymphomas (DLBCL) . The inventors have found that said B-cell malignancies has Bcl-2 expression and /or Bcl-2 G101V mutation expression.

In a first aspect, disclosed herein is a method of treating cancer with a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is a compound represented by the following Formulas (III-B) , (III-C) , (III-D) or (III-E) ,

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein,

R ², at each occurrence, is independently selected from the group consisting of hydrogen, halogen, or -C _1-8alkyl optionally substituted with halogen;

R ^1d, at each occurrence, is independently halogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO ₂, -OR ^Ba, -SO ₂R ^Ba, -COR ^Ba, -CO ₂R ^Ba, -CONR ^BaR ^Bb, -C (=NR ^Ba) NR ^BbR ^Bc, -NR ^BaR ^Bb, -NR ^BaCOR ^Bb, -NR ^BaCONR ^BbR ^Bc, -NR ^BaCO ₂R ^Bb, -NR ^BaSONR ^BbR ^Bc, -NR ^BaSO ₂NR ^BbR ^Bc, or -NR ^BaSO ₂R ^Bb; wherein said -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with 1 to 4 substituents R ^Bd;

R ^Ba, R ^Bb, and R ^Bc, are each independently hydrogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -NH ₂ or -N (C _1-6alkyl) ₂, -C _1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^Bd, at each occurrence, is independently hydrogen, halogen, oxo, -CN, -NO ₂, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C _1-8alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

m is an integer of 1-4;

R ⁵ is –L ⁵-CyC,

Wherein L ⁵ is a direct bond, - (CR ^aR ^b) _t-, - (CR ^aR ^b) _t-1- (CR ^c=CR ^d) - (CR ^aR ^b) _v-1-, - (CR ^aR ^b) _t-1- (C≡C) - (CR ^aR ^b) _v-1-, -O-, -S-, -S (O) -, -SO ₂-, -C (O) -, C (O) O-, -OC (O) -, -NR ^a-, -C (O) NR ^a-, -NR ^aC (O) -, -NR ^aC (O) O-, -NR ^aC (O) NR ^b-, -SO ₂NR ^a-, -NR ^aSO ₂-, -NR ^aS (O) ₂NR ^b-, -NR ^aS (O) NR ^b-, -C (O) NR ^aSO ₂-, -C (O) NR ^aSO-, or -C (=NR ^a) NR ^b-, wherein t and v, at each occurrence, are independently a number of 1 to 7, and one or two CR ^aR ^b moieties in - (CR ^aR ^b) _t-, - (CR ^aR ^b) _t-1- (CR ^c=CR ^d) - (CR ^aR ^b) _v-1-, - (CR ^aR ^b) _t-1- (C≡C) - (CR ^aR ^b) _v-1-are un-replaced or replaced with one or more moieties selected from O, S, SO, SO ₂, C (O) and NR ^a;

CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or two substituents R ^5a;

R ^5a, at each occurrence, is independently selected from hydrogen, halogen, cyano, oxo, -NO ₂, -OR ^5b, -SR ^5b, -NR ^5bR ^5c, -COR ^5b, -SO ₂R ^5b, -C (=O) OR ^5b, -C (=O) NR ^5bR ^5c, -C (=NR ^5b) NR ^5cR ^5d, -N (R ^5b) C (=O) R ^5c, -N (R ^5b) C (=O) OR ^5c, -N (R ^5b) C (O) NR ^5cR ^5d, -N (R ^5b) S (O) NR ^5cR ^5d, -N (R ^5b) S (O) ₂NR ^5cR ^5d, -NR ^5bSO ₂R ^5c, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C _1-8alkyl, -C _2- ₈alkenyl, -C _2-8alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or two substituents R ^5e;

wherein R ^5b, R ^5c, and R ^5d are each independently hydrogen, -C _1-8alkyl, -C _2- ₈alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C _1-8alkyl, -C _2-8alkenyl, C _2-8alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or two substituents R ^5e;

R ^5e, at each occurrence, is independently selected from hydrogen, halogen, cyano, oxo, -NO ₂, -OR ^5f, -SR ^5f, -NR ^5fR ^5g, -COR ^5f, -SO ₂R ^5f, -C (=O) OR ^5f, -C (=O) NR ^5fR ^5g, -C (=NR ^5f) NR ^5gR ^5h, -N (R ^5f) C (=O) R ^5g, -N (R ^5f) C (=O) OR ^5g, -N (R ^5f) C (O) NR ^5gR ^5h, -N (R ^5f) S (O) NR ^5gR ^5h, -N (R ^5f) S (O) ₂NR ^5gR ^5h, -NR ^5fSO ₂R ^5g, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ^5f, R ^5g, and R ^5h are each independently hydrogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

or, two adjacent R ⁵ on the phenyl ring together with the phenyl ring form a benzo ring, said ring is optionally substituted with halogen, oxo, cyano, -NO ₂, -OR ⁵ⁱ, -SR ⁵ⁱ, -NR ⁵ⁱR ^5j, -COR ⁵ⁱ, -SO ₂R ⁵ⁱ, -C (=O) OR ⁵ⁱ, -C (=O) NR ⁵ⁱR ^5j, -C (=NR ⁵ⁱ) NR ^5jR ^5k, -N (R ⁵ⁱ) C (=O) R ^5j, -N (R ⁵ⁱ) C (=O) OR ^5j, -N (R ⁵ⁱ) C (O) NR ^5jR ^5k, -N (R ⁵ⁱ) S (O) NR ^5jR ^5k, -N (R ⁵ⁱ) S (O) ₂NR ^5jR ^5k, -NR ⁵ⁱSO ₂R ^5k, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R ⁵ⁱ, R ^5j, and R ^5k are independently hydrogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2- ₈alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C _1-8alkyl, -C _2- ₈alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy or -C _1-8alkyoxy;

R ^a, R ^b, R ^c, and R ^d at each occurrence, are independently hydrogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said -C _1-8alkyl, -C _2-8alkenyl, -C _2- ₈alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently substituted with –CN, halogen, -NO ₂, -NR ^eR ^f, oxo, -OR ^e, or –SR ^e; and

wherein R ^e and R ^f are each independently hydrogen, C _1-8alkyl, C _1-8alkoxy-C _1-8alkyl-, C _2-8alkenyl, C _2-8alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

In a second aspect, disclosed herein is a Bcl-2 inhibitor of Formulas (III-B) , (III-C) , (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

In a third aspect, disclosed herein is a method of treating cancer in a subject, said method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor of Formulas (III-B) , (III-C) , (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In a fourth aspect, disclosed herein is a use of a pharmaceutical composition in the manufacture of a medicament for use in the treatment of cancer, said pharmaceutical combination comprising a Bcl-2 inhibitor of Formulas (III-B) , (III-C) , (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

.

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.

In an embodiment of each of the above aspects, the cancer is B-cell malignancies.

In an embodiment of each of the above aspects, the cancer is lymphoma or leukemia.

In one embedment of each of the above aspects, the cancer is selected from the group consisting of acute myeloid leukemias (AML) , B-cell non-Hodgkin's lymphoma (B-NHL) , indolent B-cell Non-Hodgkin Lymphoma (NHL) , diffuse large B-cell lymphomas (DLBCL) , Germinal center B-cell like diffuse large B-cell lymphomas (GCB-DLBCL) , follicular lymphomas (FL) , mantle cell lymphomas (MCL) , acute lymphoblastic leukemia (ALL) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL) .

In one embedment of each of the above aspects, the cancer is relapsed/refractory, or transformed.

In one embedment of each of the above aspects, the Bcl-2 inhibitor is orally administrated at a dose of 20 mg/per day to 700 mg/per day.

In one embedment of each of the above aspects, the cancer has Bcl-2 expression.

In one embedment of each of the above aspects, the cancer has Bcl-2 Gly101Val mutation expression.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows efficacy of Bcl-2 inhibitors in RS4; 11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model.

####p < 0.0001 versus vehicle by one-way ANOVA (Dunnett's multiple comparisons test)

*p < 0.05, ****p < 0.0001 versus venetoclax by one-way ANOVA (Tukey's multiple comparisons test) .

Abbreviation: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; BID, twice daily; p.o., oral gavage.

Figure 2 shows efficacy of Bcl-2 inhibitors in MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model.

##p < 0.01, ####p < 0.0001 versus vehicle by one-way ANOVA (Dunnett's multiple comparisons test) .

****p < 0.0001 versus venetoclax by one-way ANOVA (Tukey's multiple comparisons test) . Abbreviation: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; BID, twice daily; p.o., oral gavage.

Figure 3 shows efficacy of Bcl-2 inhibitors in Toledo diffuse large B cell lymphoma (DLBCL) subcutaneous xenograft model.

###p < 0.001, ####p < 0.0001 versus vehicle by one-way ANOVA (Dunnett's multiple comparisons test) .

**p < 0.01, ****p < 0.0001 versus venetoclax by one-way ANOVA (Tukey's multiple comparisons test) .

Figure 4 shows efficacy of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model.

##p< 0.01, ####p< 0.0001 versus vehicle by one-way ANOVA; ****p< 0.0001 versus venetoclax by one-way ANOVA.

Definitions

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

As used herein, including the appended claims, the singular forms of words such as “a, ” “an, ” and “the, ” include their corresponding plural references unless the context clearly dictates otherwise.

The term “or” is used to mean, and is used interchangeably with, the term “and/or” unless the context clearly dictates otherwise.

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, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

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

The term “subject” in the context of the present disclosure is 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.

The terms “cancer” or “tumor” herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of the present disclosure, the cancer is not limited to certain type or location.

The term “therapeutically effective amount” as herein used, refers to the amount of a Bcl-2 inhibitor that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or symptom. The “therapeutically effective amount” can vary with the agent, the disease, disorder, and/or symptoms of the disease or disorder, 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. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments. In the case of combination therapy, the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides a method of treating cancer in a subject with Bcl-2 inhibitor, in 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.

Bcl-2 inhibitor

The Bcl-2 inhibitor in present disclosure is a compound represented by the following Formulas (III-B) , (III-C) , (III-D) or (III-E) ,

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

wherein,

m is an integer of 1-4;

R ⁵ is –L ⁵-CyC,

wherein R ^e and R ^f are each independently hydrogen, C _1-8alkyl, C _1-8alkoxy-C _1-8alkyl-, C _2- ₈alkenyl, C _2-8alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

In some embodiments, R ² is hydrogen.

In some embodiments, R ^1d, when substituted on the phenyl group at position 2 of ring B (including the aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl, or azocan-1-yl, preferably the pyrrolidin-1-yl group) , is independently halogen, -C _1-8alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR ^Ba, - SO ₂R ^Ba, -CONR ^BaR ^Bb, -NO ₂, -NR ^BaR ^Bb, -NR ^BaCOR ^Bb, or -NR ^BaSO ₂R ^Bb; wherein said -C _1- ₈alkyl, -C _2-8alkenyl, -C _2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted with 1 to 4 substituents R ^Bd as defined as with Formulas (III-B) , (III-C) , (III-D) or (III-E) ., preferably 1 or 2 substituents R ^Bd as defined as with Formulas (III-B) , (III-C) , (III-D) or (III-E) . In another aspect, one R ^1d is at position 2 of the phenyl ring at position 2 of ring B.

In some embodiments, R ^1d is methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyl at position of the phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

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

In some embodiments, m is 1; and L ⁵ is a direct bond, - (CR ^aR ^b) _t-or -NR ^a-, wherein t is a number of 1 to 7, and one or two CR ^aR ^b moieties in - (CR ^aR ^b) _t-are un-replaced or replaced with one or more moieties selected from O and NR ^a, wherein R ^a and R ^b are defined with Formulas (III-B) , (III-C) , (III-D) or (III-E) .

In some embodiments, L ⁵ is a direct bond, - (CR ^aR ^b) _1-4-, -O- (CR ^aR ^b) _1-3-, -NH- (CR ^aR ^b) _1- ₃, or -NH-, wherein R ^a and R ^b are defined as with Formulas (III-B) , (III-C) , (III-D) or (III-E) , so that the –L ⁵-CyC moiety is CyC, - (CR ^aR ^b) _1-4-CyC, -O- (CR ^aR ^b) _1-3-CyC, -NH- (CR ^aR ^b) _1-3-CyC, or -NH-CyC, respectively. More preferably, L ⁵ is a direct bond, - (CH ₂) _1-4-, -O- (CH ₂) _1- ₃-, -NH- (CR ^aR ^b) - (CH ₂) ₂-, or -NH-, wherein R ^a is hydrogen and R ^b is C _1-8alkyl optionally substituted with phenyl-S-so that the –L ⁵-CyC moiety is CyC, - (CH ₂) _1-4-CyC, -O- (CH ₂) _1-3-CyC, -NH- (CR ^aR ^b) - (CH ₂) ₂-CyC, or -NH-CyC, respectively. More preferably, L ⁵ is a direct bond, -CH ₂-, -O-CH ₂-, -NH-CH ₂-, or -NH-so that the –L ⁵-CyC moiety is CyC, -CH ₂-CyC, -O-CH ₂-CyC, -NH-CH ₂-CyC, or -NH-CyC, respectively.

In some embodiments, CyC is cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or two substituents R ^5a;

R ^5a is independently selected from hydrogen, halogen, cyano, oxo, -OR ^5b, -NR ^5bR ^5c, -COR ^5b, -SO ₂R ^5b, -C _1-8alkyl, -C _2-8alkynyl, -cycloalkyl, or heterocyclyl, each of said -C _1- ₈alkyl, and heterocyclyl is optionally substituted with one or two substituents R ^5e which is selected from hydrogen, halogen, cyano, -OR ^5f, -C _1-8alkyl, -cycloalkyl, or heterocyclyl;

wherein R ^5b, and R ^5c are each independently hydrogen, -C _1-8alkyl or heterocyclyl, said -C _1-8alkyl is optionally substituted with one or two substituents R ^5e which is hydrogen, -NR ^5fR ^5g, or -cycloalkyl;

R ^5f and R ^5g are each independently hydrogen or -C _1-8alkyl;

or, two adjacent R ⁵ on the phenyl ring together with the phenyl ring form a benzo ring, said ring is optionally substituted with heteroaryl.

In some embodiments, CyC is cycloalkyl selected from monocyclic C _3-8cycloalkyl or bridged cycloalkyl

each of which is optionally substituted with 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.

In some embodiments, CyC is heterocyclyl selected from:

a) monocyclic 4 to 9-membered heterocyclyl groups containing one nitrogen or oxygen or sulfur heteroatom as ring member;

b) monocyclic 4 to 9-membered heterocyclyl groups containing two heteroatoms selected from oxygen, sulfur and nitrogen as ring members; and

c) 5 to 20-membered spiro heterocyclyl comprising one or two heteroatoms selected from nitrogen, sulfur and oxygen as ring members,

each of which is optionally substituted with one or two R ^5a.

In some embodiments, CyC is monocyclic 4 to 6-membered heterocyclyl groups containing one nitrogen or oxygen or sulfur heteroatom as ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperdinyl. 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, piperdin-4-yl, piperdin-2-yl, and piperdin-3-yl.

In some embodiments, CyC is monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is dioxanyl, morpholino, morpholinyl, or piperzinyl. Even more preferably 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.

In some embodiments, R ^5a is independently selected from hydrogen, halogen, cyano, oxo, -OR ^5b, -NR ^5bR ^5c, -COR ^5b, -SO ₂R ^5b, -C _1-8alkyl, -C _2-8alkynyl, monocyclic C _3-8cycloalkyl, or monocyclic 4 to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatom as ring members, each of said -C _1-8alkyl and monocyclic 4 to 9-membered heterocyclyl group is optionally substituted with one or two substituents R ^5e; preferably, cycloalkyl as R ^5a is C _3-6cycloalkyl; more preferably cyclopropyl; preferably, heterocyclyl as R ^5a is 4 to 6-membered heterocyclyl groups containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatom as ring members; more preferably, heterocyclyl as R ^5a is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperzinyl, or morpholinyl; even more preferably, heterocyclyl as R ^5a is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, or morphin-4-yl.

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

In some embodiments, heterocyclyl as R ^5e is tetrahydro-pyran-4-yl.

In some embodiments, R ^5a is -NR ^5bR ^5c, wherein R ^5b is hydrogen, and R ^5c is heterocyclyl.

In some embodiments, R ^5a is -NR ^5bR ^5c, wherein R ^5b is hydrogen, and R ^5c is tetrahydro-pyran-4-yl.

In some embodiments, R ^5a is -NR ^5bR ^5c, wherein R ^5b and R ^5c are each independently hydrogen or –C _1-6alkyl substituted with cycloalkyl, preferably –C _1-6alkyl substituted with monocyclic C _3-8cycloalkyl.

In some embodiments, R ^5a is -OR ^5b or -SO ₂R ^5b, wherein R ^5b is hydrogen or C _1-8alkyl, preferably methyl.

In some embodiments, R ^5a is -COR ^5b, wherein R ^5b is hydrogen or C ^1-8alkyl optionally substituted with -NR ^5fR ^5g, wherein R ^5f and R ^5g are each independently hydrogen or C _1-8alkyl, preferably methyl.

In some embodiments, two adjacent R ⁵ on the phenyl ring together with the phenyl ring form indazolyl which is substituted with tetrahydropyranyl.

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

In some embodiments, m is 1 and R ⁵ is

In some embodiments, the Bcl-2 inhibitor in present disclosure is selected form the group consist 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;

(Sor 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) -l6-sulfaneylidene) 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) -l6-sulfaneylidene) 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.

In some embodiments, the Bcl-2 inhibitor in 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 1) or a pharmaceutically acceptable salt thereof.

Preparation of Bcl-2 inhibitors

All the Bcl-2 inhibitors having Formulas (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 method disclosed in international publication WO2019/210828A1.

Preparation of Compound 1

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

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

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

The mixture of methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-fluorobenzoate (100 g) , 2, 2-dimethoxy-7-azaspiro [3.5] nonane hydrochloride (116 g, 1.5 eq. ) and DBU (160 g, 3.0 eq. ) in NMP (500 mL) was stirred for 16 hours at 85 ℃. After the reaction was completed, the mixture was cooled to 50 ± 5℃ and citric acid in water (2%, 5 L) was added drop-wise into the system under stirring. After filtered, the cake was collected and dissolved with DCM (1.5 L) . The solution of crude product was washed with citric acid in water (2%, 1.5 L) , saturated aq. NaHCO ₃ (1.5 L) and 15%aq. NaCl (1.5 L) , and then dried over anhydrous Na ₂SO ₄. Silica gel (100 g) was added into the solution of crude product under stirring and then filtered. The filtrate was concentrated to 300 mL. MTBE (500mL) was poured into the system. After stirred for 2 hours, the cake was collected after filtration and was dried in vacuum to give an off-white solid (192 g, yield: 72.1%) . ¹H NMR (400 MHz, DMSO-d ₆) δ ppm: 11.63 (s, 1H) , 8.00 (d, J = 2.4 Hz, 1H) , 7.76 (d, J = 9.2 Hz, 1H) , 7.47 (t, J = 3.2 Hz, 1H) , 7.42 (d, J = 2.4 Hz, 1H) , 6.79 (dd, J = 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.

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

To the solution of methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (2, 2-dimethoxy-7-azaspiro [3.5] nonan-7-yl) benzoate (176 g, 0.39 mol) in DCM (2 L) was added diluted HCl acid (1M, 1.5 L) and stirred for overnight. After the reaction was completed, the mixture was cooled to 10 ℃ and was adjusted to pH = 8-9 with aqueous NaOH solution (4 M) under stirring. The organic phase was separated and washed with 15%aq. NaCl (1 L) , then washed with H ₂O (1L) . After the organic phase was concentrated to 500 mL, MTBE (1 L) was poured into the solution and then the system was concentrated to 500 mL (repeated this work-up 3 times) . The resulting system was stirred for 0.5 hour. After filtration, the cake was collected and then dried in vacuum to obtain the tittle product as a white solid (152 g, yield: 96.23%) . ¹H NMR (400 MHz, DMSO-d ₆) δ ppm: 11.64 (s, 1H) , 8.02 (d, J = 2.4 Hz, 1H) , 7.78 (d, J = 9.2 Hz, 1H) , 7.47 (t, J = 3.2 Hz, 1H) , 7.44 (d, J = 2.4 Hz, 1H) , 6.83 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H) , 6.43 (d, J = 2.4 Hz, 1H) , 6.38-6.36 (m, 1H) , 3.65 (s, 3H) , 3.24-3.21 (m, 4H) , 2.80 (s, 4H) , 1.70-1.67 (m, 4H) . MS (ESI, m/e) [M+1] ⁺ 405.9.

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

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 H ₂O (50 mL) was added Cs ₂CO ₃ (100 g, 305 mmol) and Pd (dppf) Cl ₂ (6.6 g, 7.5 mmol) . The mixture was stirred at 100 ℃ for 8 hours. TLC showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE/EA (v/v) = 100/1 to 10/1) to obtain (S) -tert-butyl 2- (2- (prop-1-en-2-yl) phenyl) pyrrolidine-1-carboxylate (65 g, crude) . The crude product was used directly in next step.

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

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 ℃ under H ₂ (15 Psi) for 12 hours. TLC showed the reaction was completed. The mixture was filtered and the filtrate was concentrated in vacuum to give (S) -tert-butyl 2- (2-isopropylphenyl) pyrrolidine-1-carboxylate (60 g, crude) , which was used in next step without further purification. ¹H NMR (400 MHz, CDCl ₃) δ ppm: 7.39-6.90 (m, 4H) , 5.36-5.04 (m, 1H) , 3.77-3.52 (m, 2H) , 3.20-3.17 (m, 1H) , 2.47-2.24 (m, 1H) , 1.96-1.65 (m, 3H) , 1.54-1.38 (m, 2H) , 1.31-1.22 (m, 8H) , 1.17 (s, 7H) .

Step 6: (S) -2- (2-isopropylphenyl) pyrrolidine hydrochloride

To a solution of tert-butyl 2- (2-isopropylphenyl) pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added HCl in 1, 4-dioxane (4 M, 142 mL, 570 mmol) dropwise at room temperature. The mixture was stirred at room temperature for overnight. The mixture was concentrated in vacuum. The resulting residue was slurried with EA (100 mL) and then filtered, dried in vacuum to give (S) -2- (2-isopropylphenyl) pyrrolidine hydrochloride 26 g (yield: 60.4%) . ¹H NMR (400 MHz, DMSO-d ₆) δ ppm: 9.93 (s, 1H) , 8.81 (s, 1H) , 7.63-7.57 (m, 1H) , 7.41-7.34 (m, 2H) , 7.32-7.24 (m, 1H) , 4.91-4.75 (m, 1H) , 3.47-3.35 (m, 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.

Step 7: methyl (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

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

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

To a solution of methyl (S) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aq. NaOH (3.5 M) . It was stirred at room temperature overnight. After THF and MeOH were removed in vacuum, 3.5 L of water was added into the residue. The resulting mixture was adjusted to pH = 5～6 with 3 N HCl acid at room temperature with stirring. The precipitate was filtered and dried in vacuum to give the product as a white solid (102.4 g, yield: 99%) . ¹H NMR (400 MHz, DMSO-d ₆) δ ppm: 12.13 (s, 1H) , 11.58 (s, 1H) , 7.95 (s, 1H) , 7.67 (d, J = 8.0 Hz, 1H) , 7.56 -7.40 (m, 2H) , 7.35 (s, 1H) , 7.27 -7.04 (m, 3H) , 6.68 (d, J = 8.0 Hz, 1H) , 6.32 (s, 2H) , 3.62 (s, 1H) , 3.32 -3.26 (m, 1H) , 3.10 -3.04 (m, 4H) , 2.35-2.30 (m, 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.

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

A mixture of (S) -2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (2- (2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzoic acid (44 g, 78 mmol) , 4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrobenzenesulfonamide (26.8 g, 78 mmol) , TEA (15.7 g, 156 mmol) , EDCI (19.4 g, 101 mmol) and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After starting material 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 was consumed completely, the reaction mixture was heated to ～35 ℃ and N ¹, N ¹-dimethylethane-1, 2-diamine (17.2 g, 195 mmol) was added in one portion. The reaction was stirred for another 12 hours. The mixture was washed twice with 10 wt %aq. AcOH solution (300 mL × 2) and then washed with saturated aq. NaHCO ₃ (300 mL× 2) . The organic layer was collected and concentrated to about 90 mL. 22 g of silica gel was added and stirred for 2 hours. After filtration, 180 mL EA was added into the filtrate at reflux and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered and then the wet cake was washed twice with EA (180 mL) . After drying in vacuum at 80-90 ℃, the desired compound was obtained (48 g, yield: 69.5%) . ¹H NMR (DMSO-d ₆) δ ppm: 11.65 (s, 1H) , 11.11 (br, 1H) , 8.58-8.39 (m, 2H) , 8.00 (d, J = 2.8 Hz, 1H) , 7.74 (d, J = 8.8 Hz, 1H) , 7.57-7.37 (m, 4H) , 7.30-7.10 (m, 3H) , 7.00 (d, J = 9.2 Hz, 1H) , 6.65 (d, J = 1.2 Hz, 1H) , 6.35 (s, 1H) , 6.17 (s, 1H) , 4.24 (s, 1H) , 3.39-3.20 (m, 5H) , 3.04-2.88 (m, 4H) , 2.23 (s, 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.

Methods of Treatment

In one aspect, the present disclosure provides a method of treating cancer. In certain aspects, the method comprises administering to a patient in need an effective amount of Compound 1. The cancer can include, without limitation, B-cell malignancies, lymphoma or leukemia, selected from the group consisting of acute myeloid leukemias (AML) , B-cell non-Hodgkin's lymphoma (B-NHL) ) , indolent B-cell Non-Hodgkin Lymphoma (NHL) , diffuse large B-cell lymphomas (DLBCL) , Germinal center B-cell like diffuse large B-cell lymphomas (GCB-DLBCL) , follicular lymphomas (FL) , mantle cell lymphomas (MCL) , acute lymphoblastic leukemia (ALL) , chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL) . In some embodiments, the cancer is relapsed/refractory, or transformed.

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

Compound 1 would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration 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 delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. Compound 1 is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of Compound 1 in the formulation, the type of disorder or treatment, and other factors discussed above.

For the prevention or treatment of disease, the appropriate dosage of Compound 1 will depend on the type of disease to be treated, the severity and course of the disease, whether Compound 1is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical 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.

EXAMPLES

The present invention is further exemplified, but not limited to, by the following examples that illustrate the invention.

Example 1: Efficacy study of Bcl-2 inhibitors in RS4; 11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model

The RS4; 11 cells are of acute lymphoblastic leukemia (ALL) origin and were obtained from American Type Culture Collection (ATCC CRL-1873, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 μg/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . RS4; 11 cells were maintained as suspension cell cultures at 37 ℃ in a 5%CO ₂ atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center. All animals were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water. Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 20-26 ℃ and 37-62%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .

On the day of implantation, RS4; 11 cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 5×10 ⁷ cells/mL. Re-suspended cells were placed on ice prior to inoculation. The right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation. Each animal was injected subcutaneously with 1×10 ⁷ cells in 200 μL of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.

Animals were randomly assigned into 10 groups with 10 mice per group according to body weight and tumor volume (100 mm ³-200 mm ³) . The groups consisted of vehicle group, 5, 15, 50 mg/kg of venetoclax with QD dosing, 5, 15, 50 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5, 25 mg/kg of Compound 1with BID dosing. Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.

Individual body weight was recorded twice weekly, with mice being monitored daily for clinical signs of toxicity for the duration of the study. Mice were euthanized using carbon dioxide when their tumor volume reached 2,000 mm ³, the tumor was ulcerated, or body weight loss exceeded 20%.

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.

In vivo efficacy of Compound 1was examined and compared to venetoclax in RS4; 11 ALL xenografts grown subcutaneously in NCG mice. Following oral administration at well tolerated doses, Compound 1 potently and dose-dependently inhibited tumor growth (Figure 1 and Table 1) . At the same total daily doses of 5 and 15 mg/kg, Compound 1 demonstrated significantly better efficacy when compared with venetoclax. Venetoclax was dosed at 400 mg daily in clinic. Its clinically relevant dose in mice is around 15 mg/kg QD based on free AUC. Compound 1 2.5 mg/kg BID was more active than venetoclax at 15 mg/kg QD. Furthermore, at the same total daily doses of 15 and 50 mg/kg, Compound 1 QD and BID dosing schedule showed equivalent anti-tumor activities. These results are shown in Figure 1.

All treatment groups had no significant impact on animal body weight throughout the study.

Table 1

Agent	Dose (mg/kg)	Schedule	Route	Mean Tumor volume (Day 42) (mm ³±SEM)
Vehicle	Vehicle	BID × 21	p.o.	>2000
Compound 1	2.5	BID × 42	p.o.	512.5±115.9
Compound 1	7.5	BID × 42	p.o.	252.8±48.3
Compound 1	25	BID × 42	p.o.	136.6±2.2
Compound 1	5	QD × 42	p.o.	820.9±140.2
Compound 1	15	QD × 42	p.o.	312.6±57.9
Compound 1	50	QD × 42	p.o.	141.8±5.1
Venetoclax	5	QD × 35	p.o.	>2000
Venetoclax	15	QD × 42	p.o.	1070.6±181.1
Venetoclax	50	QD × 42	p.o.	288.4±37.8

Example 2: Efficacy study of Bcl-2 inhibitors in MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model

MAVER-1 cells are of mantle cell lymphoma (MCL) origin and were obtained from American Type Culture Collection (ATCC CRL-3008, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 μg/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . MAVER-1 cells were maintained as suspension cell cultures at 37 ℃ in a 5%CO ₂ atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center. All animals were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water. Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 21-26 ℃ and 44-61%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .

On the day of implantation, MAVER-1 cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 1.5×10 ⁷ cells/mL. Re-suspended cells were placed on ice prior to inoculation. The right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation. Each animal was injected subcutaneously with 3×10 ⁶ cells in 200 μL of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.

Animals were randomly assigned into 7 groups with 10 mice per group according to body weight and tumor volume (100 mm ³-200 mm ³) . The groups consisted of vehicle group, 5, 15 mg/kg of venetoclax with QD dosing, 5, 15 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5 mg/kg of Compound 1 with BID dosing. Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.

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. Tumor growth inhibition (TGI) was calculated using the following formula: %TGI = 100 × [1- (treated _t -treated _t0) / (vehicle _t -vehicle _t0) ] (treated t = treated tumor volume at time t, treated t0 = treated tumor volume at time 0, vehicle t = vehicle tumor volume at time t and vehicle t0 = vehicle tumor volume at time 0)

In vivo efficacy of Compound 1 was also examined and compared to venetoclax in MAVER-1 MCL xenografts grown subcutaneously in NCG mice. Compound 1 potently suppressed tumor growth in a dose-dependent manner. The tumor growth inhibition (TGI) on day 14 for 2.5, 7.5 mg/kg BID and 5, 15 mg/kg QD of Compound 1 were 77%, 103%and 86%, 103%, respectively. Venetoclax at 5 and 15 mg/kg QD achieved 38%and 91%TGI, respectively. At the same total daily doses of 5 and 15 mg/kg, Compound 1 showed more anti-tumor activities relative to venetoclax. Compound 1 15 mg/kg QD and 7.5 mg/kg BID were similarly active. These results are shown in Figure 2 and Table 2.

Table 2

Example 3: Efficacy study of Bcl-2 inhibitors in Toledo diffuse large B cell lymphoma (DLBCL) subcutaneous xenograft model

Toledo cells are of diffuse large B cell lymphoma (DLBCL) origin and were obtained from American Type Culture Collection (ATCC CRL-2631, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 μg/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . Toledo cells were maintained as suspension cell cultures at 37 ℃ in a 5%CO ₂ atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center. All animals were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water. Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 21-26 ℃ and 35-61%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .

On the day of implantation, Toledo cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 1.5×10 ⁷ cells/mL. Re-suspended cells were placed on ice prior to inoculation. The right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation. Each animal was injected subcutaneously with 3×10 ⁶ cells in 200 μL of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.

Transplanted animals were randomized into 10 groups with 10 mice per group on day 0 according to transplantation sequence and body weight. The groups consisted of vehicle group, 5, 15, 50 mg/kg of venetoclax with QD dosing, 5, 15, 50 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5, 25 mg/kg of Compound 1 with BID dosing. Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.

In vivo efficacy of Compound 1 was further examined and compared to venetoclax in Toledo DLBCL subcutaneous xenograft model. Following daily oral administration at well tolerated doses at 2.5, 7.5, 25 mg/kg BID or 5, 15, 50 mg/kg QD, Compound 1 induced dose-dependent anti-tumor effects. At the same total daily doses of 5 and 15 mg/kg, Compound 1 demonstrated significantly better efficacy when compared with venetoclax. These results are shown in Figure 3 and Table 3.

Table 3

Example 4: Efficacy study of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model

The RS4; 11 Bcl-2G101V KI cells are of acute lymphoblastic leukemia (ALL) origin and were screened in house. Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 μg/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . RS4; 11 Bcl-2G101V KI cells were maintained as suspension cell cultures at 37 ℃ in a 5%CO ₂ atmosphere. Five to six-week-old female NCG mice were supplied by GemPharmatech Co., Ltd, Jiangsu, China. All animals were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water. Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 20-26 ℃ and 37-62%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radio sterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .

On the day of implantation, RS4; 11 Bcl-2G101V KI cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 5×10 ⁷ cells/mL. Re-suspended cells were placed on ice prior to inoculation. The right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation. Each animal was injected subcutaneously with 1×10 ⁷ cells in 200 μL of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.

Animals were randomly assigned into 7 groups with 8 mice per group according to body weight and tumor volume (around 300 mm ³) . The groups consisted of vehicle group, 15, 50 and 100 mg/kg of venetoclax with QD dosing, 15, 50 and 100 mg/kg of Compound 1 with QD dosing. Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.

In vivo efficacy of Compound 1 was examined and compared to venetoclax in RS4; 11 Bcl-2G101V KI xenografts grown subcutaneously in NCG mice. venetoclax showed marginal efficacy even at higher dose level, whereas Compound 1potently and dose-dependently inhibited tumor growth. These results are shown in Figure 4 and Table 4. The curves for Compound 1 at 50 mg/kg p.o. QD and 100 mg/kg p.o. QD merged.

Table 4

The foregoing examples and description of certain embodiments should be taken as illustrating, rather than as limiting the present invention as defined by the claims. As will be readily appreciated, numerous variations and combinations of the features set forth above can be utilized without departing from the present invention as set forth in the claims. All such variations are intended to be included within the scope of the present invention. All references cited are incorporated herein by reference in their entireties.

REFERENCES

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Claims

A method of cancer treatment, the method comprising administering to a subject an effective amount of a Bcl-2 inhibitor,

wherein the Bcl-2 inhibitor is selected form the group consist 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) -l6-sulfaneylidene) 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) -l6-sulfaneylidene) 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.
The mothed of claim 1, wherein the Bcl-2 inhibitor is 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide or a pharmaceutically acceptable salt thereof.
The mothed of claim 1, wherein the cancer is B-cell malignancies.
The mothed of claim 1, wherein the cancer is lymphoma or leukemia.
The mothed of claims 3 or 4, wherein the cancer is selected from the group consisting of acute myeloid leukemias (AML) , B-cell non-Hodgkin's lymphoma (B-NHL) , indolent B-cell Non-Hodgkin Lymphoma (NHL) , diffuse large B-cell lymphomas (DLBCL) , Germinal center B-cell like diffuse large B-cell lymphomas (GCB-DLBCL) , follicular lymphomas (FL) , mantle cell lymphomas (MCL) , acute lymphoblastic leukemia (ALL) , chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL) .
The method of claim 1, wherein the cancer is relapsed/refractory, or transformed.
The method of claim 1, wherein the Bcl-2 inhibitor is orally administrated.
The method of claim 1, wherein the Bcl-2 inhibitor is orally administrated at a dose of 20 mg/per day to 700 mg/per day.
The method of claim 1, wherein the cancer has Bcl-2 expression.
The method of claim, wherein the cancer has Bcl-2 Gly101Val mutation expression.