TW202140470A - Methods of cancer treatment using bcl-2 inhibitor - Google Patents

Abstract

The present disclosure provides methods of treating cancer in a subject with a Bcl-2 inhibitor, in particularly COMPOUND 1or a pharmaceutically acceptable salt thereof.

Description

Cancer treatment methods using Bcl-2 inhibitors

This article discloses a method of treating cancer with a Bcl-2 inhibitor, particularly Compound 1 or a pharmaceutically acceptable salt thereof.

Impaired cell apoptosis has an important impact on tumor development, tumor maintenance, and treatment resistance. Apoptosis can be triggered through two main pathways: the exogenous or death receptor mediator pathway, and the endogenous or mitochondrial pathway (Czabotar et al., 2014). In lymphoid malignancies, the endogenous pathway is more often affected. Cell death mediated by this pathway is regulated by members of the B-cell lymphoma-2 (Bcl-2)-related protein family, which currently includes three subfamilies. The pro-survival subgroups (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1/Bfl-1, and possibly Bcl-B) promote cell survival by inhibiting their pro-apoptotic related proteins. Pro-apoptotic BAX/BAK-like proteins (including BOK) are important effectors of cell apoptosis, and single BH3-only protein (BIM, PUMA, BID, NOXA, BMF, BIK and HRK) is the cell The initiator of apoptosis (Anderson et al., 2014). In healthy cells, the pro-survival Bcl-2 protein binds to and inhibits BAX and BAK (after partial activation), thereby reducing the ability of BAX/BAK to oligomerize and form holes to trigger the permeation of the outer mitochondrial membrane. A single BH3 segment protein is transcribed or triggered after transcription under different pressures, and binds to the pro-survival Bcl-2 protein to release BAX/BAK, or directly activates these apoptotic effectors to initiate apoptosis . Various Bcl-2 family proteins have different binding specificities with each other, forming a complex and regular interaction network that controls cell fate (Roberts, 2016).

Bcl-2 is the first anti-apoptotic protein discovered in the 1980s. It is the result of t (14;18) chromosomal translocation and a marker of FL. The gene for BCL-2 is found 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 is restricted after the development of many tissues (Kondo et al., 2008). Mice lacking Bcl-2 die of polycystic nephropathy early in life, because Bcl-2 is essential for the survival of renal epithelial precursor cells during embryonic development (Veis et al., 1993). In addition, the number of mature unactivated B and T lymphocytes in Bcl-2 deficient mice is abnormally reduced, and premature aging due to abnormal death of melanocytes (Veis et al., 1993; Yamamura et al., 1996). Although Bcl-2 was originally thought to be a typical growth-driven oncogene, it was later proved that Bcl-2 can promote the survival of malignant cells by reducing apoptosis. Transgenic mice (VavP-BCL-2 ) with the expression of Bcl-2 that can produce various blood cells preferentially develop follicular lymphoma, which was previously an acute germinal center hyperplasia (Egle et al., 2004). Mice expressing both BCL-2 and MYC transgenic genes developed lymphoma significantly faster than littermate mice expressing either of the transgenic genes, which confirms that BCL-2 is an oncogene (Adams and Cory, 2007 ).

The high level of Bcl-2 is almost universal in CLL, FL, MCL and Waldenstrom's macroglobulinemia (WM); in contrast, the degree of Bcl-2 is slightly different in multiple myeloma (MM), and The difference between DLBCL and B-cell acute lymphoblastic leukemia is very large (Roberts and Huang 2017). When Bcl-2 is overexpressed, it will affect the ratio of pro-apoptotic and anti-apoptotic Bcl-2 family members, and can prevent cell death due to apoptosis. In addition, Bcl-2 protein is closely related to the chemoresistance of hematological tumors. Due to the resistance of Bcl-2 mediator to endogenous cell apoptosis, it is generally considered to be an important cause. Targeting Bcl-2 can promote cell apoptosis and solve the resistance of Bcl-2 to cancer therapy. Therefore, Bcl-2 has become an attractive target in cancer treatment strategies.

Venetoclax (ABT-199) is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML). However, despite such high clinical activity and good safety characteristics, patients will still develop acquired resistance to Venetog under continuous treatment over time. Blombery et al. demonstrated that the Gly101Val mutation (G101V mutation) in BCL-2 confers acquired refractory properties by reducing the binding affinity of Venetog without disrupting the binding of pro-apoptotic proteins to Bcl-2. Seven of the 15 patients identified novel Gly101Val mutations in Bcl-2 in progression. This mutation is mainly found in patients who have been exposed to Venetoque monotherapy for a long time (Tausch et al. 2019).

(III-B)、 (III-C)、 (III-D)、  

    (III-E)。   WO 2019/210828 A discloses a series of compounds having the following formulas (III-B), (III-C), (III-D) or (III-E), or stereoisomers thereof, or pharmaceutically acceptable The accepted salt acts as a Bcl-2 inhibitor,

(III-B), (III-C), (III-D),

(III-E).

The compound disclosed in WO 2019/210828 A is an effective and selective Bcl-2 protein inhibitor.

The inventors of the present disclosure have discovered that Bcl2 inhibitors having the formula (III-B), (III-C), (III-D) or (III-E), especially the compound 1 ( COMPOUND 1 ) ( Compound 1 ( Compound 1 )) or its pharmaceutically acceptable salts show effective cell killing activity against a variety of lymphoma and leukemia cell lines, including MV4-11 (acute myelogenous leukemia, AML), OCI -LY10 (B-cell non-Hodgkin's lymphoma, B-NHL), Toledo (diffuse large B-cell lymphoma, DLBCL), DOHH2 (follicular lymphoma, FL), DHL-4 (germinal center B cell Diffuse large B-cell lymphoma, GCB-DLBCL) and MAVER-1 (mantle cell lymphoma, MCL). In addition, the IC ₅₀ value was found to be in the range from 0.6 nM to 13 nM.

The inventors of the present disclosure have discovered that a Bcl2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E), especially compound 1 or a pharmaceutically acceptable salt thereof Demonstrated to significantly inhibit tumor growth in cancers with high safety, such cancers include B-cell malignancies selected from acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) . The inventors have discovered that the B-cell malignant tumor has Bcl-2 manifestations and/or Bcl-2 G101V mutation manifestations.

(III-B)、 (III-C)、 (III-D)、  

    (III-E)，   或其藥學上可接受的鹽、或其立體異構物， 其中， R² 在每次出現時獨立地選自由以下組成之群組：氫、鹵素、或視需要被鹵素取代的-C_1-8 烷基； R^1d 在每次出現時獨立地是鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^Ba 、-SO₂ R^Ba 、-COR^Ba 、-CO₂ R^Ba 、-CONR^Ba R^Bb 、-C(=NR^Ba )NR^Bb R^Bc 、-NR^Ba R^Bb 、-NR^Ba COR^Bb 、-NR^Ba CONR^Bb R^Bc 、-NR^Ba CO₂ R^Bb 、-NR^Ba SONR^Bb R^Bc 、-NR^Ba SO₂ NR^Bb R^Bc 、或-NR^Ba SO₂ R^Bb ；其中所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基或雜芳基各自獨立地視需要被1至4個取代基R^Bd 取代； R^Ba 、R^Bb 和R^Bc 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被以下取代：鹵素、羥基、-NH₂ 或-N(C_1-6 烷基)₂ 、-C_1-8 烷氧基、環烷基、雜環基、芳基、或雜芳基； R^Bd 在每次出現時獨立地是氫、鹵素、側氧基、-CN、-NO₂ 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被以下取代：鹵素、羥基、-C_1-8 烷氧基、環烷基、雜環基、芳基、或雜芳基； m係1-4的整數； R⁵ 係-L⁵ -CyC， 其中L⁵ 係直接鍵、-(CR^a R^b )_t -、-(CR^a R^b )_t-1 -(CR^c =CR^d )-(CR^a R^b )_v-1 -、-(CR^a R^b )_t-1 -(C≡C)-(CR^a R^b )_v-1 -、-O-、-S-、-S(O)-、-SO₂ -、-C(O)-、C(O)O-、-OC(O)-、-NR^a -、-C(O)NR^a -、-NR^a C(O)-、-NR^a C(O)O-、-NR^a C(O)NR^b -、-SO₂ NR^a -、-NR^a SO₂ -、-NR^a S(O)₂ NR^b -、-NR^a S(O)NR^b -、-C(O)NR^a SO₂ -、-C(O)NR^a SO-、或-C(=NR^a )NR^b -，其中t和v在每次出現時獨立地是1至7中的一個數，並且-(CR^a R^b )_t -、-(CR^a R^b )_t-1 -(CR^c =CR^d )-(CR^a R^b )_v-1 -、-(CR^a R^b )_t-1 -(C≡C)-(CR^a R^b )_v-1 -中的一個或兩個CR^a R^b 部分未被替換或被選自O、S、SO、SO₂ 、C(O) 和NR^a 的一個或多個部分替換； CyC係環烷基、雜環基、芳基、或雜芳基，它們中的每一個視需要被一個或兩個取代基R^5a 取代； R^5a 在每次出現時獨立地選自：氫、鹵素、氰基、側氧基、-NO₂ 、-OR^5b 、-SR^5b 、-NR^5b R^5c 、-COR^5b 、-SO₂ R^5b 、-C(=O)OR^5b 、-C(=O)NR^5b R^5c 、-C(=NR^5b )NR^5c R^5d 、-N(R^5b )C(=O)R^5c 、-N(R^5b )C(=O)OR^5c 、-N(R^5b )C(O)NR^5c R^5d 、-N(R^5b )S(O)NR^5c R^5d 、-N(R^5b )S(O)₂ NR^5c R^5d 、-NR^5b SO₂ R^5c 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基中的每一個視需要被一個或兩個取代基R^5e 取代； 其中R^5b 、R^5c 和R^5d 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基中的每一個視需要被一個或兩個取代基R^5e 取代； R^5e 在每次出現時獨立地選自：氫、鹵素、氰基、側氧基、-NO₂ 、-OR^5f 、-SR^5f 、-NR^5f R^5g 、-COR^5f 、-SO₂ R^5f 、-C(=O)OR^5f 、-C(=O)NR^5f R^5g 、-C(=NR^5f )NR^5g R^5h 、-N(R^5f )C(=O)R^5g 、-N(R^5f )C(=O)OR^5g 、-N(R^5f )C(O)NR^5g R^5h 、-N(R^5f )S(O)NR^5g R^5h 、-N(R^5f )S(O)₂ NR^5g R^5h 、-NR^5f SO₂ R^5g 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基； R^5f 、R^5g 和R^5h 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基； 或在苯基環上的兩個相鄰R⁵ 與苯基環一起形成苯并環，所述環視需要被以下取代：鹵素、側氧基、氰基、-NO₂ 、-OR⁵ⁱ 、-SR⁵ⁱ 、-NR⁵ⁱ R^5j 、-COR⁵ⁱ 、-SO₂ R⁵ⁱ 、-C(=O)OR⁵ⁱ 、-C(=O)NR⁵ⁱ R^5j 、-C(=NR⁵ⁱ )NR^5j R^5k 、-N(R⁵ⁱ )C(=O)R^5j 、-N(R⁵ⁱ )C(=O)OR^5j 、-N(R⁵ⁱ )C(O)NR^5j R^5k 、-N(R⁵ⁱ )S(O)NR^5j R^5k 、-N(R⁵ⁱ )S(O)₂ NR^5j R^5k 、-NR⁵ⁱ SO₂ R^5k 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基； R⁵ⁱ 、R^5j 和R^5k 獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被鹵素、羥基或-C_1-8 烷氧基取代； R^a 、R^b 、R^c 和R^d 在每次出現時獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基各自獨立地被以下取代：-CN、鹵素、-NO₂ 、-NR^e R^f 、側氧基、-OR^e 、或-SR^e ；並且 其中R^e 和R^f 各自獨立地是氫、C_1-8 烷基、C_1-8 烷氧基-C_1-8 烷基-、C_2-8 烯基、C_2-8 炔基、環烷基、芳基、雜環基、或雜芳基。In the first aspect, this paper discloses a method for treating cancer with a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is composed of the following formula (III-B), (III-C), (III-D) or ( III-E) represents the compound,

(III-B), (III-C), (III-D),

(III-E), Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ^{each occurrence of R 2} is independently selected from the group consisting of hydrogen, halogen, or -C _{1- substituted by halogen as necessary 8} Alkyl; R ^1d is independently halogen at each occurrence, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl , Heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^Ba , -SO ₂ R ^Ba , -COR ^Ba , -CO ₂ R ^Ba , -CONR ^Ba R ^Bb , -C(=NR ^Ba )NR ^Bb R ^Bc , -NR ^Ba R ^Bb , -NR ^Ba COR ^Bb , -NR ^Ba CONR ^Bb R ^Bc , -NR ^Ba CO ₂ R ^Bb , -NR ^Ba SONR ^Bb R ^Bc , -NR ^Ba SO ₂ NR ^Bb R ^Bc , Or -NR ^Ba SO ₂ R ^Bb ; wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group Each is independently substituted by 1 to 4 substituents R ^Bd as necessary; R ^Ba , R ^Bb and R ^Bc are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _{2- 8} alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, Each of the heterocyclic group, aryl group, or heteroaryl group is optionally substituted with the following: halogen, hydroxyl, -NH ₂ or -N(C _1-6 alkyl) ₂ , -C _1-8 alkoxy, Cycloalkyl, heterocyclyl, aryl, or heteroaryl; ^{each occurrence of R Bd} is independently hydrogen, halogen, pendant oxy, -CN, -NO ₂ , -C _1-8 alkyl,- C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl,- Each of C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with the following: halogen, hydroxy, -C _1-8 alkoxy, cycloalkyl, hetero Cyclic, aryl, or heteroaryl; m is an integer of 1-4; R ⁵ is -L ⁵ -CyC, where L ⁵ is a direct bond, -(CR ^a R ^b ) _t -, -(CR ^a R ^b ) _t-1 -(CR ^c =CR ^d )-(CR ^a R ^b ) _v-1 -、-(CR ^a R ^b ) _t-1 -(C≡C)-(CR ^a R ^b ) _{v- 1} -, -O-, -S-, -S(O)-, -SO ₂ -, -C(O)-, C(O)O-, -OC(O)-, -NR ^a -,- C(O)NR ^a -, -NR ^a C(O)-, -NR ^a C( O)O-, -NR ^a C(O)NR ^b -, -SO ₂ NR ^a -, -NR ^a SO ₂ -, -NR ^a S(O) ₂ NR ^b -, -NR ^a S(O)NR ^b -, -C(O)NR ^a SO ₂ -, -C(O)NR ^a SO-, or -C(=NR ^a )NR ^b -, where t and v are independently 1 to each time they appear A number in 7, and -(CR ^a R ^b ) _t -, -(CR ^a R ^b ) _t-1 -(CR ^c =CR ^d )-(CR ^a R ^b ) _v-1 -, -(CR ^a R ^b ) _t-1 -(C≡C)-(CR ^a R ^b ) _v-1 -One or two of CR ^a R ^b part is not replaced or selected from O, S, SO, SO ₂ , one or more portions C (O) NR ^a, and replacement; CyC-based cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of them optionally substituted with one or two substituents R ^5a Substitution; ^{each occurrence of R 5a} is independently selected from: hydrogen, halogen, cyano, pendant oxy, -NO ₂ , -OR ^5b , -SR ^5b , -NR ^5b R ^5c , -COR ^5b , -SO ₂ R ^5b , -C(=O)OR ^5b , -C(=O)NR ^5b R ^5c , -C(=NR ^5b )NR ^5c R ^5d , -N(R ^5b )C(=O)R ^5c ,- N(R ^5b )C(=O)OR ^5c , -N(R ^5b )C(O)NR ^5c R ^5d , -N(R ^5b )S(O)NR ^5c R ^5d , -N(R ^5b )S (O) ₂ NR ^5c R ^5d , -NR ^5b SO ₂ R ^5c , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, Aryl or heteroaryl, said -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl Each of them is optionally substituted by one or two substituents R ^5e ; wherein R ^5b , R ^5c and R ^5d are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, C _2-8 alkynyl, -cycloalkane Each of the group, heterocyclic group, aryl group, or heteroaryl group is optionally substituted by one or two substituents R ^5e ; ^{each occurrence of R 5e} is independently selected from: hydrogen, halogen, cyano, side Oxy, -NO ₂ , -OR ^5f , -SR ^5f , -NR ^5f R ^5g , -COR ^5f , -SO ₂ R ^5f , -C(=O)OR ^5f , -C(=O)NR ^5f R ^5g 、-C(=NR ^5f )NR ^5g R ^5h 、-N(R ^5f )C(=O)R ^5g 、-N(R ^5f )C(=O)OR ^5g , -N(R ^5f )C(O)NR ^5g R ^5h , -N(R ^5f )S(O)NR ^5g R ^5h , -N(R ^5f )S(O) ₂ NR ^5g R ^5h , -NR ^5f SO ₂ R ^5g , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^5f , R ^5g and R ^5h are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or two adjacent R ⁵ on the phenyl ring and the phenyl ring together form a benzo ring, and the ring is optionally substituted by the following: halogen, pendant oxy, cyano, -NO ₂ , -OR ⁵ⁱ , -SR ⁵ⁱ , -NR ⁵ⁱ R ^5j , -COR ⁵ⁱ , -SO ₂ R ⁵ⁱ , -C(=O)OR ⁵ⁱ , -C(=O)NR ⁵ⁱ R ^5j , -C(=NR ⁵ⁱ )NR ^5j R ^5k , -N(R ⁵ⁱ )C(=O)R ^5j , -N(R ⁵ⁱ )C(=O)OR ^5j , -N(R ⁵ⁱ )C(O)NR ^5j R ^5k , -N(R ⁵ⁱ )S (O)NR ^5j R ^5k , -N(R ⁵ⁱ )S(O) ₂ NR ^5j R ^5k , -NR ⁵ⁱ SO ₂ R ^5k , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ⁵ⁱ , R ^5j and R ^{5k are} independently hydrogen, -C _1-8 alkyl, -C _2-8 alkene Group, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an aryl or heteroaryl group each optionally substituted with halogen, hydroxy or -C _1-8 ^{alkoxy; R a, R b, R} c and R ^d are in Each occurrence is independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, so The -C _1-8 alkyl group, -C _2-8 alkenyl group, -C _2-8 alkynyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group are each independently substituted by the following: -CN, Halogen, -NO ₂ , -NR ^e R ^f , pendant oxy group, -OR ^e , or -SR ^e ; and wherein R ^e and R ^f are each independently hydrogen, C _1-8 alkyl, C _1-8 alkane Oxygen-C _1-8 alkyl-, C _2-8 alkenyl, C _2-8 alkynyl, ring Alkyl, aryl, heterocyclyl, or heteroaryl.

In the second aspect, this document discloses a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharmacological agent thereof An acceptable salt for use in the treatment of cancer.

In a third aspect, this document discloses a method of treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of formula (III-B), (III-C), (III-D) Or (III-E) Bcl-2 inhibitor, or its stereoisomer, or its pharmaceutically acceptable salt.

In the fourth aspect, this article discloses the use of the pharmaceutical composition in the manufacture of drugs for the treatment of cancer, the pharmaceutical combination comprising formula (III-B), (III-C), (III-D) or (III-B), (III-C), (III-D) or (III-D). -E) The Bcl-2 inhibitor, or its stereoisomer, or its pharmaceutically acceptable salt.

In an embodiment of each of the above aspects, the Bcl-2 inhibitor is Compound 1 ( Compound 1 ) or a pharmaceutically acceptable salt thereof.

In an embodiment of each of the above aspects, the cancer is a B cell malignancy.

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

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

In one embodiment of each of the above aspects, the cancer is relapsed/refractory, or transformative.

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

In one embodiment of each of the above aspects, the cancer has Bcl-2 manifestations.

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

definition

Unless specifically defined elsewhere in this document, all other technical and scientific terms used in this article have the meanings commonly understood by those familiar with the technology.

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

Unless the context clearly dictates otherwise, the term " or " means the term "and/or" and is used interchangeably with the term "and/or".

The term " anti-cancer agent " as used herein refers to any agent that can be used to treat cell proliferative disorders (such as cancer), including but not limited to cytotoxic agents, chemotherapeutics, radiotherapy and radiotherapeutics, targeted anti- Cancer agent, and immunotherapeutic agent.

The term "administration (administration / administering)" herein and "treatment (treating / treatment)", when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means exogenous drugs , The therapeutic agent, diagnostic agent or composition is in contact with the animal, human, subject, cell, tissue, organ or biological fluid. The treatment of cells encompasses the contact of the reagent with the cell and the contact of the reagent with the fluid, where the fluid is in contact with the cell. The terms "administration" and "treatment" also mean the in vitro and ex vivo treatment of cells, for example, by reagents, diagnostic agents, binding compounds, or another kind of cells. The term "subject" as used herein includes any organism, preferably animals, more preferably mammals (for example, rats, mice, dogs, cats, rabbits), and most preferably humans. In one aspect, treating any disease or disorder refers to ameliorating the disease or disorder (ie, slowing down or preventing or reducing the development of the disease or at least one clinical symptom thereof). In another aspect, "treat/treating/treatment" refers to alleviation or improvement of at least one physical parameter, including those that the patient may not be able to distinguish. In yet another aspect, "treat/treating/treatment" refers to the regulation of disease physically (for example, stabilization of discernible symptoms), physiologically (for example, stabilization of physical parameters), or both Or obstacles. In yet another aspect, "treat/treating/treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.

In the context of the present disclosure, the term " subject " refers to a mammal, for example, a primate, preferably a higher primate, such as a human (for example, suffering from the disorders described herein or suffering from Patients at risk of the disorders described in this article). In some embodiments, the subject is a human or patient.

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

The term " therapeutically effective amount " as used herein refers to the amount of a Bcl-2 inhibitor that is sufficient to affect the treatment of the disease, disorder, or symptom when administered to a subject to treat at least one clinical symptom of the disease, disorder, or disorder quantity. The " therapeutically effective amount " may vary depending on the medicament, disease, disorder, and/or symptoms of the disease or disorder, the severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or The weight of the subject to be treated varies. The appropriate amount in any given situation is obvious to those skilled in the art, or can be determined by routine experimentation. In the case of combination therapy, the " therapeutically effective amount " refers to the total amount of constituents used to effectively treat a disease, disorder, or condition. Implementation

The present disclosure provides a method for treating cancer in a subject with a Bcl-2 inhibitor, particularly Compound 1 (Compound 1) or a pharmaceutically acceptable salt thereof. Bcl-2 inhibitor

(III-B)、 (III-C)、 (III-D)、  

    (III-E)，   或其藥學上可接受的鹽、或其立體異構物， 其中， R² 在每次出現時獨立地選自由以下組成之群組：氫、鹵素、或視需要被鹵素取代的-C_1-8 烷基； R^1d 在每次出現時獨立地是鹵素、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、雜芳基、側氧基、-CN、-NO₂ 、-OR^Ba 、-SO₂ R^Ba 、-COR^Ba 、-CO₂ R^Ba 、-CONR^Ba R^Bb 、-C(=NR^Ba )NR^Bb R^Bc 、-NR^Ba R^Bb 、-NR^Ba COR^Bb 、-NR^Ba CONR^Bb R^Bc 、-NR^Ba CO₂ R^Bb 、-NR^Ba SONR^Bb R^Bc 、-NR^Ba SO₂ NR^Bb R^Bc 、或-NR^Ba SO₂ R^Bb ；其中所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基或雜芳基各自獨立地視需要被1至4個取代基R^Bd 取代； R^Ba 、R^Bb 和R^Bc 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被以下取代：鹵素、羥基、-NH₂ 或-N(C_1-6 烷基)₂ 、-C_1-8 烷氧基、環烷基、雜環基、芳基、或雜芳基； R^Bd 在每次出現時獨立地是氫、鹵素、側氧基、-CN、-NO₂ 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被以下取代：鹵素、羥基、-C_1-8 烷氧基、環烷基、雜環基、芳基、或雜芳基； m係1-4的整數； R⁵ 係-L⁵ -CyC， 其中L⁵ 係直接鍵、-(CR^a R^b )_t -、-(CR^a R^b )_t-1 -(CR^c =CR^d )-(CR^a R^b )_v-1 -、-(CR^a R^b )_t-1 -(C≡C)-(CR^a R^b )_v-1 -、-O-、-S-、-S(O)-、-SO₂ -、-C(O)-、C(O)O-、-OC(O)-、-NR^a -、-C(O)NR^a -、-NR^a C(O)-、-NR^a C(O)O-、-NR^a C(O)NR^b -、-SO₂ NR^a -、-NR^a SO₂ -、-NR^a S(O)₂ NR^b -、-NR^a S(O)NR^b -、-C(O)NR^a SO₂ -、-C(O)NR^a SO-、或-C(=NR^a )NR^b -，其中t和v在每次出現時獨立地是1至7中的一個數，並且-(CR^a R^b )_t -、-(CR^a R^b )_t-1 -(CR^c =CR^d )-(CR^a R^b )_v-1 -、-(CR^a R^b )_t-1 -(C≡C)-(CR^a R^b )_v-1 -中的一個或兩個CRaRb部分未被替換或被選自O、S、SO、SO₂ 、C(O) 和NR^a 的一個或多個部分替換； CyC係環烷基、雜環基、芳基、或雜芳基，它們中的每一個視需要被一個或兩個取代基R^5a 取代； R^5a 在每次出現時獨立地選自：氫、鹵素、氰基、側氧基、-NO₂ 、-OR^5b 、-SR^5b 、-NR^5b R^5c 、-COR^5b 、-SO₂ R^5b 、-C(=O)OR^5b 、-C(=O)NR^5b R^5c 、-C(=NR^5b )NR^5c R^5d 、-N(R^5b )C(=O)R^5c 、-N(R^5b )C(=O)OR^5c 、-N(R^5b )C(O)NR^5c R^5d 、-N(R^5b )S(O)NR^5c R^5d 、-N(R^5b )S(O)₂ NR^5c R^5d 、-NR^5b SO₂ R^5c 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基中的每一個視需要被一個或兩個取代基R^5e 取代； 其中R^5b 、R^5c 和R^5d 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基中的每一個視需要被一個或兩個取代基R^5e 取代； R^5e 在每次出現時獨立地選自：氫、鹵素、氰基、側氧基、-NO₂ 、-OR^5f 、-SR^5f 、-NR^5f R^5g 、-COR^5f 、-SO₂ R^5f 、-C(=O)OR^5f 、-C(=O)NR^5f R^5g 、-C(=NR^5f )NR^5g R^5h 、-N(R^5f )C(=O)R^5g 、-N(R^5f )C(=O)OR^5g 、-N(R^5f )C(O)NR^5g R^5h 、-N(R^5f )S(O)NR^5g R^5h 、-N(R^5f )S(O)₂ NR^5g R^5h 、-NR^5f SO₂ R^5g 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基； R^5f 、R^5g 和R^5h 各自獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基； 或在苯基環上的兩個相鄰R⁵ 與苯基環一起形成苯并環，所述環視需要被以下取代：鹵素、側氧基、氰基、-NO₂ 、-OR⁵ⁱ 、-SR⁵ⁱ 、-NR⁵ⁱ R^5j 、-COR⁵ⁱ 、-SO₂ R⁵ⁱ 、-C(=O)OR⁵ⁱ 、-C(=O)NR⁵ⁱ R^5j 、-C(=NR⁵ⁱ )NR^5j R^5k 、-N(R⁵ⁱ )C(=O)R^5j 、-N(R⁵ⁱ )C(=O)OR^5j 、-N(R⁵ⁱ )C(O)NR^5j R^5k 、-N(R⁵ⁱ )S(O)NR^5j R^5k 、-N(R⁵ⁱ )S(O)₂ NR^5j R^5k 、-NR⁵ⁱ SO₂ R^5k 、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、-環烷基、雜環基、芳基、或雜芳基； R⁵ⁱ 、R^5j 和R^5k 獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基中的每一個視需要被鹵素、羥基或-C_1-8 烷氧基取代； R^a 、R^b 、R^c 和R^d 在每次出現時獨立地是氫、-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基，所述-C_1-8 烷基、-C_2-8 烯基、-C_2-8 炔基、環烷基、雜環基、芳基、或雜芳基各自獨立地被以下取代：-CN、鹵素、-NO₂ 、-NR^e R^f 、側氧基、-OR^e 、或-SR^e ；並且 其中R^e 和R^f 各自獨立地是氫、C_1-8 烷基、C_1-8 烷氧基-C_1-8 烷基-、C_2-8 烯基、C_2-8 炔基、環烷基、芳基、雜環基、或雜芳基。The Bcl-2 inhibitor of the present disclosure is a compound represented by the following formula (III-B), (III-C), (III-D) or (III-E),

(III-B), (III-C), (III-D),

(III-E), Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein ^{each occurrence of R 2} is independently selected from the group consisting of hydrogen, halogen, or -C _{1- substituted by halogen as necessary 8} Alkyl; R ^1d is independently halogen at each occurrence, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl , Heteroaryl, pendant oxy, -CN, -NO ₂ , -OR ^Ba , -SO ₂ R ^Ba , -COR ^Ba , -CO ₂ R ^Ba , -CONR ^Ba R ^Bb , -C(=NR ^Ba )NR ^Bb R ^Bc , -NR ^Ba R ^Bb , -NR ^Ba COR ^Bb , -NR ^Ba CONR ^Bb R ^Bc , -NR ^Ba CO ₂ R ^Bb , -NR ^Ba SONR ^Bb R ^Bc , -NR ^Ba SO ₂ NR ^Bb R ^Bc , Or -NR ^Ba SO ₂ R ^Bb ; wherein the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group Each is independently substituted by 1 to 4 substituents R ^Bd as necessary; R ^Ba , R ^Bb and R ^Bc are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _{2- 8} alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, Each of the heterocyclic group, aryl group, or heteroaryl group is optionally substituted with the following: halogen, hydroxyl, -NH ₂ or -N(C _1-6 alkyl) ₂ , -C _1-8 alkoxy, Cycloalkyl, heterocyclyl, aryl, or heteroaryl; ^{each occurrence of R Bd} is independently hydrogen, halogen, pendant oxy, -CN, -NO ₂ , -C _1-8 alkyl,- C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl,- Each of C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with the following: halogen, hydroxy, -C _1-8 alkoxy, cycloalkyl, hetero Cyclic, aryl, or heteroaryl; m is an integer of 1-4; R ⁵ is -L ⁵ -CyC, where L ⁵ is a direct bond, -(CR ^a R ^b ) _t -, -(CR ^a R ^b ) _t-1 -(CR ^c =CR ^d )-(CR ^a R ^b ) _v-1 -、-(CR ^a R ^b ) _t-1 -(C≡C)-(CR ^a R ^b ) _{v- 1} -, -O-, -S-, -S(O)-, -SO ₂ -, -C(O)-, C(O)O-, -OC(O)-, -NR ^a -,- C(O)NR ^a -, -NR ^a C(O)-, -NR ^a C( O)O-, -NR ^a C(O)NR ^b -, -SO ₂ NR ^a -, -NR ^a SO ₂ -, -NR ^a S(O) ₂ NR ^b -, -NR ^a S(O)NR ^b -, -C(O)NR ^a SO ₂ -, -C(O)NR ^a SO-, or -C(=NR ^a )NR ^b -, where t and v are independently 1 to each time they appear A number in 7, and -(CR ^a R ^b ) _t -, -(CR ^a R ^b ) _t-1 -(CR ^c =CR ^d )-(CR ^a R ^b ) _v-1 -, -(CR ^a R ^b ) _t-1 -(C≡C)-(CR ^a R ^b ) _v-1 -One or two CRaRb parts are not replaced or selected from O, S, SO, SO ₂ , C( O) and NR ^a partial replacement; CyC is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is optionally substituted by one or two substituents R ^5a ; R ^{Each occurrence of 5a} is independently selected from: hydrogen, halogen, cyano, pendant oxy, -NO ₂ , -OR ^5b , -SR ^5b , -NR ^5b R ^5c , -COR ^5b , -SO ₂ R ^5b , -C(=O)OR ^5b , -C(=O)NR ^5b R ^5c , -C(=NR ^5b )NR ^5c R ^5d , -N(R ^5b )C(=O)R ^5c , -N(R ^5b )C(=O)OR ^5c , -N(R ^5b )C(O)NR ^5c R ^5d , -N(R ^5b )S(O)NR ^5c R ^5d , -N(R ^5b )S(O) ₂ NR ^5c R ^5d , -NR ^5b SO ₂ R ^5c , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, Or heteroaryl, each of the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclic, aryl, or heteroaryl group One is optionally substituted by one or two substituents R ^5e ; wherein R ^5b , R ^5c and R ^5d are each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, C _2-8 alkynyl, -cycloalkyl, hetero Each of the cyclic group, aryl group, or heteroaryl group is optionally substituted by one or two substituents R ^5e ; ^{each occurrence of R 5e} is independently selected from: hydrogen, halogen, cyano, pendant oxy, -NO ₂ , -OR ^5f , -SR ^5f , -NR ^5f R ^5g , -COR ^5f , -SO ₂ R ^5f , -C(=O)OR ^5f , -C( =O)NR ^5f R ^5g , -C(=NR ^5f )NR ^5g R ^5h , -N(R ^5f )C(=O)R ^5g , -N(R ^5f )C(=O)OR ^5g , -N (R ^5f )C(O)NR ^5g R ^5h , -N(R ^5f )S(O)NR ^5g R ^5h , -N(R ^5f )S(O) ₂ NR ^5g R ^5h , -NR ^5f SO ₂ R ^5g , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ^5f , R ^5g and R ^{5h is} each independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or in benzene Two adjacent R ⁵ on the radical ring together with the phenyl ring form a benzo ring, and the ring is optionally substituted with the following: halogen, pendant oxy, cyano, -NO ₂ , -OR ⁵ⁱ , -SR ⁵ⁱ ,- NR ⁵ⁱ R ^5j , -COR ⁵ⁱ , -SO ₂ R ⁵ⁱ , -C(=O)OR ⁵ⁱ , -C(=O)NR ⁵ⁱ R ^5j , -C(=NR ⁵ⁱ )NR ^5j R ^5k , -N( R ⁵ⁱ )C(=O)R ^5j , -N(R ⁵ⁱ )C(=O)OR ^5j , -N(R ⁵ⁱ )C(O)NR ^5j R ^5k , -N(R ⁵ⁱ )S(O) NR ^5j R ^5k , -N(R ⁵ⁱ )S(O) ₂ NR ^5j R ^5k , -NR ⁵ⁱ SO ₂ R ^5k , -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R ⁵ⁱ , R ^5j and R ^{5k are} independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl,- C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, ring Each of the alkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally substituted by halogen, hydroxyl, or -C _1-8 alkoxy; R ^a , R ^b , R ^c, and R ^d appear at each occurrence When is independently hydrogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently substituted with the following: -CN, halogen,- NO ₂ , -NR ^e R ^f , pendant oxy, -OR ^e , or -SR ^e ; and wherein R ^e and R ^f are each independently hydrogen, C _1-8 alkyl, C _1-8 alkoxy- C _1-8 alkyl-, C _2-8 alkenyl, C _2-8 alkynyl, cycloalkyl, Aryl, heterocyclic, or heteroaryl.

In some embodiments, R ² is hydrogen.

In some embodiments, when in ring B (including aziridin-1-yl, azetidine-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl , Azepan-1-yl, or azepan-1-yl, preferably a pyrrolidin-1-yl group) when substituted on the phenyl group at position 2, R ^{1d is} independent Ground is halogen, -C _1-8 alkyl, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR ^Ba , -SO ₂ R ^Ba , -CONR ^Ba R ^Bb , -NO ₂ , -NR ^Ba R ^Bb , -NR ^Ba COR ^Bb , or -NR ^Ba SO ₂ R ^Bb ; wherein the -C _1-8 alkyl group, -C _2-8 alkenyl, -C _2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally substituted by 1 to 4 substituents R ^Bd (as in the formula (III-B ), (III-C), (III-D) or (III-E) defined) unsubstituted, preferably substituted with 1 or 2 substituents R ^Bd (as represented by the formula (III-B), (III- C), (III-D) or (III-E) definition) substitution. 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 groups at the position of the phenyl ring; or propenyl; or cyclopropyl, Cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

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

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In some embodiments, m is 1; and L ⁵ is a direct bond, -(CR ^a R ^b ) _t -or -NR ^a -, where t is a number from 1 to 7, and -(CR ^a R ^b ) _t - one or two CR ^a R ^b or more portions of a replacement part is not replaced or selected from O and NR ^a, wherein R ^a and R ^b are represented by the formula (III-B), (III- C), (III-D) or (III-E) definition.

In some embodiments, L ⁵ is a direct bond, -(CR ^a R ^b ) _1-4 -, -O-(CR ^a R ^b ) _1-3 -, -NH-(CR ^a R ^b ) _1-3 , or -NH-, wherein, (III-C), ( III-D) or (III-E) R ^a and R ^{b are} defined as with formula (III-B), and therefore are part -L ⁵ -CyC CyC , -(CR ^a R ^b ) _1-4 -CyC, -O-(CR ^a R ^b ) _1-3 -CyC, -NH-(CR ^a R ^b ) _1-3 -CyC, or -NH-CyC. More preferably, L ⁵ is a direct bond, -(CH ₂ ) _1-4 -, -O-(CH ₂ ) _1-3 -, -NH-(CR ^a R ^b )-(CH ₂ ) _2- , or -NH-, wherein R ^a hydrogen-based, and R ^b based -S- optionally substituted phenyl C _1-8 alkyl group, thus are part -L ⁵ -CyC CyC, - (CH _{2) 1 -4} -CyC, -O-(CH ₂ ) _1-3 -CyC, -NH-(CR ^a R ^b )-(CH ₂ ) ₂ -CyC, or -NH-CyC. More preferably, L ⁵ is a direct bond, -CH ₂ -, -O-CH ₂ -, -NH-CH ₂ -, or -NH-, so the -L ⁵ -CyC part is CyC, -CH _{2 respectively} -CyC, -O-CH ₂ -CyC, -NH-CH ₂ -CyC, or -NH-CyC.

In some embodiments, CyC is a cycloalkyl or heterocyclic group, each of which is optionally substituted by one or two substituents R ^5a ; R ^{5a is} independently selected from hydrogen, halogen, cyano, pendant oxy , -OR ^5b , -NR ^5b R ^5c , -COR ^5b , -SO ₂ R ^5b , -C _1-8 alkyl, -C _2-8 alkynyl, -cycloalkyl, or heterocyclic group, the- Each of the C _1-8 alkyl group and the heterocyclic group is optionally substituted with one or two substituents R ^5e selected from the group consisting of hydrogen, halogen, cyano, -OR ^5f , -C _1-8 alkane Group, -cycloalkyl, or heterocyclyl; wherein R ^5b and R ^5c are each independently hydrogen, -C _1-8 alkyl or heterocyclyl, and the -C _1-8 alkyl group is optionally substituted by one or Two substituents R ^{5e are} substituted. The substituents are hydrogen, -NR ^5f R ^5g or -cycloalkyl; R ^5f and R ^5g are each independently hydrogen or -C _1-8 alkyl; or on the phenyl ring Two adjacent R ^{5 of} and together with the phenyl ring form a benzo ring, and the ring is optionally substituted with a heteroaryl group.

）（它們中的每一個視需要被一個或兩個取代基R^5a 取代）的環烷基。較佳的是，CyC係環戊基或環己基，它們中的每一個視需要被一個或兩個取代基R^5a 取代。In some embodiments, CyC is selected from monocyclic C _3-8 cycloalkyl or bridged cycloalkyl (

) (Each of them is optionally substituted with one or two substituents R ^5a ) cycloalkyl. Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted by one or two substituents R ^5a .

In some embodiments, CyC is a heterocyclic group selected from the following: a) a monocyclic 4-membered to 9-membered heterocyclic group containing a nitrogen or oxygen or sulfur heteroatom as a ring member; b) a monocyclic ring 4 A to 9-membered heterocyclic group containing two heteroatoms selected from oxygen, sulfur and nitrogen as ring members; and c) a 5- to 20-membered spiro heterocyclic group containing a group selected from nitrogen, sulfur and oxygen One or two heteroatoms of as ring members, and each of them is substituted ^{by one or two R 5a as necessary.}

In some embodiments, CyC is a monocyclic 4-membered to 6-membered heterocyclic group, which contains a nitrogen or oxygen or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, azetidinyl, pyrrolidinyl and piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-3-yl Piperan-2-yl, tetrahydropiperan-3-yl, tetrahydropiperan-4-yl, azetidine-3-yl, azetidine-2-yl, pyrrolidine-2- Yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl, and piperidin-3-yl.

In some embodiments, CyC is a monocyclic 6-membered heterocyclic group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is a diethyl group, a lino group, a linyl group, or a piperyl group. Even more preferred are 1,3-di-e-2-yl, 1,3-di-e-4-yl, 1,4-di-e-2-yl, lin-1-yl, lin-2-yl , Or lin-3-yl.

In some embodiments, R ^{5a is} independently selected from hydrogen, halogen, cyano, pendant oxy, -OR ^5b , -NR ^5b R ^5c , -COR ^5b , -SO ₂ R ^5b , -C _1-8 alkyl , -C _2-8 alkynyl, monocyclic C _3-8 cycloalkyl, or monocyclic 4 to 9 member heterocyclic group (containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms As a ring member), each of the -C _1-8 alkyl group and the monocyclic 4- to 9-membered heterocyclic group is optionally substituted with one or two substituents R ^5e ; preferably, as The cycloalkyl group of R ^{5a is} _{a C 3-6} cycloalkyl group; more preferably a cyclopropyl group; preferably, ^{the heterocyclic group of R 5a is} a 4- to 6-membered heterocyclic group, which contains One or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms are used as ring members; more preferably, ^{the heterocyclic group of R 5a} is oxetanyl, tetrahydrofuranyl, tetrahydropiperanyl, Piperyl, or linyl; even more preferably, ^{the heterocyclic group of R 5a} is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-piperan-4-yl, Or morphine-4-yl.

In some embodiments, ^{the heterocyclic group as R 5e} is a monocyclic 4-membered to 9-membered heterocyclic group, which contains one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members.

In some embodiments, ^{the heterocyclic group as R 5e} is tetrahydro-piperan-4-yl.

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

In some embodiments, R ^5a is -NR ^5b R ^5c , where R ^5b is hydrogen, and R ^5c is tetrahydro-piperan-4-yl.

In some embodiments, R ^5a is -NR ^5b R ^5c , wherein R ^5b and R ^5c are each independently hydrogen or -C _1-6 alkyl substituted by cycloalkyl, preferably a monocyclic C _{3- 8} -C _1-6 alkyl substituted with cycloalkyl.

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

In some embodiments, R ^5a is -COR ^5b , wherein R ^5b is hydrogen or a C ^{1-8 alkyl group optionally substituted by -NR 5f} R ^5g , wherein R ^5f and R ^5g are each independently hydrogen or C _{1 -8} alkyl, preferably methyl.

In some embodiments, two adjacent R ⁵ on the phenyl ring together with the phenyl ring form an indazolyl group substituted with a tetrahydropiperanyl group.

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

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。In some embodiments, m is 1, and R ⁵ is

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In some embodiments, the Bcl-2 inhibitor of the present disclosure is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-( 2-((S)-2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-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] Nonane-7-yl)-N-((4-(((4-Fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfon (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan- 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]nonane-7-yl)-N-((3-nitro- 4-(((Tetrahydro-2H-piperan-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]nonane-7 -Yl)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide ; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4- (2-(2-(2-Cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4- (((Tetrahydro-2H-piperan-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]nonane-7- Base)-N-((4-(((4-Fluorotetrahydro-2H- Piperan-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]nonane-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)pyrrolidine-1- Yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undec-3-yl)-N- ((3-nitro-4-(((tetrahydro-2H-piperan-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-aza Spiro[5.5]undecane-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl Yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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-piperan-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 ]Nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4- ((((S)-1,4-Diethyl)-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]nonane-7-yl)benzamide; N-((4-((((R)- 1,4-Diethyl-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]nonane-7-yl)benzene Formamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decane-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]decane-8-yl)-N-((3- Nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S) -1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzene Formamide; N-((4-((((R)-1,4-Diethyl-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]nonane-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]decane-2-yl)-N-((3-nitro-4 -(((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; compound 1 ; N-((4-((((S)- 1,4-Diethyl-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] Nonane-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]nonane-7-yl)-N-((3-nitro-4-(((四Hydrogen-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl) -4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; N-(( 4-((((R)-1,4-Diethyl-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 ]Nonane-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-isopropyl Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl )-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide ; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methyl ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-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]nonane-7-yl)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)- N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro -2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane -7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piper (Pyr-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro -4-(((Tetrahydro-2H-piperan-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]nonane-7 -Yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl )Sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N -((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)benzene Yl)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]nonane-7-yl)-N-((4-((((1r,4r)- 4-Hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzene Yl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonane-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-( ((Tetrahydro-2H-piperan-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]nonane-7-yl )-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-((( Tetrahydro-2H-piperan-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]nonane-7-yl)- N-((3-nitro-4-(((tetrahydro-2H-piperan-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-aza Spiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piper (Pyr-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N- ((3-Nitro-4-(((tetrahydro-2H-piperan-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-aza Spiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan -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]nonane-7-yl)-N- ((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl Yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylbenzene Yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4- (L)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]nonane-7-yl)-N-((3-nitro-4- (((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine- 5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidine- 1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(( (Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro [3.5] Nonane-7-yl) -N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan -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]nonane-7-yl)-N-(( 3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonamide Yl)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]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy -4-Methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridine-5- Yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(dimethylamino)pyrrolidin-1-yl)-7-azaspiro[3.5]non Alk-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro -2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy Yl)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl )-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(side oxy )-l6-Hydroxysulfanyl)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 ]Nonane-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)(Pendant oxy )-l6-Hydroxythiol)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((- 3-oxabicyclo[3.1.0]hexane-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-( 2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2 ,3-b)pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-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]nonane-7-yl)benzamide; 2-( (1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl) ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)- 7-Azaspiro[3.5]nonane-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]nonane-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] Nonane-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitro 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-(propyl- 1-En-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2, 3-b)pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitro Phenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7- Yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropyl Phenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methyl (Cyclohexyl) methyl) amino)-3-nitrophenyl) sulfonyl) benzyl Amide; N-((4-((((S)-1,4-Diethyl-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-diethyl-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-nitrobenzene Yl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl ) Benzamide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2 -((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidine-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-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridine -5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptane-2- Yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-piperan -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]nonane-7-yl)-N-((4-( (2-Pholinoethyl)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]nonane-7-yl)-N-((3-nitro-4-((2-(3-oxolineo)ethyl)amino)phenyl)sulfonyl ) Benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0 ]Hexane-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonane-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]nonane-7-yl)-N-(( 4-(((2,6-Dimethyltetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-piperan- 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]octane-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]octane-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]Nonane-2-yl)-N-((4-((((1r,4 r)-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]non Alk-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-piperan-4-yl)methyl)amino)-3-nitrophenyl)sulfon (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropyl) Phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-piper 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]nonane-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] Nonane-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]nonane-7-yl)-N-((4-((((trans or cis)-4-hydroxy Tetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the Bcl-2 inhibitor of the present disclosure is Compound 1 ( Compound 1 ) or a pharmaceutically acceptable salt thereof. Preparation of Bcl-2 inhibitor

Including compound 1 ( compound 1 ), all Bcl-2 inhibitors of formula (III-B), (III-C), (III-D) or (III-E) can be disclosed in International Publication WO 2019/210828 Prepared by the method disclosed in A1. Preparation of compound 1

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

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

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

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

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

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

To (S)-tertiary butyl 2-(2-bromophenyl) pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(propane -1-En-2-yl)-1,3,2-Dioxolane (38.6 g, 229.9 mmol) was added to the mixture of _{dioxane (500 mL) and H 2 O (50 mL)} Cs ₂ CO ₃ (100 g, 305 mmol) and Pd(dppf)Cl ₂ (6.6 g, 7.5 mmol). The mixture was stirred at 100°C for 8 hours. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EA (v/v) = 100/1 to 10/1) to obtain (S)-tertiary butyl 2-(2-(propylene) -1-En-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.

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

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

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

At room temperature, to a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-Di㗁 (4 M, 142 mL, 570 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was slurried with EA (100 mL), then filtered, and dried in vacuum to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4 %). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 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]nonane-7-yl)benzoate

Combine (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridine-5 -Yl)oxy)-4-(2-side oxy-7-azaspiro[3.5]nonane-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) The mixture is charged into the reactor. The temperature was controlled below 30°C, and NaBH(OAc) ₃ (216 g, 1.018 mol) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After the starting material ketone was completely consumed, the mixture was adjusted to pH = 4 to 5 with dilute HCl (0.5 M). The separated organic phase was washed with H ₂ O (600 mL × 2), and then washed with aqueous NaHCO ₃ (600 mL × 2) and saturated aqueous NaCl (600 mL). The organic phase was collected, then it was dried over anhydrous Na ₂ SO ₄ and concentrated. 256 g of off-white solid was obtained as a crude product, which was directly used in the next step. 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)pyrrole (Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoic acid

To methyl(S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrole (Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoate (105 g, 181.7 mmol) was added to a solution of THF (525 mL) and MeOH (525 mL) NaOH aqueous solution (3.5 M) was stirred at room temperature overnight. After removing THF and MeOH in vacuo, 3.5 L of water was added to the residue. At room temperature, with stirring, the resulting mixture was adjusted to pH=5 to 6 with 3 N HCl. The precipitate was filtered and dried in vacuum to give the product (102.4 g, yield: 99%) as a white solid. ¹ H 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: Compound 1

At room temperature, (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylbenzene Yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-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 ( A mixture of 19 g, 156 mmol) in dry DCM (880 mL) was stirred overnight. The reaction was monitored by HPLC. Starting material (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrole After the pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)benzoic acid is completely consumed, the reaction mixture is heated to about 35°C, and N ¹ ,N ¹ -dimethyl is added all at once Ethane-1,2-diamine (17.2 g, 195 mmol). The reaction was stirred for another 12 hours. The mixture was washed twice with 10 wt% AcOH aqueous solution (300 mL × 2), and then washed with NaHCO ₃ saturated aqueous solution (300 mL × 2). The organic layer was collected and concentrated to about 90 mL. Add 22 g of silicone gel and stir for 2 hours. After filtration, 180 mL of EA was added to the filtrate under reflux, and further stirred for 5 hours. After the mixture was cooled to room temperature, the precipitate was filtered, and then the wet cake was washed twice with EA (180 mL). After drying in vacuum at 80°C-90°C, the desired compound (48 g, yield: 69.5%) was obtained. ¹ H 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. treatment method

In one aspect, the present disclosure provides a method of treating cancer. In certain aspects, the method includes administering an effective amount of Compound 1 to a patient in need. The cancer may include, but is not limited to, B-cell malignancies, lymphomas, or leukemias selected from the group consisting of: acute myeloid leukemia (AML), B-cell non-Hodgkin’s lymphoma (B-NHL), indolent B Cell non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), follicular lymphoma (FL), Mantle cell lymphoma (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 transformative.

Compound 1 can be administered by any suitable means, including oral administration, parenteral administration, intrapulmonary administration, and intranasal administration, and if local treatment is required, by intralesional administration. It can be administered by any suitable route. Various dosing regimens are considered herein, including but not limited to single administration or multiple administrations at different time points, bolus administration, and pulse infusion.

Compound 1 will be formulated, administered and administered in a manner consistent with good medical practice. The factors to be considered in this regard include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to the medical practitioner . Compound 1 is optionally formulated with one or more agents currently used to prevent or treat the disorder under study. 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.

To prevent or treat the disease, the appropriate dose of Compound 1 will depend on the type of disease to be treated, the severity and course of the disease, whether compound 1 is administered for preventive or therapeutic purposes, previous therapies, the patient’s clinical history, and the compound 1 ’s response and the judgment of the attending doctor. Compound 1 is suitably administered to the patient at one time or over a series of treatments. Instance

The present invention is further illustrated by the following examples illustrating the present invention, but is not limited to these examples. Example 1 : Efficacy study of Bcl-2 inhibitor in RS4; 11 acute lymphocytic leukemia (ALL) subcutaneous xenograft model

RS4; 11 cells were derived from acute lymphoblastic leukemia (ALL) and were obtained from the American Type Culture Collection (ATCC CRL-1873, Manassas, Virginia (VA) ), District of Columbia (DC), United States). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). RS4; 11 cells were maintained as a suspension cell culture at 37°C in an atmosphere of _{5% CO 2.} Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). Maintain all animals under "full barrier" conditions free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyunboji (Beijing) Technology Co., Ltd.), at a temperature of 20°C-26°C and a humidity of 37%-62%, at 12 Hours of light: The mice are housed in groups under a dark cycle (light on at 08:00). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.

On the day of implantation, harvest RS4;11 cells and resuspend them with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 5 × 10 ⁷ cells /mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Via a 26-gauge needle, each animal was injected subcutaneously with 1 × 10 ⁷ cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.

According to body weight and tumor volume (100 mm ³ -200 mm ³ ), the animals were randomly assigned to 10 groups, each with 10 mice. These groups consisted of the following: vehicle group, 5, 15, 50 mg/kg of Venetog was administered in QD, 5, 15, 50 mg/kg of Compound 1 was administered in QD, and 2.5, 7.5, Compound 1 at 25 mg/kg was administered as BID. The treatment was administered by oral gavage (po) in a volume of 10 mL/kg body weight. Administer immediately after assessing body weight, and adjust the dose accordingly.

Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm ³ , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.

Use the following formula to calculate the tumor volume: V = 0.5 (a × b ² ), where a and b are the long and short diameters of the tumor, respectively.

In RS4; 11 ALL xenografts grown subcutaneously in NCG mice, the in vivo efficacy of Compound 1 was examined and compared with Venetog. After oral administration at a well-tolerated dose, Compound 1 effectively and dose-dependently inhibited tumor growth ( Figure 1 and Table 1 ). At the same total daily doses of 5 mg/kg and 15 mg/kg, compound 1 showed significantly better efficacy compared with Venetog. Clinically, Venetog is administered at 400 mg per day. Based on free AUC, its clinically relevant dose in mice is approximately 15 mg/kg QD. The activity of 2.5 mg/kg compound 1 BID is higher than that of 15 mg/kg venetog QD. In addition, under the same total daily dose of 15 mg/kg and 50 mg/kg, the QD and BID dosing regimens of Compound 1 showed equivalent anti-tumor activity. These results are shown in Figure 1 .

Throughout the study, all treatment groups had no significant effect on animal body weight. [ Table 1 ] Pharmacy Dose ( mg/kg ) plan way Average tumor volume (day 42 ) ( mm ³ ± SEM ) vehicle vehicle BID × 21 po ＞ 2000 Compound 1 2.5 BID × 42 po 512.5 ± 115.9 Compound 1 7.5 BID × 42 po 252.8 ± 48.3 Compound 1 25 BID × 42 po 136.6 ± 2.2 Compound 1 5 QD × 42 po 820.9 ± 140.2 Compound 1 15 QD × 42 po 312.6 ± 57.9 Compound 1 50 QD × 42 po 141.8 ± 5.1 Venetok 5 QD × 35 po ＞ 2000 Venetok 15 QD × 42 po 1070.6 ± 181.1 Venetok 50 QD × 42 po 288.4 ± 37.8 Example 2 : Efficacy study of Bcl-2 inhibitor in MAVER-1 mantle cell lymphoma ( MCL ) subcutaneous xenograft model

MAVER-1 cells were derived from mantle cell lymphoma (MCL) and were obtained from the American Type Culture Collection (ATCC CRL-3008, Manassas, Virginia, District of Columbia, USA). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). MAVER-1 cells were maintained as a suspension cell culture in a 5% CO ₂ atmosphere at 37°C. Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyun Boji (Beijing) Technology Co., Ltd.), at a temperature of 21°C-26°C and a humidity of 44%-61%, 12 hours of light: dark cycle (open at 08:00 The mice are grouped and housed under the light). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.

On the day of implantation, harvest MAVER-1 cells and resuspend them with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 1.5 × 10 ⁷ cells /mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 3 × 10 ⁶ cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.

According to body weight and tumor volume (100 mm ³ -200 mm ³ ), the animals were randomly assigned to 7 groups, each with 10 mice. The groups consisted of the following: vehicle group, 5 and 15 mg/kg of Venetog were administered in QD, 5, 15 mg/kg of compound 1 was administered in QD, and 2.5, 7.5 mg/kg of compound 1 Administer as BID. The treatment was administered by oral gavage (po) in a volume of 10 mL/kg body weight. Administer immediately after assessing body weight, and adjust the dose accordingly.

Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm ³ , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.

Use the following formula to calculate the tumor volume: V = 0.5 (a × b ² ), where a and b are the long and short diameters of the tumor, respectively. Use the following formula to calculate tumor growth inhibition (TGI): %TGI = 100 × [1-(treated _t -treated _t0 )/(vehicle _t -vehicle _t0 )] (treated t = treated t0 at time t Tumor volume treated, treated t0 = treated tumor volume at time 0, vehicle t = tumor volume at time t, and vehicle t0 = vehicle tumor volume at time 0)

The in vivo efficacy of Compound 1 was also examined in MAVER-1 MCL xenografts grown subcutaneously in NCG mice and compared with Venetog. Compound 1 effectively inhibited tumor growth in a dose-dependent manner. For compound 1 with 2.5, 7.5 mg/kg BID and 5, 15  mg/kg QD, the tumor growth inhibition (TGI) on day 14 was 77%, 103% and 86%, 103%, respectively. Venetok at 5 mg/kg and 15  mg/kg QD reached 38% and 91% TGI, respectively. At the same total daily dose of 5 mg/kg and 15  mg/kg, compound 1 showed higher anti-tumor activity compared with Venetog. The activity of 15 mg/kg QD is similar to that of 7.5 mg/kg BID compound 1. The results are shown in Figure 2 and Table 2.

Throughout the study, all treatment groups had no significant effect on animal body weight. [ Table 2 ] Pharmacy Dose ( mg/kg ) plan way Average tumor volume (day 14 ) ( mm ³ ± SEM ) TGI (day 14 ) vehicle vehicle BID × 17 po 1637.7 ± 143.0 - Compound 1 2.5 BID × 17 po 511.5 ± 49.9 77% Compound 1 7.5 BID × 17 po 136.2 ± 2.6 103% Compound 1 5 QD × 17 po 383.5 ± 29.6 86% Compound 1 15 QD × 17 po 140.5 ± 5.3 103% Venetok 5 QD × 17 po 1082.1 ± 109.4 38% Venetok 15 QD × 17 po 315.4 ± 23.1 91% Example 3 : Efficacy study of Bcl-2 inhibitor in Toledo diffuse large B- cell lymphoma ( DLBCL ) subcutaneous xenograft model

Toledo cells were derived from diffuse large B-cell lymphoma (DLBCL) and were obtained from the American Type Culture Collection (ATCC CRL-2631, Manassas, Virginia, District of Columbia, USA). The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). Toledo cells were maintained as a suspension cell culture in a 5% CO ₂ atmosphere at 37°C. Female NCG mice aged five to six weeks were purchased from Gempharmatech of Information Technology Center (Gempharmatech of Information Technology Center). All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyun Boji (Beijing) Technology Co., Ltd.), at a temperature of 21°C-26°C and a humidity of 35%-61%, 12 hours of light: dark cycle (open at 08:00 The mice are grouped and housed under the light). Mice were fed with whole pellet feed (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation.

On the day of implantation, Toledo cells were harvested and resuspended with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 1.5 × 10 ⁷ cells/mL . Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 3 × 10 ⁶ cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.

According to the transplantation order and body weight, the transplanted animals were randomly divided into 10 groups on day 0, with 10 mice in each group. These groups consisted of the following: vehicle group, 5, 15, 50 mg/kg of Venetog was administered in QD, 5, 15, 50 mg/kg of Compound 1 was administered in QD, and 2.5, 7.5, Compound 1 at 25 mg/kg was administered as BID. The treatment was administered by oral gavage (po) in a volume of 10 mL/kg body weight. Administer immediately after assessing body weight, and adjust the dose accordingly.

Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm ³ , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.

Use the following formula to calculate the tumor volume: V = 0.5 (a × b ² ), where a and b are the long and short diameters of the tumor, respectively. Use the following formula to calculate tumor growth inhibition (TGI): %TGI = 100 × [1-(treated _t -treated _t0 )/(vehicle _t -vehicle _t0 )] (treated t = treated t0 at time t Tumor volume treated, treated t0 = treated tumor volume at time 0, vehicle t = tumor volume at time t, and vehicle t0 = vehicle tumor volume at time 0)

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

Throughout the study, all treatment groups had no significant effect on animal body weight. [ Table 3 ] Pharmacy Dose ( mg/kg ) plan way Average tumor volume (day 31 ) ( mm ³ ± SEM ) TGI (day 31 ) vehicle vehicle BID × 31 po 1703.1 ± 190.9 - Compound 1 2.5 BID × 31 po 515.7 ± 79.1 70% Compound 1 7.5 BID × 31 po 230.5 ± 25.9 86% Compound 1 25 BID × 31 po 182.5 ± 15.9 89% Compound 1 5 QD × 31 po 679.3 ± 63.2 60% Compound 1 15 QD × 31 po 267.4 ± 30.4 84% Compound 1 50 QD × 31 po 214.8 ± 19.4 87% Venetok 5 QD × 31 po 1256.5 ± 136.5 26% Venetok 15 QD × 31 po 847.8 ± 109.4 50% Venetok 50 QD × 31 po 258.3 ± 22.6 85% Example 4 : Efficacy study of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia ( ALL ) subcutaneous xenograft model

RS4; 11 Bcl-2G101V KI cells were derived from acute lymphoblastic leukemia (ALL) and were screened internally. The cells are supplemented with 10% (v/v) fetal bovine serum (Gibco, catalog number 10099-141C) and 100 μg/mL penicillin and streptomycin (Gibco, catalog number 15140-122) RPMI 1640 medium (Corning, catalog number 10-040-CVR). RS4; 11 Bcl-2G101V KI cells were maintained as a suspension cell culture at 37°C in a 5% CO ₂ atmosphere. Five to six weeks old female NCG mice were provided by GemPharmatech Co., Ltd (GemPharmatech Co., Ltd) in Jiangsu, China. All animals are maintained under a "full barrier" condition free of specific pathogens (SPF) and have free access to food and water. In the IVC cage (Lingyunboji (Beijing) Technology Co., Ltd.), at a temperature of 20°C-26°C and a humidity of 37%-62%, at 12 Hours of light: The mice are housed in groups under a dark cycle (light on at 08:00). Mice were fed with whole pellet feed (Beijing Kooseli Feed Co., Ltd.) sterilized by Co60 radiation.

On the day of implantation, RS4; 11 Bcl-2G101V KI cells were harvested and resuspended with an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, catalog number 356237) to give a final concentration of 5 × 10 ⁷ cells/mL. Before inoculation, place the resuspended cells on ice. Before cell inoculation, the right anterior flank area of each mouse was washed with 75% ethanol. Through a 26-gauge needle, each animal was injected subcutaneously with 1 × 10 ⁷ cells in 200 μL of cell suspension at the right anterior flank. After implantation, use a vernier to measure the two-dimensional initial volume of the tumor.

According to body weight and tumor volume (approximately 300 mm ³ ), the animals were randomly assigned to 7 groups, each with 8 mice. The groups consisted of the following: vehicle group, 15, 50, and 100 mg/kg of Venetog were administered QD, and 15, 50, and 100 mg/kg of Compound 1 were administered QD. The treatment was administered by oral gavage (po) in a volume of 10 mL/kg body weight. Administer immediately after assessing body weight, and adjust the dose accordingly.

Individual body weights were recorded twice a week, and mice were monitored daily for clinical signs of toxicity during the study. When the tumor volume of the mouse reached 2,000 mm ³ , the tumor was ulcerated, or the weight loss exceeded 20%, the mice were euthanized with carbon dioxide.

Use the following formula to calculate the tumor volume: V = 0.5 (a × b ² ), where a and b are the long and short diameters of the tumor, respectively.

In RS4; 11 Bcl-2G101V KI xenografts grown subcutaneously in NCG mice, the in vivo efficacy of compound 1 was examined and compared with Venetog. Venetog showed almost no efficacy even at higher dose levels, while Compound 1 effectively and dose-dependently inhibited tumor growth. The results are shown in Figure 4 and Table 4 . The curves of compound 1 at 50 mg/kg po QD and 100 mg/kg po QD were combined.

Throughout the study, all treatment groups had no significant effect on animal body weight. [ Table 4 ] Pharmacy Dose ( mg/kg ) plan way Average tumor volume (day 10 ) ( mm ³ ± SEM ) TGI (day 10 ) vehicle N/A QD × 10 po 1515.4 ± 84.2 N/A Compound 1 15 QD × 10 po 554.2 ± 70.3 78% Compound 1 50 QD × 10 po 155.1 ± 4.3 110% Compound 1 100 QD × 10 po 144.5 ± 3.5 111% Venetok 15 QD × 10 po 976.6 ± 64.0 44% Venetok 50 QD × 10 po 711.8 ± 49.7 65% Venetok 100 QD × 10 po 530.4 ± 75.4 80%

The foregoing examples and descriptions of certain implementations should be regarded as illustrative rather than limiting the invention defined by the claims. As will be readily understood, many variations and combinations of the above-mentioned features can be used without departing from the invention as set forth in the claims. All these changes are intended to fall within the scope of the present invention. All references cited are incorporated by reference in their entirety.

References Adams, JM, and Cory, S. (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26, 1324-1337. Anderson, MA, Huang, D., and Roberts, A. (2014) Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol 51, 219-227. Czabotar, PE, Lessene, G., Strasser, A., and Adams, JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49-63. Egle, A., Harris, AW, Bath, ML, O'Reilly, L., and Cory, S. (2004) VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276- 2283. Kondo, S., Oakes, MG, and Sorenson, CM (2008) Rescue of renal hypoplasia and cystic dysplasia in Bcl-2 -/- mice expressing Bcl-2 in ureteric bud derived epithelia. Dev Dyn 237, 2450-2459. Roberts, AW (2016) Targeting apoptotic pathways to treat lymphoid malignancies. Rinsho Ketsueki 57, 2054-2058. Roberts, AW, and Huang, D. (2017) Targeting BCL2 With BH3 Mimetics: Basic Sc ience and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies. Clin Pharmacol Ther 101, 89-98. Schenk, RL, Strasser, A., and Dewson, G. (2017) BCL-2: Long and winding path from discovery to therapeutic target. Biochem Biophys Res Commun 482, 459-469. Tausch, E., Close, W., Dolnik, A., Bloehdorn, J., Chyla, B., Bullinger, L., Dohner, H. , Mertens, D., and Stilgenbauer, S. (2019) Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica 104, e434-e437. Veis, DJ, Sorenson, CM, Shutter, JR and Korsmeyer, SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75, 229-240. Yamamura, K., Kamada, S., Ito, S., Nakagawa, K., Ichihashi, M. , and Tsujimoto, Y. (1996) Accelerated disappearance of melanocytes in bcl-2-deficient mice. Cancer Res 56, 3546-3550.

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Figure 1 shows the efficacy of Bcl-2 inhibitors in the RS4; 11 acute lymphomaternal leukemia (ALL) subcutaneous xenograft model. By one-way ANOVA (Dunnett's multiple comparison test), #### p <0.0001 relative to the vehicle, and by one-way ANOVA (Tukey's multiple comparison test), relative to Veneto Grams, * p <0.05, **** p <0.0001. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 2 shows the efficacy of Bcl-2 inhibitors in the MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model. By one-way ANOVA (Dunnett's multiple comparison test), ## p <0.01, #### p <0.0001 relative to the vehicle. With one-way ANOVA (Tukey's multiple comparison test), **** p <0.0001 relative to Venetog. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 3 shows the efficacy of Bcl-2 inhibitors in a subcutaneous xenograft model of Toledo diffuse large B-cell lymphoma (DLBCL). By one-way ANOVA (Dunnett's multiple comparison test), ### p <0.001 and #### p <0.0001 relative to the vehicle. With one-way ANOVA (Tukey's multiple comparison test), ** p ＜ 0.01, **** p ＜ 0.0001 relative to Venetog. Abbreviations: ANOVA, analysis of variance; SEM, standard deviation of the mean; QD, once a day; BID, twice a day; po, oral gavage. Figure 4 shows the efficacy of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. With one-way ANOVA, relative to the vehicle, ## p <0.01, #### p <0.0001; with one-way ANOVA, relative to Venetog, **** p <0.0001.

Claims (10)

A cancer treatment method, the method comprising administering to a subject an effective amount of a Bcl-2 inhibitor, The Bcl-2 inhibitor is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino) -3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino )Phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino)- 3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-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)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((4-fluorotetrahydro-2H-piperan-4-yl)methyl)amino) -3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-3-azaspiro[5.5]undecyl-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino) phenyl) sulfonyl) benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-3-azaspiro[5.5]undecyl-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino) phenyl) sulfonyl) benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) (Methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonane-7-yl)benzamide; N-((4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonane-7-yl)benzamide; (S)2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrole Pyridin-1-yl)-8-azaspiro[4.5]decane-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl (Amino)phenyl)sulfonyl)benzamide; (R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrole Pyridin-1-yl)-8-azaspiro[4.5]decane-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl (Amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)benzamide; N-((4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[4.5]decane-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; Compound 1; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-piperan-4 -Yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonane-7-yl)benzamide; N-((4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-nitrogen Heterospiro[3.5]nonane-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]nonane-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]nonane-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]nonane-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl ) Sulfonyl) benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl ) Sulfonyl) benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-piperan -4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane -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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino) (Phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-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]nonane-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methyl Cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl )Methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro [3.5] Nonane-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]nonane-7-yl)-N-((3-nitro-4- (((Tetrahydro-2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidine-4- Yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan -4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidine- 1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino) phenyl) sulfonyl) benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) (Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amine (Phenyl)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrole Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) )Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl)amino )Phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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)pyrrole Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl (Amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidine- 1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl) Amino) phenyl) sulfonyl) benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidine -1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-7-yl) -N-((3-nitro-4-(((tetrahydro-2H-piper (Pan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethyl Pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) (Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrole Pyridin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-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]nonane-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-(dimethylamine Yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4- (Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2-(二Methylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro- 2H-piperan-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethyl Pyrrolidin-1-yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-piperan-4-yl) (Methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl (Pendant oxy)-16-Hydroxythione)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-piperan-4-yl)methyl )Amino)phenyl)(Pendant oxy)-l6-hydrosulfanyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((-3-oxabicyclo[3.1.0]hexane-6 -Yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl) -7-azaspiro[3.5]nonane-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-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)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-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)pyrrolidine-1- Yl)-7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-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)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-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)pyrrole (Pyridin-1-yl)-7-azaspiro[3.5]nonane-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]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-nitrogen Heterospiro[3.3]heptan-2-yl)benzamide; N-((4-((((R)-1,4-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-nitrogen Heterospiro[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-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-nitrogen Heterospiro[3.3]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidine-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-Diethyl-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrole And [2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-aza Spiro[3.3]heptan-2-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-piperan-4-yl)ethyl )Amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((2-linoethyl)amino)-3-nitrophenyl)sulfonyl) Benzamide (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-((2-(3-oxolineo)ethyl)amino) (Phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0]hexane-6- Yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)- 7-azaspiro[3.5]nonane-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((2,6-dimethyltetrahydro-2H-piperan-4-yl)methyl )Amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H- Piperan-4-yl) methyl) amino) phenyl) sulfonyl) benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-6-azaspiro[3.4]octane-6-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-2-azaspiro[3.4]octane-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S)-2-(2-cyclopropylbenzene Yl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methyl ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylbenzene Yl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methyl ring (Hexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-piperan-4-yl)methyl )Amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-piperan-4-yl)methyl )Urea)-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] Nonane-7-yl) benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((cis or trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidine-1 -Yl)-7-azaspiro[3.5]nonane-7-yl)-N-((4-((((trans or cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amine )-3-nitrophenyl)sulfonyl)benzamide; Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The method according to claim 1, wherein the Bcl-2 inhibitor is compound 1 or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein the cancer is a B-cell malignant tumor. The method according to claim 1, wherein the cancer is lymphoma or leukemia. The method according to claim 3 or 4, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), B-cell non-Hodgkin’s lymphoma (B-NHL), chronic B-cell non-Hodgkin’s lymphoma (B-NHL) Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), follicular lymphoma (FL), mantle cell Lymphoma (MCL), Acute Lymphatic Leukemia (ALL), Chronic Lymphatic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Marginal Zone Lymphoma (MZL). The method according to claim 1, wherein the cancer is relapsed/refractory, or transformative. The method according to claim 1, wherein the Bcl-2 inhibitor is administered orally. The method according to claim 1, wherein the Bcl-2 inhibitor is orally administered at a dose of 20 mg/day to 700 mg/day. The method according to claim 1, wherein the cancer has Bcl-2 manifestations. The method according to the claim, wherein the cancer has Bcl-2 Gly101Val mutation manifestations.

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