Methods for Treating B-Cell Malignancies Using BCL-2 Inhibitors

Abstract

The present disclosure provides a method of treating a B-cell malignancy in a subject with a Bcl-2 inhibitor, particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof, or a Bruton's tyrosine kinase (BTK) inhibitor, particularly (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Patent Application No. 63 / 340,642, filed May 11, 2022, and U.S. Patent Application No. 63 / 195,892, filed June 2, 2021, the disclosures of which are incorporated by reference in their entireties herein for all purposes.

[0002] Disclosed herein are methods of treating B-cell malignancies with a Bcl-2 inhibitor, particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharma- ceutically acceptable salt thereof, or a Bruton's tyrosine kinase (BTK) inhibitor, particularly (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidine-3-carboxamide. [Background technology]

[0003] Impaired apoptosis plays a central role in tumor initiation, tumor maintenance, and therapeutic resistance. Apoptosis can be induced via two major pathways: the extrinsic or death receptor-mediated pathway and the intrinsic or mitochondrial pathway (Czabotar et al., 2014). It is the intrinsic pathway that is more commonly perturbed in lymphoid malignancies. Cell death mediated via this pathway is regulated by members of the B-cell lymphoma-2 (Bcl-2)-related protein family, which is thought to include three subfamilies. The pro-survival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1 / Bfl-1, and possibly Bcl-B) promote cell survival by inhibiting their pro-apoptotic relatives. Pro-apoptotic BAX / BAK-like proteins, including BOK, are essential effectors of apoptosis, while BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are initiators of apoptosis (Anderson et al., 2014). In healthy cells, pro-survival Bcl-2 proteins bind and inhibit BAX and BAK after partial activation, impairing the ability of BAX / BAK to oligomerize and form pores to induce mitochondrial outer membrane permeabilization. BH3-only proteins are transcriptionally or post-transcriptionally induced in response to diverse stresses and initiate apoptosis by binding to pro-survival Bcl-2 proteins and thereby releasing BAX / BAK or by directly activating these effectors of apoptosis. Various Bcl-2 family proteins differ in their specificity of binding to each other, resulting in a complex but ordered network of interactions that govern cell fate (Roberts 2016).

[0004] Bcl-2 was the first anti-apoptotic protein discovered in the 1980s as a result of the t(14;18) chromosomal translocation and a feature of FL. The BCL-2 gene resides on chromosome 18q21.33. The Bcl-2 protein has 239 amino acids and a molecular weight of 26 kDa (Schenk et al., 2017). Bcl-2 is widely expressed during development and becomes restricted upon maturation in many tissues (Kondo et al., 2008). As Bcl-2 is critical for the survival of renal epithelial progenitor cells during embryogenesis, mice lacking Bcl-2 succumb to polycystic kidney disease early in life (Veis et al., 1993). Bcl-2-deficient mice also have an abnormally reduced number of mature resting B and T lymphocytes and become gray early due to abnormal death of melanocytes (Veis et al., 1993, Yamamura et al., 1996). Initially thought to act as a classical proliferation-driving oncogene, it was later shown that Bcl-2 instead promotes the survival of malignant cells by attenuating apoptosis. Transgenic mice with pan-hematopoietic Bcl-2 expression (VavP-BCL-2) preferentially develop follicular lymphomas followed by squamous germinal center hyperplasia (Egle et al. 2004). Mice co-expressing BCL-2 and MYC transgenes developed lymphomas significantly faster than littermates expressing either transgene alone, validating BCL-2 as an oncogene (Adams and Cory 2007).

[0005] High Bcl-2 expression is nearly universal in CLL, FL, MCL, and Waldenström's macroglobulinemia (WM); in contrast, the levels of Bcl-2 expression are somewhat more variable among multiple myeloma (MM) and substantially more variable among DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang, 2017). When Bcl-2 is overexpressed, the ratio of pro- and anti-apoptotic Bcl-2 family members can be disturbed, preventing apoptotic cell death. Furthermore, Bcl-2 protein is closely related to chemoresistance in hematological tumors. As Bcl-2-mediated resistance to intrinsic apoptosis is thought to be key to pathogenesis, targeting Bcl-2 can improve apoptosis and overcome drug resistance to cancer treatment. Thus, Bcl-2 has become an attractive target for therapeutic strategies in cancer.

[0006] Venetoclax (ABT-199) was approved to treat patients with chronic lymphocytic leukemia (CLL) and acute myeloblastic leukemia (AML). However, despite this high clinical activity and favorable safety profile, patients may develop acquired resistance to venetoclax over time with successive treatments. Blombery et al. demonstrated that the Gly101 Val mutation in BCL-2 (G101V mutation) confers acquired refractoriness by reducing the binding affinity of venetoclax without interfering with the binding of proapoptotic proteins to Bcl-2. A novel Gly101Val mutation in Bcl-2 was identified at progression in 7 of 15 patients. This mutation is primarily found in patients after prolonged exposure to venetoclax monotherapy (Tausch et al., 2019).

[0007] WO 2019 / 210828A disclosed a series of compounds having the following formula (III-B), (III-C), (III-D) or (III-E), or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, as Bcl-2 inhibitors. [ka]

[0008] The compounds disclosed in WO 2019 / 210828A are potent and selective inhibitors of the Bcl-2 protein. Summary of the Invention [Means for solving the problem]

[0009] The inventors of the present disclosure have disclosed a method for the preparation of Bcl2 inhibitors having formula (III-B), (III-C), (III-D) or (III-E), in particular 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzamide (compound We have found that compound 1) or a pharma- ceutically acceptable salt thereof exhibits potent cell killing activity against various lymphoma and leukemia cell lines, including MV4-11 (acute myeloid 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-like diffuse large B-cell lymphoma, GCB-DLBCL) and MAVER-1 (mantle cell lymphoma, MCL). 50 Values ​​were found to range from 0.6 nM to 13 nM.

[0010] The inventors of the present disclosure have also found that Bcl2 inhibitors having formula (III-B), (III-C), (III-D) or (III-E), in particular compound 1 or a pharma- ceutically acceptable salt thereof, have demonstrated significant inhibition of tumor growth in cancers with good safety profile, including B-cell malignancies selected from non-Hodgkin's lymphoma (NHL) predicted to be at low risk for tumor lysis syndrome, low tumor burden chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SL), high tumor burden CLL / SL, mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM) or acute lymphoblastic leukemia (ALL).

[0011] Furthermore, the inventors of the present disclosure have found that Bcl2 inhibitors having formula (III-B), (III-C), (III-D) or (III-E), particularly Compound 1 or a pharma- ceutically acceptable salt thereof, in combination with BTK inhibitors disclosed in WO 2014 / 173289A, particularly (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (zanubrutinib, Compound B), provide significant inhibition of tumor growth in cancers compared to the efficacy of each therapeutic agent as a single agent. Furthermore, the combination therapy has demonstrated significant inhibition of tumor growth in cancers with high safety, including B-cell malignancies selected from chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) or mantle cell lymphoma (MCL).

[0012] In a first aspect, there is provided a method of treating a B-cell malignancy with a Bcl-2 inhibitor, the Bcl-2 inhibitor being a compound represented by formula (III-B), (III-C), (III-D) or (III-E): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof; During the ceremony, R 2is, independently in each occurrence, hydrogen, halogen, and -C optionally substituted with halogen; 1-8 selected from the group consisting of alkyl; R 1d are each independently a halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , -. OR Ba , -SO 2 R Ba , -COR Ba , -CO 2 R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb R Bc , -NR Ba R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc , -NR Ba CO 2 R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO 2 NR Bb R Bc , or -NR Ba SO 2 R Bb wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each independently represent 1 to 4 substituents R Bd may be substituted with R Ba , R Bb , and R Bc are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy, -NH 2 or -N(C 1-6 Alkyl) 2 , -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ba are independently hydrogen, halogen, -CN, -NO 2 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy, -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R 5 Ga-L 5 -CyC, Here, 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 -, in which t and v are each independently a number from 1 to 7, -(CR a R b ) t -, -(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -, -(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -One or two CRs in a R b is unsubstituted or O, S, SO, SO 2 , C(O) or NR a and; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is represented by one or two substituents R 5a may be substituted with; R 5a In each case, hydrogen, halogen, cyano, oxo, -NO 2 , -OR5b , -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 above -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with one or two substituents R 5e may be substituted with; R 5b , R 5c , and R 5d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, C 2-8Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with one or two substituents R 5e may be substituted with; R 5e In each occurrence, hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO 2 R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR 5g R 5h , -N(R 5f )S(O)NR 5g R 5h , -N(R 5f )S(O) 2 NR 5g R 5h , -NR 5f SO 2 R 5g , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5f , R 5g , and R 5h are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Or, two adjacent R on a phenyl ring 5together with the phenyl ring to form a benzo ring, said ring being free of halogen, oxo, cyano, -NO 2 , -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO 2 R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR 5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O) 2 NR 5j R 5k , -NR 5i SO 2 R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5i , R 5j , and R 5k are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy, or -C 1-8 optionally substituted with alkyloxy; R a , R b , Rc , and R d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or -SR e are independently substituted with; and In the formula, R e and R f are independently hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy-C 1-8 Alkyl-, C 2-8 Alkenyl, C 2-8 Disclosed herein is a method wherein the aryl group is alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0013] In a second aspect, disclosed herein is a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E) or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, for use in the treatment of a B-cell malignancy.

[0014] In a third aspect, disclosed herein is a method of treating a B-cell malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0015] In a fourth aspect, disclosed herein is a method of treating a B-cell malignancy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a Bcl-2 inhibitor, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B), or a pharma- ceutically acceptable salt thereof.

[0016] In a fifth aspect, disclosed herein is the use of a pharmaceutical composition in the manufacture of a medicament for use in the treatment of a B-cell malignancy, comprising a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E) or a stereoisomer thereof, or a pharma- ceutical acceptable salt thereof.

[0017] In a sixth aspect, disclosed herein is the use of a pharmaceutical combination in the manufacture of a medicament for use in the treatment of cancer, the pharmaceutical combination comprising a Bcl-2 inhibitor, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, and (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B, zanubrutinib), or a pharma- ceutically acceptable salt thereof.

[0018] In an embodiment of each of the above aspects, the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1), or a pharma- ceutical acceptable salt thereof.

[0019] In one embodiment of each of the above aspects, the B cell malignancy is relapsed / refractory.

[0020] In one embodiment of each of the above aspects, the B cell malignancy is a B cell malignancy selected from non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM) or acute lymphoblastic leukemia (ALL).

[0021] In a preferred embodiment of each of the above aspects, the B cell malignancy is a non-Hodgkin's lymphoma (NHL) selected from follicular lymphoma (FL), diffuse large B cell lymphoma (DLBL), marginal zone lymphoma (MZL) or transformed NHL.

[0022] In a preferred embodiment of each of the above aspects, the B cell malignancy is low tumor burden chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) or high tumor burden CLL / SLL.

[0023] In a preferred embodiment of each of the above aspects, the B cell malignancy is mantle cell lymphoma (MCL).

[0024] In a preferred embodiment of each of the above aspects, the B cell malignancy is Waldenstrom's Macroglobulinemia (WM).

[0025] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally once daily (QD) at a dose of 1 mg to 640 mg QD, or 20 mg QD to 640 mg QD according to a dose ramp-up schedule.

[0026] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is orally administered in doses according to a daily ramp-up schedule. Preferably, the daily ramp-up schedule includes a first dose on day 1, a second dose on day 2, and a recommended dose on days 3 and beyond, with the second dose on days 3 and beyond being higher than the second dose on day 2, and the second dose on day 2 being higher than the first dose on day 1. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg daily, and the Bcl-2 inhibitor is orally administered in a daily ramp-up schedule including a first dose on day 1 at 25% of the recommended dose, a second dose on day 2 at 50% of the recommended dose, and a daily dose on days 3 and beyond at 100% of the recommended dose. In some more preferred embodiments, the first dose on day 1 is about 10-160 mg / day, the second dose on day 2 is about 20-320 mg / day, and the daily dose on days 3 and thereafter is about 40-640 mg / day. In some more preferred embodiments, the first dose on day 1 is about 10, 20, 40, 80, or 160 mg / day, the second dose on day 2 is about 20, 40, 80, 160, or 320 mg / day, and the daily dose on days 3 and thereafter is about 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg / day. In particular, the first dose on day 1 is about 160 mg / day, the second dose on day 2 is about 320 mg / day, and the daily dose on days 3 and thereafter is about 640 mg / day. In some embodiments, the period of daily ramp-up schedule administration lasts for 2 days. In some embodiments, the administration period lasts for 3 days or more. In some embodiments, the B cell malignancy is at lower risk of TLS. In some embodiments, the B cell malignancy is NHL (excluding MCL). In some preferred embodiments, the B cell malignancy is FL, DLBCL, MZL or transformed NHL.

[0027] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is orally administered in doses according to a weekly ramp-up schedule. Preferably, the weekly ramp-up schedule includes a first dose in week 1, a second dose in week 2, a third dose in week 3, a fourth dose in week 4, a fifth dose in week 5, followed by a weekly ramp-up schedule and a recommended dose from that particular week onwards, where each subsequent week's dose is at least twice the previous week's dose until the recommended weekly dose is met, and the subsequent weekly ramp-up schedule is a 0, 1, 2, 3, or 4 week weekly ramp-up dosing schedule.

[0028] In some embodiments, the Bcl-2 inhibitor is orally administered at a dose according to a weekly ramp-up schedule starting with 1 mg daily in week 1. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg daily, and the Bcl-2 inhibitor is 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg daily. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, and the fourth dose in week 4 is about 5 mg / day. The fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, and the seventh dose in weeks 7 and thereafter is about 80 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, and the eighth dose in week 8 is about 160 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, the eighth dose in week 8 is about 160 mg / day, and the ninth dose in week 9 is about 320 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, the eighth dose in week 8 is about 160 mg / day, the ninth dose in week 9 is about 320 mg / day, and the tenth dose from week 10 onwards is about 640 mg / day. In some embodiments, the period of weekly ramp-up schedule administration lasts for 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.In some embodiments, the administration period lasts for 6, 7, 8, 9 or 10 weeks or more. In some embodiments, the B cell malignancy is selected from CLL / SLL, MCL or WM. In some embodiments, the B cell malignancy is selected from CLL / SLL with low tumor burden, CLL / SLL with high tumor burden, or CLL / SLL with prior venetoclax treatment, MCL or WM.

[0029] In one embodiment of the above aspect, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) is administered orally at a dose of 320 mg / day (160 mg twice daily or 320 mg once daily) and the Bcl-2 inhibitor is administered orally on a weekly ramp-up schedule. Preferably, Compound B is administered orally for 8-12 weeks prior to administration of Compound 1. Preferably, the weekly ramp-up schedule includes a first dose in week 1, a second dose in week 2, a third dose in week 3, a fourth dose in week 4, a fifth dose in week 5, followed by a weekly ramp-up schedule and the recommended dose from that particular week onwards, where each subsequent week's dose is at least twice the previous week's dose until the recommended weekly dose is met, and the subsequent weekly ramp-up schedule is a 0, 1, 2, 3, or 4 week weekly ramp-up dosing schedule.

[0030] In some embodiments, the Bcl-2 inhibitor is orally administered at a dose according to a weekly ramp-up schedule starting at 1 mg per day in week 1. In some more preferred embodiments, the recommended dose is 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg per day, and the Bcl-2 inhibitor is orally administered by a weekly ramp-up schedule including administration of 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg per day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, and the seventh dose in week 7 is about 80 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, and the eighth dose in week 8 is about 160 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, the eighth dose in week 8 is about 160 mg / day, and the ninth dose in week 9 is about 320 mg / day. In some embodiments, the first dose in week 1 is about 1 mg / day, the second dose in week 2 is about 2 mg / day, the third dose in week 3 is about 5 mg / day, the fourth dose in week 4 is about 10 mg / day, the fifth dose in week 5 is about 20 mg / day, the sixth dose in week 6 is about 40 mg / day, the seventh dose in week 7 is about 80 mg / day, the eighth dose in week 8 is about 160 mg / day, the ninth dose in week 9 is about 320 mg / day, and the tenth dose from week 10 onwards is about 640 mg / day. In some embodiments, the period of weekly ramp-up schedule administration lasts for 5 weeks, 6 weeks, 7 weeks, 8 weeks, or 9 weeks.In some embodiments, the administration period lasts for 6, 7, 8, 9 or 10 weeks or more. In some embodiments, the B cell malignancy is CLL / SLL, including R / R CLL / SLL or naive CLL / SLL, or MCL.

[0031] In monotherapy, among patients with R / R NHL, most patients had a significant reduction in SPD from baseline, with 2 of 20 (10%) patients responding, including 1 PR at 160 mg and 1 CR at 320 mg, and 23 patients discontinued treatment due to progressive disease (n=20), adverse events (n=1), and other or physician decision (n=2). Among patients with R / R WM, 1 of 2 (50%) achieved a minor response at 80 mg. In combination therapy, among patients with R / R MCL, 5 of 10 (50%) patients achieved a PR or better at either 80 or 100 mg, including 1 CR at each dose level, and 1 R / R MCL discontinued treatment due to progressive disease. Additionally, among patients with CLL / SLL in monotherapy and combination therapy, significant reductions in absolute lymphocyte counts (ALC) were noted among all patients with CLL during ramp-up, with lymphocytosis noted at dose levels as low as 1 mg. In monotherapy, 4 of 6 (67%) patients achieved partial response with lymphocytosis (PR-L) or greater at 80 mg or 160 mg of compound 1. In combination therapy, 16 of 20 (80%) R / R CLL / SLL patients achieved PR-L or greater across dose levels ranging from 40 to 320 mg, with one R / R CLL / SLL patient discontinuing treatment due to progressive disease.

[0032] Results from 78 patients suggest that compound 1 is well tolerated in patients with CLL or NHL at the dose levels tested. Only one DLT was observed in NHL monotherapy patients, where the MTD was not reached and dose escalation was terminated, and only one DLT was observed in CLL monotherapy patients. Grade ≥3 AEs were infrequent and manageable.

[0033] Findings suggest that the combination of compound 1 and zanubrutinib is well tolerated, similar to compound 1 monotherapy. The risk of TLS appears to be limited and manageable, including laboratory TLS in only one patient with CLL at high risk for TLS receiving monotherapy.

[0034] Furthermore, transient neutropenia was the most frequent grade ≥3 AE, and significant decreases in ALC were observed during accrual of CLL patients, with early response rates expected in R / R CLL patients.

[0035] In one embodiment of each of the above aspects, Bcl-2 is administered orally once daily (QD).

[0036] In one embodiment of each of the above aspects, the B cell malignancy has Bcl-2 expression.

[0037] In one embodiment of each of the above aspects, the B cell malignancy has Bcl-2 Gly101Val mutant expression. [Brief description of the drawings]

[0038] [Figure 1A] Figure 1 shows efficacy of Bcl-2 inhibitors in the RS4;11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparison test). *p<0.05, ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 1B]Figure 1 shows efficacy of Bcl-2 inhibitors in the RS4;11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparison test). *p<0.05, ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 2A] Efficacy of Bcl-2 inhibitors in the MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model. ##p<0.01, ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparisons test). ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparisons test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 2B] Efficacy of Bcl-2 inhibitors in the MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model. ##p<0.01, ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparisons test). ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparisons test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 3A] Figure 1 shows efficacy of Bcl-2 inhibitors in the Toledo diffuse large B-cell lymphoma (DLBCL) subcutaneous xenograft model. ###p<0.001, ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparison test). **p<0.01, ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 3B]Figure 1 shows efficacy of Bcl-2 inhibitors in the Toledo diffuse large B-cell lymphoma (DLBCL) subcutaneous xenograft model. ###p<0.001, ####p<0.0001 vs. vehicle by one-way ANOVA (Dunnett's multiple comparison test). **p<0.01, ****p<0.0001 vs. venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; QD, once daily; twice daily; oral gavage. [Figure 4A] Showing efficacy of Bcl-2 inhibitors in the RS4;11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. ##p<0.01, ####p<0.0001 vs. vehicle by one-way ANOVA; ****p<0.0001 vs. venetoclax by one-way ANOVA. [Figure 4B] Showing efficacy of Bcl-2 inhibitors in the RS4;11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. ##p<0.01, ####p<0.0001 vs. vehicle by one-way ANOVA; ****p<0.0001 vs. venetoclax by one-way ANOVA. [Figure 5A] Effect of Compound 1 (Bcl-2 inhibitor) and Compound B (BTK inhibitor) on tumor growth in human JeKo-1 MCL xenograft model. *p<0.05, ***p<0.001, ****p<0.0001 vs. combination treatment group by one-way ANOVA test. [Figure 5B] Effect of Compound 1 (Bcl-2 inhibitor) and Compound B (BTK inhibitor) on tumor growth in human JeKo-1 MCL xenograft model. *p<0.05, ***p<0.001, ****p<0.0001 vs. combination treatment group by one-way ANOVA test. [Figure 5C] Effect of Compound 1 (Bcl-2 inhibitor) and Compound B (BTK inhibitor) on tumor growth in human JeKo-1 MCL xenograft model. *p<0.05, ***p<0.001, ****p<0.0001 vs. combination treatment group by one-way ANOVA test. [Figure 5D] Effect of Compound 1 (Bcl-2 inhibitor) and Compound B (BTK inhibitor) on tumor growth in human JeKo-1 MCL xenograft model. *p<0.05, ***p<0.001, ****p<0.0001 vs. combination treatment group by one-way ANOVA test. [Figure 6A] Denotes treatment-emergent AEs, regardless of causality, that occurred in at least two patients receiving (A) monotherapy (N=25) or (B) combination therapy (N=11). aNeutropenia combines "decreased neutrophil count" and "neutropenia". bThrombocytopenia combines "decreased platelet count" and "thrombocytopenia"; ALT=alanine transaminase. [Figure 6B] Treatment duration and best response are shown. a Treatment duration included 8-12 weeks of zanubrutinib monotherapy prior to initiation of the combination of compound 1 + zanubrutinib; nPR = nodal partial response; PD = progressive disease; PR = partial response; PR-L = PR with lymphocytosis; SD = stable disease. [Figure 6C] Changes in SPD among NHLa patients are shown. a Includes all patients in cohort 1A who had a post-baseline CT scan at the time of data cutoff (n=11); CT = computed tomography; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; MZL = marginal zone lymphoma; SPD = sum of products of perpendicular diameters. [Figure 6D] Figure 1 shows the reduction in ALC over ramp-up in CLLa patients. a Figure represents the reduction in ALC above the ULN (4x109 / L) compared to pre-compound 1 baseline before the next dose escalation per dose (or after 1 week at target dose). Patients received each compound 1 dose level for 1 week before escalating to the next dose. Patients on combination therapy also received zanubrutinib during compound 1 ramp-up, starting 8-12 weeks prior to the first compound 1 dose (note: one patient with normal baseline ALC was excluded from the monotherapy figure). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] definition Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0040] As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include references to their corresponding plurals unless the context clearly dictates otherwise.

[0041] The term "or" is used to mean and is used synonymously with the term "and / or," unless context clearly dictates otherwise.

[0042] The term "anti-cancer agent" as used herein refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including, but not limited to, cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapy agents, targeted anti-cancer agents, and immunotherapy agents.

[0043] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, which contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit), and most preferably a human. In one aspect, treating any disease or disorder refers to alleviating the disease or disorder (i.e., delaying, preventing, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating", or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat", "treating", or "treatment" refers to modulating a disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating", or "treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder.

[0044] The term "subject" in the context of this disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having or at risk of having a disorder described herein). In some embodiments, the subject is a human or a patient.

[0045] The term "cancer" or "tumor" as used herein has the broadest meaning as understood in the art and refers to a physiological condition in a mammal that is typically characterized by unregulated cell proliferation. In the context of this disclosure, cancer is not limited to a particular type or location.

[0046] The term "therapeutically effective amount" as used herein refers to an amount of a Bcl-2 inhibitor that, when administered to a subject to treat a disease or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary with the agent, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case may be apparent to one of skill in the art or can be determined by routine experimentation. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject for effective treatment of a disease, disorder, or condition.

[0047] The term "ramp-up scheme" or "ramp-up schedule" as used herein refers to a dosing regimen or schedule in which an active ingredient of interest is administered at an increased dose periodically, such as daily or weekly, for a specified period, such as several days or weeks, and then administered at the recommended dose (daily or weekly).

[0048] Detailed Description of the Disclosure The present disclosure provides methods of treating a B-cell malignancy in a subject with a Bcl-2 inhibitor, particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1), or a pharma- ceutical acceptable salt thereof.

[0049] The present disclosure also provides a method of treating a B-cell malignancy in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a Bcl-2 inhibitor, or a stereoisomer thereof, or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B), or a pharma- ceutically acceptable salt thereof.

[0050] Bcl-2 inhibitors 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): [ka] or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof; During the ceremony, R 2 is, in each occurrence, independently, hydrogen, halogen, and -C which may be substituted with halogen; 1-8 selected from the group consisting of alkyl; R 1d are each independently a halogen, -C 1-8 Alkyl, -C 2~8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 , OR Ba , -SO 2 R Ba , -COR Ba , -CO 2 R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb R Bc , -NR Ba R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc, -NR Ba CO 2 R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO 2 NR Bb R Bc , or -NR Ba SO 2 R Bb wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each independently represent 1 to 4 substituents R Bd may be substituted with R Ba , R Bb , and R Bc are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy, -NH 2 or -N(C 1-6 Alkyl) 2 , -C 1-8 optionally substituted with alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R Ba are each independently hydrogen, halogen, -CN, -NO 2 , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently selected from halogen, hydroxy, -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 4; R 5 -L 5 -CyC, Here, 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 -, in which t and v are each independently a number from 1 to 7, -(CR a R b ) t-, -(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -, -(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -One or two CRs a R b The moiety may be unsubstituted or may be O, S, SO, SO 2 , C(O) or NR a is replaced by; CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is represented by one or two substituents R 5a may be substituted with; R 5a In each case, hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C(=O)OR 5b , -C(=O)NR 5b R 5c , -C(=NR 5b )NR 5c R 5d , -N(R 5b )C(=O)R 5c , -N(R 5b )C(=O)OR 5c , -N(R 5b )C(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -N(R 5b )S(O) 2 NR 5c R 5d , -NR 5b SO 2 R5c , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of the above -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with one or two substituents R 5e may be substituted with; R 5b , R 5c , and R 5d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, C 2-8 Alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl may be substituted with one or two substituents R 5e may be substituted with; R 5e is hydrogen, halogen, cyano, oxo, -NO 2 , -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO 2 R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR 5g R 5h , -N(R 5f )S(O)NR5g 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 on a phenyl ring 5は Together with the phenyl ring, it forms a benzo ring, which ring is not substituted with halogen, oxo, cyano, -NO 2 , -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO 2 R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR 5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O) 2 NR 5j R 5k , -NR 5i SO2 R 5k , -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 5i , R 5j , and R 5k are independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with halogen, hydroxy or -C 1-8 optionally substituted with alkyloxy; R a , R b , R c , and R d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently -CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or -SR e is replaced by; and In the formula, 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 2-8It is alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0051] In some embodiments, R 2 is hydrogen.

[0052] In some embodiments, R 1d is substituted with a phenyl group at the 2-position of ring B (including an aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl, or azocan-1-yl, preferably a pyrrolidin-1-yl group), each independently represents a 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 said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl each independently represent one to four substituents R defined as in formula (III-B), (III-C), (III-D) or (III-E). Bd and preferably one or two substituents R defined as in formula (III-B), (III-C), (III-D) or (III-E). Bd In another embodiment, one R 1d is at the 2-position of the phenyl ring at the 2-position of ring B.

[0053] In some embodiments, R 1dis methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyls at positions on a phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0054] In some embodiments, the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety of formula (III-B), (III-C), (III-D), or (III-E) is selected from the group consisting of: [ka] [ka]

[0055] In some embodiments, m is 1; L 5 is a direct bond, -(CR a R b ) t -OR-NR a -, where t is a number from 1 to 7, -(CR a R b ) t -One or two CRs in a R b The moiety is unsubstituted or is O or NR a wherein R a and R b is defined by formula (III-B), (III-C), (III-D) or (III-E).

[0056] In some embodiments, L 5 is a direct bond, -(CR a R b ) 1-4 -, -O-(CR a R b ) 1-3 -, -NH-(CR a R b ) 1-3or -NH-, where R a and R b is defined as in formula (III-B), (III-C), (III-D) or (III-E), so that -L 5 The -CyC portion is CyC, -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b ) 1-3 More preferably, L is -CyC or -NH-CyC. 5 is a direct bond, -(CH 2 ) 1-4 -, -O-(CH 2 ) 1-3 -, -NH-(CR a R b )-(CH 2 ) 2 - or -NH-, where R a is hydrogen, and R b -L 5 The -CyC moieties are CyC and -(CH 2 ) 1-4 -CyC, -O-(CH 2 ) 1-3 -CyC, -NH-(CR a R b )-(CH 2 ) 2 C optionally substituted with phenyl-S-, such as -CyC, or -NH-CyC 1-8 More preferably, L 5 -L 5 The -CyC moieties are CyC and -CH 2 -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC, or -NH-CyC, 2 -, -O-CH 2 -, -NH-CH 2 -, or -NH-.

[0057] In some embodiments, CyC is cycloalkyl or heterocyclyl, each of which is substituted with one or two substituents R 5a optionally substituted with; R 5a is hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 Alkyl, -C 2-8 alkynyl, -cycloalkyl, or heterocycloalkyl; 1-8 Each of alkyl and heterocyclyl is selected from hydrogen, halogen, cyano, -OR 5f , -C 1-8 one or two substituents R selected from alkyl, -cycloalkyl, or heterocyclyl; 5e is optionally substituted with; In the formula, R 5b and R 5c are each independently hydrogen, -C 1-8 alkyl or heterocyclyl, 1-8 Alkyl is hydrogen, -NR 5f R 5g or one or two substituents R which are cycloalkyl; 5e In some cases it has been replaced; R 5f and R 5g are each independently hydrogen or -C 1-8 is alkyl; Or, two adjacent R on a phenyl ring 5 together with the phenyl ring form a benzo ring, which may be substituted with heteroaryl.

[0058] In some embodiments, CyC is a monocyclic C 3-8 Cycloalkyl or bridged cycloalkyl [ka] each of which is selected from one or two substituents R 5a Preferably, CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two substituents R 5a is optionally replaced by

[0059] In some embodiments, CyC is: a) monocyclic 4- to 9-membered heterocyclyl groups containing one nitrogen or oxygen or sulfur heteroatom as a ring member; b) a monocyclic 4- to 9-membered heterocyclyl group containing two heteroatoms selected from oxygen, sulfur or nitrogen as ring members; or c) heterocyclyl selected from 5- to 20-membered spiroheterocyclyl containing 1 or 2 heteroatoms selected from nitrogen, sulfur or oxygen as ring members; Each of these has one or two R 5a may be optionally substituted with

[0060] In some embodiments, CyC is a monocyclic 4-6 membered heterocyclyl group containing one nitrogen or oxygen or sulfur heteroatom as a ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl or piperidinyl. Even more preferably, CyC is selected from oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-2-yl or piperidin-3-yl.

[0061] In some embodiments, CyC is a monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen or nitrogen as ring members. More preferably, CyC is dioxanyl, morpholino, morpholinyl, or piperidinyl. Even more preferably, CyC is 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl.

[0062] In some embodiments, R 5a are independently hydrogen, halogen, cyano, oxo, -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 a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members, 1-8 Each of the alkyl and monocyclic 4- to 9-membered heterocyclyl groups may contain one or two substituents R 5e and optionally substituted with; preferably, R 5a Cycloalkyl as C 3-6 is cycloalkyl; more preferably cyclopropyl; preferably R 5a Heterocyclyl as R is a 4- to 6-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members; more preferably, R 5a Heterocyclyl as R is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl; even more preferably, R 5a Heterocyclyl as is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morphin-4-yl.

[0063] In some embodiments, R 5e Heterocyclyl as is a monocyclic 4- to 9-membered heterocyclyl group containing 1 or 2 heteroatoms selected from nitrogen or oxygen or sulfur heteroatoms as ring members.

[0064] In some embodiments, R 5e The heterocyclyl as used herein is tetrahydro-pyran-4-yl.

[0065] In some embodiments, R 5a -NR 5b R 5c where R 5b is hydrogen and R 5c is heterocyclyl.

[0066] In some embodiments, R 5a -NR 5b R 5c where R 5b is hydrogen and R 5c is tetrahydro-pyran-4-yl.

[0067] In some embodiments, R 5a -NR 5b R 5c where R 5b and R 5c each independently represents hydrogen or a -C substituted with cycloalkyl; 1-6 Alkyl, preferably monocyclic C 3-8 Cycloalkyl-substituted -C 1-6 It is an alkyl.

[0068] In some embodiments, R 5a -OR 5b OR -SO 2 R 5b where R 5b is hydrogen or C 1-8 It is alkyl, preferably methyl.

[0069] In some embodiments, R5a -COR 5b where R 5b is hydrogen or -NR 5f R 5g C optionally substituted with 1-8 is alkyl, R 5f and R 5g are each independently hydrogen or C 1-8 It is alkyl, preferably methyl.

[0070] In some embodiments, two adjacent R 5 together with the phenyl ring forms an indazolyl substituted with tetrahydropyranyl.

[0071] In some embodiments, m is 1 and R 5 is selected from the group consisting of: 5 -CyC: [ka] [ka]

[0072] In some embodiments, m is 1 and R 5 teeth, [ka] It is.

[0073] In some embodiments, the Bcl-2 inhibitor of the present disclosure is selected from the group consisting of: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-fluorotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((R)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(7-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.5]nonan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(9-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-3-azaspiro[5.5]undecan-3-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R) 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-8-azaspiro[4.5]decan-8-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(8-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.5]decan-2-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((4-fluorotetrahydro-2H-pyran-)4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((R)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isobutylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(o-tolyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-bromophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(4-chlorophenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-ethoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(dimethylamino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-(bis(methyl-d3)amino)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(2-(2-(2-(pyrrolidin-1-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methyl-1,2,3,6)-tetrahydropyridin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(1-methylpiperidin-4-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-methoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropoxyphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(methoxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(hydroxymethyl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(5-chloro-2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; (S or R)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-chloro-2-ethylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,4-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2,5-dicyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(3-(2-chlorophenyl)thiophen-2-yl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-methylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(4-cyclopropyl-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-phenyl-2,5-dihydro-1H-pyrrol-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4,4-difluoropyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(trifluoromethyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(dimethylamino)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-4-(2-(dimethylamino)ethoxy)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)-3,3-dimethylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(oxo)-16-sulfanylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-16-sulfanylidene)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1s,4s)-4-hydroxy-4-(trifluoromethyl)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((1r,4r)-4-methoxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((S)-4-methylcyclohex-3-en-1-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-(prop-1-en-2-yl)phenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-propylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; N-((4-((((R)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(6-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]pyridin)-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)phenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((2-morpholinoethyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-((2-(3-oxomorpholino)ethyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-(((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((3-nitro-4-(((2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-6-azaspiro[3.4]octan-6-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(6-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.4]octan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7R or 7S)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-((7S or 7R)-7-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-2-azaspiro[4.4]nonan-2-yl)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)ureido)-3-nitrophenyl)sulfonyl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-phenylpyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide; 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((cis or trans)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; and 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-((((trans or cis)-4-hydroxytetrahydrofuran-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide; or a pharma- ceutically acceptable salt thereof, or a stereoisomer thereof.

[0074] In some embodiments, the Bcl-2 inhibitor of the disclosure is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1), or a pharma- ceutical acceptable salt thereof.

[0075] Preparation of Bcl-2 inhibitors All Bcl-2 inhibitors having formula (III-B), (III-C), (III-D) or (III-E), including 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (compound 1), can be prepared by the methods disclosed in WO 2019 / 210828 A1.

[0076] Preparation of Compound 1 Step 1: 2,2-Dimethoxy-7-azaspiro[3.5]nonane hydrochloride To a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (500 g, 2.09 mol) in MeOH (750 mL) and EA (750 mL) was added concentrated HCl acid (350 mL, 4.18 mol) at room temperature and stirred for 4 h. After concentration in vacuum, MeOH (750 mL) was added to the residue and then the resulting mixture was concentrated in vacuum (this workup was repeated twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 h. The solid precipitate was filtered and dried in vacuum to give the title product as an off-white powder (350 g, yield: 76.0%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm:3.03(s,6H),2.96-2.89(m,4H),1.93(s,4H),1.74-1.67(m,4H).MS(ESI,m / e)[M+1] + 186.0.

[0077] Step 2: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (100 g), 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (116 g, 1.5 eq.) and DBU (160 g, 3.0 eq.) in NMP (500 mL) was stirred at 85° C. for 16 h. After the reaction was completed, the mixture was cooled to 50±5° C. and citric acid in water (2%, 5 L) was added dropwise to the system with stirring. After filtration, the cake was collected and dissolved in DCM (1.5 L). The crude product solution was washed with aqueous citric acid (2%, 1.5 L), saturated aqueous NaHCO 3 (1.5 L) and 15% aqueous NaCl (1.5 L), then washed with anhydrous Na 2 SO 4 The mixture was dried at rt. Silica gel (100 g) was added to the solution of the crude product under stirring and then filtered. The filtrate was concentrated to 300 mL. MTBE (500 mL) was poured into the system. After stirring for 2 h, the cake was collected after filtration and dried in vacuum to give an off-white solid (192 g, yield: 72.1%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm:11.63(s,1H),8.00(d,J=2.4Hz,1H),7.76(d,J=9.2Hz,1H),7.47(t,J=3.2Hz,1H),7.42(d,J=2.4Hz,1H),6.79(dd,J=2.4Hz, J=9.2Hz,1H),6.39-6.36(m,2H),3.64(s,3H),3.17-3.12(m,4H),3.01(s,6H),1.86(s,4H),1.54-1.50(m,4H).MS(ESI,m / e)[M+1] + 451.9.

[0078] Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate To a solution of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2,2-dimethoxy-7-azaspiro[3.5]nonan-7-yl)benzoate (176 g, 0.39 mol) in DCM (2 L) was added dilute HCl acid (1 M, 1.5 L) and stirred overnight. After the reaction was complete, the mixture was cooled to 10 °C and adjusted to pH = 8-9 with aqueous NaOH (4 M) while stirring. The organic phase was separated and washed with 15% aqueous NaCl (1 L), followed by H 2 The organic phase was concentrated to 500 mL, and then MTBE (1 L) was poured into the solution, and the system was then concentrated to 500 mL (this workup was repeated three times). The resulting system was stirred for 0.5 h. After filtration, the cake was collected and then dried in vacuum to give the title product as a white solid (152 g, yield: 96.23%). 1 H NMR (400MHz, DMSO-d 6 )δ ppm:11.64(s,1H),8.02(d,J=2.4Hz,1H),7.78(d,J=9.2Hz,1H),7.47(t,J=3.2Hz,1H),7.44(d,J=2.4Hz,1H),6.83(dd,J=2.4Hz,J=9. 2Hz,1H),6.43(d,J=2.4Hz,1H),6.38-6.36(m,1H),3.65(s,3H),3.24-3.21(m,4H),2.80(s,4H),1.70-1.67(m,4H).MS(ESI,m / e)[M+1] + 405.9.

[0079] Step 4: (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate Dioxane (500 mL) and H 2 A mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in 200 mL was diluted with Cs 2 CO 3 (100 g, 305 mmol) and Pd(dppf)Cl2 (6.6 g, 7.5 mmol) was added. The mixture was stirred at 100° C. for 8 h. TLC showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: PE / EA (v / v)=100 / 1 to 10 / 1) to give (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (65 g, crude). The crude product was used directly in the next step.

[0080] Step 5: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd / C (10 g, 10%) and the mixture was heated under H 2 The mixture was stirred at 20° C. under (15 Psi) for 12 h. TLC showed the reaction was complete. The mixture was filtered and the filtrate was concentrated in vacuo to give (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 )δ ppm:7.39-6.90(m,4H),5.36-5.04(m,1H),3.77-3.52(m,2H),3.20-3.17(m,1H),2.4 7-2.24(m,1H),1.96-1.65(m,3H),1.54-1.38(m,2H),1.31-1.22(m,8H),1.17(s,7H).

[0081] Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) dropwise at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was slurried with EA (100 mL), then filtered and dried in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR (400MHz, DMSO-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=6.7Hz,3H),1.17(d,J=6.7Hz,3H).MS(ESI,m / e)[M+1] + 190.0.

[0082] Step 7: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) was charged to the reactor. The temperature was controlled below 30° C., and NaBH(OAc) 3 (216 g, 1.018 mol) was added to the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After the starting ketone was completely consumed, the mixture was adjusted to pH=4-5 with dilute HCl acid (0.5 M). The separated organic phase was washed with H 2 HO (600 mL × 2), then NaHCO3 The organic phase was collected and then washed with anhydrous NaCl (600 mL×2). 2 SO 4 The mixture was dried at 40° C. and concentrated. 256 g of an off-white solid was obtained as crude product, which was used directly in the next step. MS (ESI, m / e) [M+1] + 579.0.

[0083] Step 8: Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). This was stirred at room temperature overnight. After removing THF and MeOH in vacuum, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH=5-6 with 3N HCl acid at room temperature under stirring. The precipitate was filtered and dried in vacuum to give the product as a white solid (102.4 g, yield: 99%). 1 H NMR (400MHz, DMSO-d 6 ) δ ppm:12.13(s,1H),11.58(s,1H),7.95(s,1H),7.67(d,J=8.0Hz,1H),7.56-7.40 (m,2H),7.35(s,1H),7.27-7.04(m,3H),6.68(d,J=8.0Hz,1H),6.32(s,2H),3.6 2(s,1H),3.32-3.26(m,1H),3.10-3.04(m,4H),2.35-2.30(m,1H),2.9-2.15(m, 1H),1.74-1.64(m,4H),1.52-1.37(m,6H),1.28-1.06(m,6H).MS(ESI,m / e)[M+1] + 564.9.

[0084] Step 9: 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol) and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred at room temperature overnight. The reaction was monitored by HPLC. After complete consumption of the (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid starting material, the reaction mixture was heated to about 35° C. and N 1 ,N 1 -Dimethylethane-1,2-diamine (17.2 g, 195 mmol) was added in one portion. The reaction was stirred for an additional 12 h. The mixture was washed twice with 10 wt% aqueous AcOH solution (300 mL x 2), followed by saturated NaHCO 3 The mixture was cooled to room temperature, and the precipitate was filtered, and then the wet cake was washed twice with EA (180 mL). After drying in vacuum at 80-90 °C, the desired compound was obtained (48 g, yield: 69.5%). 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=2.8Hz,1H),7.74(d,J=8.8Hz,1H ),7.57-7.37(m,4H),7.30-7.10(m,3H),7.00(d,J=9.2Hz,1H),6.65(d,J=1.2Hz,1H),6.35(s,1H) ,6.17(s,1H),4.24(s,1H),3.39-3.20(m,5H),3.04-2.88(m,4H),2.23(s,1H),1.94-1.47(m,11H) ,1.44-1.26(m,7H),1.19(d,J=8.0Hz,3H),1.14(d,J=8.0Hz,3H),1.10(s,4H).MS(ESI,m / e)[M+1] + 889.9.

[0085] Treatment method In one embodiment, the disclosure provides a method for treating cancer. In certain embodiments, the method comprises administering to a patient in need thereof an effective amount of Compound 1. The cancer is a B-cell malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL), low tumor burden chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), high tumor burden CLL / SLL, mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM), which is predicted to have a low risk of tumor lysis syndrome. In some embodiments, the B-cell malignancy is relapsed / refractory.

[0086] Compound 1 can be administered by any suitable means, including oral, parenteral, pulmonary, and nasal, and, if desired for localized treatment, intralesional administration. Administration can be by any suitable route. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple administrations at various times, bolus administration, and pulse infusion.

[0087] Compound 1 is formulated, dispensed, and administered in a manner consistent with good medical practice. 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 delivery of the drug, the method of administration, the administration schedule, and other factors known to medical practitioners. Compound 1 is optionally formulated with one or more drugs currently used to prevent or treat the disorder in question. The effective amount of such other drugs depends on the amount of Compound 1 in the formulation, the type of disorder or treatment, and other factors mentioned above.

[0088] For the prevention or treatment of disease, the appropriate dosage of Compound 1 will depend on the type of disease being treated, the severity and course of the disease, whether Compound 1 is being administered for prophylactic or therapeutic purposes, previous treatments, the patient's medical history and response to Compound 1, and the discretion of the attending physician. Compound 1 is suitably administered to the patient at one time or over a series of treatments. EXAMPLES

[0089] The present invention is further illustrated by the following examples which illustrate, but are not limited to, the present invention.

[0090] Example 1: Efficacy Study of Bcl-2 Inhibitors in the RS4;11 Acute Lymphoblastic Leukemia (ALL) Subcutaneous Xenograft Model RS4;11 cells are of acute lymphoblastic leukemia (ALL) origin and were obtained from the American Type Culture Collection (ATCC CRL-1873, Manassas, VA, DC, USA). Cells were grown in RPMI 1640 medium (Corning, Catalog No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Catalog No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Catalog No. 15140-122). RS4;11 cells were incubated at 4 °C for 2 h at 37 °C for 3 h at 25 °C for 1 h at 37 °C. 2The mice were maintained as suspension cell cultures at 37°C in a co-cultured room temperature atmosphere. Five- to six-week-old female NCG mice were purchased from Gempharmtech, Information Technology Center. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions with free access to food and water. Mice were group-housed in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.) at temperatures of 20–26°C and humidity of 37–62% with a 12-h light-dark cycle (lights on at 08:00). Mice were fed a complete granular diet (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized with Co60 radiation.

[0091] On the day of transplantation, RS4;11 cells were harvested and resuspended in an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to give 5 × 10 7 A final concentration of 1 × 10 cells / mL was obtained. Resuspended cells were placed on ice prior to inoculation. Prior to cell inoculation, the right front flank area of ​​each mouse was washed with 75% ethanol. 1 × 10 cells in 200 μL of cell suspension were added to the right front flank of each animal. 7 Cells were injected subcutaneously through a 26-gauge needle. After implantation, the volume of the primary tumor was measured in two dimensions using calipers.

[0092] Animals were quantified based on body weight and tumor volume (100 mm 3 ~200mm 3 ) were randomly assigned into 10 groups with 10 mice per group. Groups consisted of vehicle, venetoclax at 5, 15, 50 mg / kg administered QD, compound 1 at 5, 15, 50 mg / kg administered QD, and compound 1 at 2.5, 7.5, 25 mg / kg administered BID. Treatments were administered by oral gavage (po) in a volume of 10 mL / kg body weight. Body weight was assessed immediately prior to dosing, and doses were adjusted accordingly.

[0093] Individual body weights were recorded twice weekly, and mice were monitored daily for clinical signs of toxicity for the duration of the study. 3Mice were euthanized using carbon dioxide when the tumor reached 0.01 mg / kg / day, tumors ulcerated, or body weight loss exceeded 20%.

[0094] Tumor volume is calculated using the formula: V = 0.5 × (a × b 2 ) where a and b are the long and short diameters of the tumor, respectively.

[0095] The in vivo efficacy of compound 1 was tested and compared to venetoclax in RS4;11 ALL xenografts grown subcutaneously in NCG mice. After oral administration at well-tolerated doses, compound 1 potently and dose-dependently inhibited tumor growth (Figures 1A-1B and Table 1). At the same total daily doses of 5 mg / kg and 15 mg / kg, compound 1 showed significantly superior efficacy when compared to venetoclax. Venetoclax was administered at 400 mg daily in the clinic. Its clinically relevant dose in mice is approximately 15 mg / kg QD based on free AUC. Compound 1 2.5 mg / kg BID was more active than venetoclax at 15 mg / kg QD. Furthermore, at the same total daily doses of 15 and 50 mg / kg, the QD and BID administration schedules of compound 1 showed comparable antitumor activity. These results are shown in Figures 1A-1B.

[0096] All treatment groups did not significantly affect the body weight of the animals throughout the study. [Table 1]

[0097] Example 2: Efficacy study of Bcl-2 inhibitors in the MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model MAVER-1 cells are of mantle cell lymphoma (MCL) origin and were obtained from the American Type Culture Collection (ATCC CRL-3008, Manassas, VA, DC, USA). Cells were grown in RPMI 1640 medium (Corning, catalog number 10-040-CVR) 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). MAVER-1 cells were cultured at 4 °C for 24 h at 20 °C for 30 min at 37 °C for 1 h at 20 °C. 2 The mice were maintained as suspension cell cultures at 37°C in an ambient atmosphere. Five- to six-week-old female NCG mice were purchased from Gempharmtech, Information Technology Center. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions with free access to food and water. Mice were group-housed in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.) at temperatures of 21–26°C and humidity of 44–61% with a 12-h light-dark cycle (lights on at 08:00). Mice were fed a complete granular diet (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized with Co60 radiation.

[0098] On the day of transplantation, MAVER-1 cells were harvested and resuspended in an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to give 1.5 × 10 7 A final concentration of 100 x 10 cells / mL was obtained. The resuspended cells were placed on ice prior to inoculation. Prior to cell inoculation, the right front flank area of ​​each mouse was washed with 75% ethanol. Each animal was inoculated with 3 x 10 cells in 200 μL of cell suspension on the right front flank. 6 Cells were injected subcutaneously through a 26-gauge needle. After implantation, the volume of the primary tumor was measured in two dimensions using calipers.

[0099] Animals were quantified based on body weight and tumor volume (100 mm 3 ~200mm 3) were randomly assigned into 7 groups with 10 mice per group. Groups consisted of vehicle, venetoclax at 5, 15 mg / kg with QD administration, compound 1 at 5, 15 mg / kg with QD administration, and compound 1 at 2.5, 7.5 mg / kg with BID administration. Treatments were administered by oral gavage (po) in a volume of 10 mL / kg body weight. Body weight was assessed immediately prior to administration and doses were adjusted accordingly.

[0100] Individual body weights were recorded twice weekly, and mice were monitored daily for clinical signs of toxicity for the duration of the study. 3 Mice were euthanized using carbon dioxide when the tumor reached 0.05 mg / kg, tumors ulcerated, or body weight loss exceeded 20%.

[0101] Tumor volume is calculated using the formula: V = 0.5 × (a × b 2 ) where a and b are the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: % TGI=100×[1-(treatment t -Treatment t0 ) / (Vehicle t -Vehicle t0 )] (treatment t = treatment tumor volume at time t, treatment t0 = treatment tumor volume at time 0, vehicle t = vehicle tumor volume at time t, and vehicle t0 = vehicle tumor volume at time 0).

[0102] The in vivo efficacy of compound 1 was also examined and compared to venetoclax in MAVER-1 MCL xenografts grown subcutaneously in NCG mice. Compound 1 potently inhibited tumor growth in a dose-dependent manner. The tumor growth inhibition (TGI) at day 14 of compound 1 at 2.5, 7.5 mg / kg BID and 5, 15 mg / kg QD was 77%, 103% and 86%, 103%, respectively. Venetoclax at 5 and 15 mg / kg QD achieved TGI of 38% and 91%, respectively. At the same total daily doses of 5 and 15 mg / kg, compound 1 showed more antitumor activity compared to venetoclax. Compound 1 at 15 mg / kg QD and 7.5 mg / kg BID was similarly active. These results are shown in Figure 2A-B and Table 2.

[0103] All treatment groups did not significantly affect the body weight of the animals throughout the study. [Table 2]

[0104] Example 3: Efficacy study of Bcl-2 inhibitors in the Toledo diffuse large B-cell lymphoma (DLBCL) subcutaneous xenograft model Toledo cells were of diffuse large B-cell lymphoma (DLBCL) origin and obtained from the American Type Culture Collection (ATCC CRL-2631, Manassas, VA, DC, USA). Cells were grown in RPMI 1640 medium (Corning, catalog number 10-040-CVR) 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). Toledo cells were cultured at 4°C for 24 hours at 37°C for 12 h at 20°C for 30 min at 5% CO. 2The mice were maintained as suspension cell cultures at 37°C in a co-cultured room temperature atmosphere. Five- to six-week-old female NCG mice were purchased from Gempharmtech, Information Technology Center. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions with free access to food and water. Mice were group-housed in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.) at temperatures of 21–26°C and humidity of 35–61% with a 12-h light-dark cycle (lights on at 08:00). Mice were fed a complete granular diet (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized with Co60 radiation.

[0105] On the day of transplantation, Toledo cells were harvested and resuspended in an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to give 1.5 × 10 7 A final concentration of 100 x 10 cells / mL was obtained. The resuspended cells were placed on ice prior to inoculation. Prior to cell inoculation, the right front flank area of ​​each mouse was washed with 75% ethanol. Each animal was inoculated with 3 x 10 cells in 200 μL of cell suspension on the right front flank. 6 Cells were injected subcutaneously through a 26-gauge needle. After implantation, the volume of the primary tumor was measured in two dimensions using calipers.

[0106] The implanted animals were randomized into 10 groups with 10 mice per group on day 0 according to implantation order and body weight. Groups consisted of vehicle, venetoclax at 5, 15, 50 mg / kg with QD administration, compound 1 at 5, 15, 50 mg / kg with QD administration, and compound 1 at 2.5, 7.5, 25 mg / kg with BID administration. Treatments were administered by oral gavage (po) in a volume of 10 mL / kg body weight. Body weight was assessed immediately prior to administration and doses were adjusted accordingly.

[0107] Individual body weights were recorded twice weekly, and mice were monitored daily for clinical signs of toxicity for the duration of the study. 3 Mice were euthanized using carbon dioxide when the tumor reached 0.05 mg / kg, tumors ulcerated, or body weight loss exceeded 20%.

[0108] Tumor volume is calculated using the formula: V = 0.5 × (a × b 2 ) where a and b are the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: % TGI=100×[1-(treatment t -Treatment t0 ) / (Vehicle t -Vehicle t0 )] (treatment t = treatment tumor volume at time t, treatment t0 = treatment tumor volume at time 0, vehicle t = vehicle tumor volume at time t, and vehicle t0 = vehicle tumor volume at time 0).

[0109] The in vivo efficacy of compound 1 was further investigated and compared to venetoclax in the Toledo DLBCL subcutaneous xenograft model. After daily oral administration at well-tolerated doses of 2.5, 7.5, 25 mg / kg BID or 5, 15, 50 mg / kg QD, compound 1 induced a dose-dependent antitumor effect. At the same total daily doses of 5 mg / kg and 15 mg / kg, compound 1 showed significantly superior efficacy when compared to venetoclax. These results are shown in Figures 3A-B and Table 3.

[0110] All treatment groups did not significantly affect the body weight of the animals throughout the study. [Table 3]

[0111] Example 4: Efficacy study of Bcl-2 inhibitors in the RS 4;11 Bcl-2 G 101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model RS4;11 Bcl-2 G 101V KI cells were of acute lymphoblastic leukemia (ALL) origin and screened in-house. Cells were grown in RPMI 1640 medium (Corning, Catalog No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Catalog No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Catalog No. 15140-122). RS 4;11 Bcl-2G101V KI cells were cultured at 37 °C for 24 h at 5% CO 2 The mice were maintained as suspension cell cultures at 37°C in a co-cultured room temperature atmosphere. Five- to six-week-old female NCG mice were supplied by GemPharmatech Co.,Ltd, Jiangsu, China. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions with free access to food and water. Mice were group-housed in IVC cages (Lingyunboji (Beijing) Technology Co.,Ltd) at temperatures of 20–26°C and humidity of 37–62% with a 12-h light / dark cycle (lights on at 08:00). Mice were fed a complete granular diet (Beijing Ke Ao Xie Li Feed Co.,Ltd.) sterilized with Co60 radiation.

[0112] On the day of transplantation, RS 4;11Bcl-2G101V KI cells were harvested and resuspended in an appropriate volume of ice-cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to give 5 × 10 7 A final concentration of 1 × 10 cells / mL was obtained. Resuspended cells were placed on ice prior to inoculation. Prior to cell inoculation, the right front flank area of ​​each mouse was washed with 75% ethanol. 1 × 10 cells in 200 μL of cell suspension were added to the right front flank of each animal. 7 Cells were injected subcutaneously through a 26-gauge needle. After implantation, the volume of the primary tumor was measured in two dimensions using calipers.

[0113] Animals were quantified based on body weight and tumor volume (approximately 300 mm 3Mice were randomly assigned to 7 groups with 8 mice per group according to the protocol outlined in the FDA guidelines. Groups consisted of vehicle, venetoclax at 15, 50 and 100 mg / kg QD, and compound 1 at 15, 50 and 100 mg / kg QD. Treatments were administered by oral gavage (po) in a volume of 10 mL / kg body weight. Body weight was assessed immediately prior to dosing, and doses were adjusted accordingly.

[0114] Individual body weights were recorded twice weekly, and mice were monitored daily for clinical signs of toxicity for the duration of the study. 3 Mice were euthanized using carbon dioxide when the tumor reached 0.05 mg / kg, tumors ulcerated, or body weight loss exceeded 20%.

[0115] Tumor volume is calculated using the formula: V = 0.5 × (a × b 2 ) where a and b are the long and short diameters of the tumor, respectively.

[0116] The in vivo efficacy of compound 1 was tested and compared to venetoclax in RS4;11 Bcl-2G101V KI xenografts grown subcutaneously in NCG mice. Venetoclax showed marginal efficacy even at higher dose levels, whereas compound 1 potently and dose-dependently inhibited tumor growth. These results are shown in Figure 4A-B and Table 4. Curves for compound 1 at 50 mg / kg po. QD and 100 mg / kg po QD are merged.

[0117] All treatment groups did not significantly affect the body weight of the animals throughout the study. [Table 4]

[0118] Example 5: Evaluating the efficacy of Bcl-2 inhibitors in combination with BTK inhibitors in the JeKo-1 human mantle cell lymphoma (MCL) subcutaneous xenograft model JeKo-1 cells are of mantle cell lymphoma (MCL) origin and were obtained from the American Type Culture Collection (ATCC CRL-3006, Manassas, VA, DC, USA). Cells were grown in RPMI 1640 medium (Corning, catalog number 10-040-CVR) 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). Jeko-1 cells were cultured at 4 °C for 24 h at 37 °C for 1 h at 25 °C for 3 h at 37 °C. 2 The mice were maintained as suspension cell cultures at 37°C in a co-cultured room temperature atmosphere. Five- to six-week-old female NCG mice were purchased from Gempharmtech, Information Technology Center. All animals were maintained under specific pathogen-free (SPF) "total barrier" conditions with free access to food and water. Mice were group-housed in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.) at temperatures of 23–27°C and humidity of 28–51% with a 12-h light-dark cycle (lights on at 08:00). Mice were fed complete granulated diet (Beijing Ke Ao Xie Li Feed Co., Ltd.) sterilized by Co60 radiation. All experiments were performed in accordance with BeiGene's IACUC.

[0119] On the day of transplantation, JeKo-1 cells were harvested and resuspended in an appropriate volume of ice-cold PBS and the same volume of Matrigel (Corning, Cat. No. 356237) to give 5 × 10 7 A final concentration of 1 × 10 cells / mL was obtained. Resuspended cells were placed on ice prior to inoculation. Prior to cell inoculation, the right front flank area of ​​each mouse was washed with 75% ethanol. 1 × 10 cells in 200 μL of cell suspension were added to the right front flank of each animal. 7 Cells were injected subcutaneously through a 26-gauge needle. After implantation, the volume of the primary tumor was measured in two dimensions using calipers.

[0120] The implanted animals were randomized into 8 groups with 10 mice per group on day 0 according to implantation order and body weight. The groups consisted of vehicle group, compound 1 (Bcl-2 inhibitor) at 5, 15, 50 mg / kg with QD administration, and compound B (BTK inhibitor zanubrutinib, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide) at 20 mg / kg with BID administration, as well as combinations thereof. Treatments were administered by oral gavage (po) in a volume of 10 mL per kg body weight. Body weight was assessed immediately prior to administration and the dose was adjusted accordingly.

[0121] Individual body weights were recorded twice weekly, and mice were monitored daily for clinical signs of toxicity for the duration of the study. 3 Mice were euthanized using carbon dioxide when the tumor reached 0.05 mg / kg, tumors ulcerated, or body weight loss exceeded 20%.

[0122] Tumor volume (TV) is calculated by the formula: TV = 0.5 × (a × b 2 ) where a and b are the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: %TGI=100×[1−(treatment t ) / (Vehicle t )] (treated t = treated tumor volume at time t, vehicle t = vehicle tumor volume at time t)

[0123] The in vivo efficacy of compound 1 and compound B was investigated in a JeKo-1 MCL subcutaneous xenograft model grown subcutaneously in NCG mice. The results are shown in Figure 5A, Figure 5B, Figure 5C, and Figure 5D. At day 21, compound 1 at 5, 15, and 50 mg / kg QD and compound B at 20 mg / kg BID resulted in tumor growth inhibition (TGI) of 29%, 49%, 49%, and 56%, respectively. The combination of compound B at 20 mg / kg BID with compound 1 at 5, 15, or 50 mpk QD resulted in TGI of 62%, 74%, and 71%, respectively (see Table 1). The combination of compound 1 at 15 or 50 mpk QD with compound B at 20 mpk BID showed better antitumor activity than either single agent (Figure 1C and 1D). All treatment groups did not significantly affect the animal's body weight throughout the study. [Table 5]

[0124] Example 6: Clinical Trials 1. Method Research design / purpose A Phase 1 study (dose escalation and safety expansion) was conducted to determine the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of Compound 1 in patients with R / RB cell malignancies (Table 6-1A).

[0125] Dose escalation (Part 1) will occur in separate cohorts stratified by patient disease type. These cohorts will continue until a recommended Phase 2 dose (RP2D) is identified, which will then be used in the corresponding expansion cohorts (Part 2).

[0126] Part 1. Monotherapy ramp-up schedule and dosing insights 1) Cohort 1A: Cohort 1A consists of patients with relapsed / refractory B-cell non-Hodgkin's lymphoma (R / RB-cell NHL) excluding mantle cell lymphoma (MCL). These patients are expected to be at low risk for tumor lysis syndrome (low TLS risk) and will be treated with a short ramp-up schedule reaching the target dose on day 3. Patients in this cohort will receive escalating doses of Compound 1 monotherapy: 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg (unless adjusted by Safety Monitoring Committee [SMC] recommendation). 2) If one or more tolerated dose levels of Cohort 1A are determined, open Cohort 1B. It consists of patients with low tumor burden R / R CLL / SLL. This cohort will pursue dose discovery, including evaluation of both ramp-up schedules and target doses. Patients will receive weekly ramp-up dose increases until they reach the cohort's target dose. Ramp-up steps are 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg (unless adjusted by SMC recommendation). This cohort will not be dosed until the SMC. 3) Cohort 1C: This cohort consists of patients with high tumor burden R / R chronic lymphocytic leukemia / small lymphocytic lymphoma (R / R CLL / SLL). This cohort will not be dosed until the RP2D of Cohort 1B has been established. The purpose of this cohort is to confirm the safety of the monotherapy ramp-up schedule and RP2D established in patients with low tumor burden CLL / SLL in patients with high tumor burden CLL / SLL. 4) Cohort 1D: This cohort consists of patients with R / R MCL. This cohort will not be dosed until the RP2D of Cohort 1B has been established. The purpose of this cohort is to confirm the safety of the monotherapy ramp-up schedule and RP2D established in patients with low tumor burden CLL / SLL in patients with R / R MCL. - Cohort 1D: This cohort consists of patients with R / R MCL and has target doses of 160 and 320 mg. 5) Cohort 1E: This cohort consists of patients with R / R Waldenström's Macroglobulinemia (R / R WM). This cohort will not be dosed until the RP2D of Cohort 1B has been established. The purpose of this cohort is to confirm the safety of the monotherapy ramp-up schedule and RP2D established in patients with low tumor burden CLL / SLL in patients with R / R WM.

[0127] All dose cohorts will be reviewed by the Safety Monitoring Committee (SMC) to open subsequent dose levels or declare the MTD / RP2D.

[0128] Part 2 Monotherapy expansion cohort 1) Cohort 2A: R / R indolent NHL (follicular lymphoma [FL] and marginal zone lymphoma [MZL]). 2) Cohort 2B: R / R aggressive NHL (diffuse large B-cell lymphoma [DLBCL] and transformed B-cell NHL). 3) Cohort 2C: R / R CLL / SLL with low tumor burden. 4) Cohort 2D: R / R CLL / SLL with high tumor burden. 5) Cohort 2E: R / R CLL / SLL with prior venetoclax (ven) treatment. 6) Cohort 2F: R / R MCL. 7) Cohort 2G: R / R WM.

[0129] The study also includes dose escalation and dose expansion cohorts for the combination of Compound 1 with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in patients with selected B-cell malignancies, such as CLL / SLL and mantle cell lymphoma (MCL) (Table 6-2A). Patients in the combination therapy cohorts will receive zanubrutinib at 320 mg daily (160 mg twice daily [BID] or 320 mg once daily [QD]) beginning 8-12 weeks before Compound 1 is introduced, with corresponding dose escalation and dose expansion in Parts 3 and 4):

[0130] Part 3. Combination Ramp-up Schedule and Dosage Findings Cohort 3A and Cohort 3B study patients with R / R CLL / SLL or R / R MCL, respectively, will establish the RP2D and MTD or MAD of Compound 1 in combination with zanubrutinib 320 mg daily.

[0131] In patients with Bcl-2 inhibitor-naïve R / R CLL / SLL or R / R MCL who have not progressed on a BTK inhibitor, dose titration (including evaluation of the ramp-up schedule and target dose of Compound 1 when used in combination with zanubrutinib) will be pursued. Compound 1 doses will vary, while zanubrutinib doses will be fixed at 320 mg / day (160 mg twice daily or 320 mg once daily). Ramp-up doses will increase weekly until the cohort's target dose is reached. Compound 1 ramp-up steps are 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg (unless adjusted by SMC recommendation).

[0132] Cohort 3A will be dosed until SMC identifies a safe starting dose for this high TLR risk disease (based on data from Part 1) and sets the initial target dose after target dose +1 is cleared as safe in the Part 1 cohort. Patients in Cohort 3B are expected to have a similar TLS risk compared to CLL / SLL, and patients in this cohort may begin titrating at or below the current best tolerated dose (or RP 2 D, if established) for CLL / SLL patients with combination titration (Cohort 3A).

[0133] Part 4. Combined expansion cohort 1) In Cohort 4A, R / R CLL / SLL patients receiving zanubrutinib 320 mg / day (160 mg twice daily or 320 mg once daily) will be studied with Compound 1 at the ramp-up schedule and target dose identified in Cohort 3A to expand the safety evaluation of treatment dose and ramp-up schedule. 2) Cohort 4B will study patients with treatment-naïve (TN) CLL / SLL and will use the same dose and schedule as Cohort 4A unless modified by the SMC. 3) Cohort 4C will study patients with R / R MCL and will use the RP2D declared from Cohort 3B unless amended by the SMC.

[0134] Compound 1 will be administered orally once daily (QD) in all cohorts in the Phase 1 study. [Table 6] [Table 7]

[0135] Main eligibility criteria Each patient eligible to participate in this study must meet all of the following criteria: 1. Age 18 or older 2. Confirmation of a diagnosis of any of the following: NHL Cohort a.MZL, i.) R / R extranodal MZL, splenic MZL or nodal MZL (defined as disease that has relapsed after or was refractory to at least one prior therapy); ii.) active disease requiring treatment. b.FL, i.) R / R FL (grade 1, 2 or 3a according to the WHO 2008 classification of tumors of the hematopoietic and lymphoid tissues) defined as disease that has relapsed after or is refractory to at least one prior systemic therapy; ii.) active disease requiring treatment. c. DLBCL, i.) R / R DLBCL (including all subtypes of DLBCL) defined as disease that has relapsed after or refractory to at least one prior systemic therapy and progressing after or not a candidate for autologous stem cell transplant (due to comorbidities or non-responsiveness to salvage chemotherapy); ii.) active disease requiring treatment. d. Transformed indolent B-cell NHL, i) Other lymphomas that have transformed into more aggressive lymphomas and are eligible for Part 1. Patients with transformation from CLL or SLL (Richter's transformation) are not eligible for Part 1 ii) Active disease requiring treatment. MCL cohort e. WHO-defined MCL, i.) R / R MCL defined as disease that has relapsed after or was refractory to at least one prior systemic therapy; ii) requiring treatment in the opinion of the investigator. CLL / SLL cohort: f. CLL / SLL diagnosis fulfilling the International Workshop on Chronic Lymphocytic Leukemia criteria (Hallek et al 2008). i. Meet the following set of prior treatment criteria: (1) For the R / R cohorts (Cohorts 1C, 2C, 2D, 2E, 3A, and 4A), disease that has relapsed after or was refractory to at least one prior therapy; (2) For the venetoclax-treated cohort (Cohort 2E): prior treatment history must include progression after ≥2 months of venetoclax treatment (monotherapy or combination therapy); (3) For the treatment-naive cohort (Cohort 4B), patients should have had no prior treatment for CLL / SLL (other than a single discontinued regimen of duration <2 weeks and >4 weeks prior to enrollment). ii. Needs medical treatment WM cohort: g. WHO-defined WM (clinical and definitive histological diagnosis), i.) R / R disease defined as disease that has relapsed after at least one previous treatment or that was refractory to treatment; ii) fulfilling at least one criterion for treatment according to the consensus panel criteria of the 7th International Workshop on Waldenstrom's Macroglobulinemia (Dimopoulos et al., 2014). Measurable disease by computed tomography / magnetic resonance imaging defined as follows: a.CLL: At least one lymph node >1.5 cm in greatest diameter and measurable in two perpendicular dimensions or clonal lymphocytes by flow cytometry. b. DLBCL, FL, MZL, MCL or SLL: At least one lymph node >1.5 cm in greatest diameter or one extranodal lesion >1.0 cm in greatest diameter and measurable in two perpendicular dimensions. In the case of MZL, isolated splenomegaly is considered measurable for this study. c.WM: Serum IgM level >0.5 g / Dl. 3. Measurable disease by computed tomography (CT) / magnetic resonance imaging (MRI). 4. Eastern Cooperative Oncology Group (ECOG) activity status 0-2 6. Adequate pancreatic function as demonstrated by: Serum amylase less than 1.5 x the upper limit of normal (ULN) Serum lipase < 1.5xULN

[0136] Exclusion criteria Known central nervous system involvement from lymphoma / leukemia · History or current suspicion of known plasma cell neoplasm, prolymphocytic leukemia, or Richter's syndrome.

[0137] Dose escalation For dose escalation, patients were enrolled in one of five planned daily oral Compound 1 dose levels in cohorts of at least three patients: 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg daily.

[0138] Dose Ramp Up To protect against potential tumor lysis syndrome (TLS), all patients received dose ramp-up to target dose levels, which were 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg daily for both monotherapy and combination therapy (Table 5-1B). 1) Patients with NHL (excluding MCL) as part of cohorts 1A, 2A, and 2B will receive a 2-day ramp-up (day 1, 25% of target dose; day 2, 50% of target dose) before reaching the target daily dose (day 3+, 100%). 2) Patients with CLL / SLL, MCL or WM as part of cohorts 1B, 1C, 1D, 1E, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 4A, 4B and 4C will receive weekly ramp-ups (starting at 1 mg per day and doubling the dose each week until the target dose is reached). Dose tiers are 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg.

[0139] Other TLS prophylaxis included 1) Hydration: 1.5-2 L / day orally or intravenously for at least 1 day before and at least 1 day after each new dose level; 2) Antihyperuricemia drugs (allopurinol, rasburicase if necessary): from 2 days before the first dose until 1 week after the final target dose level is reached; and 3) Hospitalization for observation: TLS labs and PK will be monitored frequently. ---NHL: required during ramp-up for at least the first 3 ramp-up doses; and ---CLL: Required on day 1 of each week for at least the first 3 escalating doses. [Table 8]

[0140] Report etc. Adverse events (AEs) were reported per CTCAE v5.0 (iwCLL for selected hematologic toxicities in CLL patient 7).

[0141] Terminology Criteria for AEs v5.0 (International Workshop on CLL [iwCLL] for selecting hematologic toxicities in CLL patients). Response to treatment was evaluated by the Lugano classification for NHL patients12 and by the iwCLL guidelines for CLL patients13.

[0142] Dose-limiting toxicity (DLT) during dose escalation was assessed up to 21 days at the target dose per patient. To model the relationship between dose level and dose-limiting toxicity (DLT) rates in dose-level cohorts, a Bayesian logistic regression model is used for target dose finding.

[0143] 2.Results Alignment and Baseline In monotherapy, 7 patients with R / R NHL were treated in cohort 1A, and 2 patients with R / R CLL were treated in cohort 1B. Then, a total of 36 patients were further enrolled in cohorts 1A, 1B, 3A, and 3B (Table 5-2A): 1) in monotherapy, 19 patients with R / R NHL were treated in cohort 1A, and 6 and 10 patients with R / R CLL were treated in cohorts 1B and 1C. 2) in combination therapy, 10 patients with R / R CLL were treated in cohort 3A, and 1 patient with R / R MCL was treated in cohort 3B. [Table 9] [Table 10]

[0144] safety Safety data for 36 patients (monotherapy [N=25], combination therapy [N=11]) who received compound 1 are shown in Table 6-3A and Figure 6A. Additionally, safety data for 58 patients who received compound 1 are shown in Table 6-3B. Of the 58 patients receiving monotherapy, 26 with R / R non-Hodgkin's lymphoma (NHL; 17 DLBCL, 6 FL, and 3 MZL) received compound 1 ≤ 640 mg, and 6 with R / R CLL / SLL received compound 1 ≤ 160 mg. Of the 58 patients receiving combination therapy, 19 with R / R CLL / SLL received compound 1 ≤ 160 mg, and 7 with R / R MCL received compound 1 ≤ 80 mg. The MTD has not yet been reached. Median follow-up was 3.9 months (range, 0.1-20.4). and 20 of 58 patients discontinued treatment (17 disease progression; 1 AE; 2 other reasons).

[0145] In monotherapy, the most common treatment-emergent adverse events (AEs) included nausea. Patient-reported grade ≥3 AEs were observed: abdominal pain, enterocolitis, small bowel obstruction, increased blood alkaline phosphatase, increased GGT, increased platelet count, cachexia, fever, back pain, and laboratory TLS. One high-risk patient with CLL on monotherapy had laboratory TLS that resolved without intervention (laboratory TLS <2%). Two deaths secondary to disease progression were observed.

[0146] Two grade ≥3 AEs (1 neutropenia, 1 autoimmune hemolytic anemia) were reported with combination therapy. [Table 11] [Table 12]

[0147] Dose-escalation status Cohort 1A NHL: The 40 mg (n=3; 1 MZL, 2 DLBCL), 80 mg (n=4; 1 FL, 3 DLBCL) and 320 mg (n=3) dose cohorts were completed with no disease-limiting toxicities (DLTs); the 160 mg (n=3+1) dose cohort had one DLT of grade 3 febrile neutropenia; all dose cohorts were completed, including the 320 mg and 640 mg dose cohorts, and the MTD was not reached up to 640 mg.

[0148] Cohort 1B R / R CLL: After being declared tolerable in cohort 1A, dose escalation was initiated at a target dose level of 80 mg (n=4) with one DLT of grade 4 neutropenia. The 160 mg, 320 mg, and 640 mg dose cohorts are ongoing. Cohort 1B only allowed patients at low risk for TLS, but a patient at high risk for TLS was erroneously enrolled. Retrospective review of baseline CT by the site radiologist upgraded the largest lymph node to 6.5×2.4 cm with an absolute lymphocyte count (ALC) of 37.4×10 9 / L (n=2, 80 mg target dose level).

[0149] Cohort 3A R / R CLL: The 40 mg (n=4), 80 mg (n=3), and 160 mg (n=3) dose cohorts were completed without disease-limiting toxicities (DLTs); the 320 mg and 640 mg dose cohorts are ongoing.

[0150] Cohort 3B R / R MCL: The 80 mg dose cohort completed without disease-limiting toxicity (DLT); the 160 mg, 320 mg, and 640 mg dose cohorts are ongoing.

[0151] Cohort 4B TN CLL: The 160 mg dose cohort was open and was well tolerated and showed encouraging activity.

[0152] Objective adverse events of BCL2 inhibitors TLS: A mis-enrolled patient with high baseline TLS risk developed laboratory TLS and had a large tumor flare upon BTK inhibitor withdrawal during early ramp-up with lactate dehydrogenase 1500, largest nodule to 5-10 cm, and ALC 135.9×109 / L. This patient also had a history of baseline and hyperuricemia. During dose escalation, the patient met criteria for laboratory TLS according to Howard criteria8 in the late ramp-up at both the 40 mg and 80 mg dose levels. Urate baseline: 430 mmol / L; urate peak: 570 mmol / L; phosphate baseline: 0.35 mmol / L; phosphate peak: 2.16 mmol / L. The patient experienced no sequelae from the laboratory TLS, recovered by the next day, and did not require retention of compound 1.

[0153] In monotherapy, neutropenia was observed in six patients (five experienced grade 3 or higher neutropenia), with two patients resolving with initial compound 1 treatment.

[0154] One patient receiving monotherapy with high baseline TLS risk had a significant tumor flare upon discontinuation of the BTK inhibitor and developed laboratory TLS in the late ramp-up. The patient experienced no sequelae from the laboratory TLS, recovered by the next day, and did not require retention of Compound 1.

[0155] Effectiveness Most patients had a decrease in the sum of the products of perpendicular diameters. CLL / SLL patients also had a significant decrease in absolute lymphocyte counts at doses as low as 1 mg. Early efficacy in 36 patients (monotherapy [N=25], combination therapy [N=11]) is shown below.

[0156] NHL: No NHL patients achieved a response to Compound 1 (Figure 6B), two patients (80 mg, both with DLBCL) had lymphadenopathy and are continuing treatment, with five patients progressing. With continued treatment (treatment duration of approximately 5 months), it was observed that two patients achieved a response to Compound 1, including one complete response (CR). Reductions in the sum of perpendicular diameters (SPD) were seen at all dose levels tested.

[0157] CLL / SLL: With monotherapy treatment, 1 of 4 CLL patients reached first response assessment and achieved a partial response at the 80 mg dose level (Figure 6C), with deletion (17p) CLL, and 2 responses (partial response or better) were seen with continued treatment, whereas with combination treatment, some patients responded with lymphocytosis or better partial response (n=2, both 40 mg and 80 mg).

[0158] All patients showed significant absolute lymphocyte count (ALC) declines during dose escalation, with one patient responding after overcoming an initial tumor flare and the other showing declines even at the 1 mg dose level (Figure 6D). A significant decline in absolute ALC was noted in all patients with CLL during ramp-up, with lymphocyte declines noted at dose levels as low as 1 mg.

[0159] 3. Conclusion In early phase 1, results on nine patients (monotherapy [N=9]) suggest that compound 1 is tolerable in patients at the dose levels tested. No dose-limiting toxicities (DLTs) were seen across the two dose levels. Grade ≥3 AEs were rare and manageable, with only two patients experiencing neutropenia. The risk of TLS appears to be limited and manageable, with only one case of laboratory TLS seen in a patient with high TLR risk. And preliminary activity in this patient population is being evaluated with increased enrollment and follow-up, with reductions in absolute lymphocyte counts (ALC) seen at the initial ramp-up dose of 1 mg, although enrollment of patients with R / R CLL has only recently begun.

[0160] Results from 36 patients (monotherapy [N=25], combination therapy [N=11]) suggest that compound 1 is tolerable in patients, including those with CLL or NHL, at the dose levels tested. a) Only one dose-limiting toxicity (DLT) was seen across the four dose levels tested in NHL and one DLT in the CLL cohort; b) Grade ≥3 AEs were infrequent and manageable, with only two patients experiencing neutropenia. c) The risk of TLS appears to be limited and manageable, with none seen in the combined cohort; The risk of TLS appears to be limited and manageable, with only one case of laboratory TLS seen in a CLL patient with high TLR risk. d) neutropenia was the most frequent grade ≥3 AE, but it was transient and not well correlated with treatment dose; preliminary activity in this patient population is being evaluated with increased enrollment and follow-up; substantial decreases in ALC were seen during ramp-up in CLL patients; decreases in absolute lymphocyte counts (ALC) were seen with the initial ramp-up dose of 1 mg; and e) Evaluation of patients with MCL, treatment-naïve CLL or WM is planned for future cohorts.

[0161] Results from 58 patients show that compound 1 treatment showed promising efficacy and an improved safety profile, especially in the combination cohort. Grade ≥3 neutropenia was rare. Compound 1 is tolerated at doses up to 640 mg as monotherapy and up to 160 mg in combination with zanubrutinib. Dose escalation will continue as the MTD has not yet been reached in the dose escalation cohorts. Enrollment continues, and data from the Waldenstrom's macroglobulinemia and treatment-naïve CLL / SLL cohorts are forthcoming.

[0162] Furthermore, more patients were enrolled in the study. In total, 78 patients with the following conditions were medicated and the corresponding efficacy was estimated: (1) In monotherapy (N=34), patients with R / R NHL (n=26, median follow-up=6.0 months [range, 1.7-22.0]), R / R CLL / SLL (n=6, median follow-up=8.2 months [range, 5.2-15.0]), and R / R WM (n=2, median follow-up=2.6 months [range, 2.0-3.2]) were treated, and patients with R / R NHL included patients with FL (n=6), DLBCL (n=17), and MZL (n=3). Among patients with R / R NHL, most patients had a significant reduction in baseline SPD morphology, 2 of 20 (10%) patients responded, including 1 PR at 160 mg and 1 CR at 320 mg, and 23 patients discontinued treatment due to progressive disease (n=20), adverse events (n=1), and other or physician decision (n=2). Among patients with R / R WM, 1 of 2 (50%) achieved a minor response at 80 mg. (2) The combination therapy (N=44) treated patients with R / R CLL / SLL (n=20, median follow-up=5.2 months [range, 0.8-11.8]), R / R MCL (n=10, median follow-up=2.4 months [range, 0.1-5.6]), and TN CLL / SLL (expansion cohort at 160 mg daily, n=14, median follow-up=2.1 months [range, 0.0-2.8]). Of the R / R MCL patients, 5 of 10 (50%) patients achieved a PR or better with either 80 mg or 100 mg, including one CR at each dose level, and one R / R MCL patient had treatment discontinued due to progressive disease. (3) Among patients with CLL / SLL in monotherapy and combination therapy, significant reductions in absolute lymphocyte counts (ALC) were observed among all patients with CLL during ramp-up, with lymphocytosis observed at dose levels as low as 1 mg. In monotherapy, 4 of 6 (67%) patients achieved partial response with lymphocytosis (PR-L) or greater at 80 mg or 160 mg of compound 1. In combination therapy, 16 of 20 (80%) R / R CLL / SLL patients achieved PR-L or greater across dose levels ranging from 40 to 320 mg, with one R / R CLL / SLL patient discontinuing treatment due to progressive disease.

[0163] Results from 78 patients suggest that compound 1 is well tolerated in patients with CLL or NHL at the dose levels tested. For NHL monotherapy patients, only one DLT was observed, the MTD was not reached, and dose escalation was terminated. Also, only one DLT was observed in CLL monotherapy patients. Grade ≥3 AEs were infrequent and manageable.

[0164] Findings suggest that the combination of compound 1 and zanubrutinib is well tolerated, similar to compound 1 monotherapy. The risk of TLS appears to be limited and manageable, including laboratory TLS in only one patient with CLL at high risk for TLS receiving monotherapy.

[0165] Furthermore, transient neutropenia was the most frequent grade ≥3 AE, and a significant decrease in ALC was observed during the accrual of CLL patients, with early response rates expected in R / R CLL patients.

[0166] Furthermore, when administered as monotherapy or in combination with zanubrutinib (compound B), CR and PR cases in CLL patients were observed, and a significant reduction in SPD was observed at all dose levels. All doses from 40 mg to 640 mg appeared to be safe, and the incidence of adverse events did not increase significantly with increasing dose. The 40 mg and 80 mg doses may be suboptimal, with less ALC reduction, and blood MRD (minimal residual disease) negativity was observed in the 160 mg cohort after 6 months of treatment but not in the 40 mg and 80 mg cohorts, and 640 mg appears to be a safe but pill-loading dose. Thus, 320 mg is likely to be the recommended phase 2 dose in CLL, as it is likely to give the best balance between efficacy, safety, and convenience.

[0167] The foregoing examples and descriptions of specific embodiments should be construed as illustrative, rather than limiting, of the invention defined by the claims. As will be readily understood, numerous variations and combinations of the features described above can be utilized without departing from the invention as set forth in the claims. All such variations are intended to be within the scope of the present invention. All references cited are incorporated herein by reference in their entirety.

[0168] 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,M.G.,and Sorenson,C.M.(2008)Rescue of renal hypoplasia and cystic dysplasia in Bcl-2- / -mice expressing Bcl-2 in ureteric bud derived epithelia.Dev Dyn 237,2450-2459 Roberts,A.W.(2016)Targeting apoptotic pathways to treat lymphoid malignancies.Rinsho Ketsueki 57,2054-2058 Roberts,A.W.,and Huang,D.(2017)Targeting BCL2 With BH3 Mimetics:Basic Science and Clinical Application of Venetoclax in Chronic Lymphocytic Leukemia and Related B Cell Malignancies.Clin Pharmacol Ther 101,89-98 Schenk,R.L.,Strasser,A.,and Dewson,G.(2017)BCL-2:Long and winding path from discovery to therapeutic target.Biochem Biophys Res Commun 482,459-469 Tausch,E.,Close,W.,Dolnik,A.,Bloehdorn,J.,Chyla,B.,Bullinger,L.,Dohner,H.,Mertens,D.,and Stilgenbauer,S.(2019)Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia.Haematologica 104,e434-e437. Veis,D.J.,Sorenson,C.M.,Shutter,J.R.and Korsmeyer,S.J.(1993)Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis,polycystic kidneys,and hypopigmented hair.Cell,75,229-240. Yamamura,K.,Kamada,S.,Ito,S.,Nakagawa,K.,Ichihashi,M.,and Tsujimoto,Y.(1996)Accelerated disappearance of melanocytes in bcl-2-deficient mice.Cancer Res 56,3546-3550. Delbridge,A.R.,et al.,Thirty years of BCL-2:translating cell death discoveries into novel cancer therapies.Nat Rev Cancer,2016.16(2):p.99-109. Tsujimoto,Y.and C.M.Croce,Analysis of the structure,transcripts,and protein products of bcl-2,the gene involved in human follicular lymphoma.Proc Natl Acad Sci USA,1986.83(14):p.5214-8. Placzek,W.J.,et al.,A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy.Cell Death Dis、2010.1:p.e40. Roberts,A.W.,et al.,Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.N Engl J Med,2016.374(4):p.311-22. DiNardo,C.D.,et al.,Venetoclax combined with decitabine or azacitidine in treatment-naive,elderly patients with acute myeloid leukemia.Blood,2019.133(1):p.7-17. Seymour,J.F.,et al.,Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia:a phase 1b study.Lancet Oncol,2017.18(2):p.230-240. Jain,N.,V.Gandhi,and W.Wierda,Ibrutinib and Venetoclax for First-Line Treatment of CLL.Reply.N Engl J Med,2019.381(8):p.789. Hillmen,P.,et al.,Ibrutinib Plus Venetoclax in Relapsed / Refractory Chronic Lymphocytic Leukemia:The CLARITY Study.J Clin Oncol,2019.37(30):p.2722-2729.

Claims

1. A composition for use in treating a B cell malignancy in a subject, comprising a Bcl-2 inhibitor, wherein a therapeutically effective amount of the Bcl-2 inhibitor is administered to the subject, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]non-7-yl)benzamide, or a pharma- ceutical acceptable salt thereof, or a stereoisomer thereof.

2. The composition of claim 1, characterized in that the composition is administered orally once daily (QD) or twice daily (BID).

3. The composition of claim 2, wherein the composition is orally administered once daily (QD) at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg.

4. The composition described in claim 2, characterized in that the composition is administered orally twice daily (BID) at a dose of 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg.

5. The composition of claim 3, wherein the composition is orally administered once daily (QD) at a dose of 320 mg.

6. The composition of claim 5, wherein the B-cell malignant tumor is non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), or Waldenstrom's macroglobulinemia (WM).

7. The composition described in claim 6, wherein the B cell malignant tumor is chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

8. The composition described in claim 7, wherein the B cell malignant tumor is low-tumor burden chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

9. The composition described in claim 7, wherein the B cell malignancy is high tumor burden chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

10. The composition described in claim 7, wherein the subject has previously been treated with venetoclax.

11. The composition of claim 7, wherein the B cell malignancy is relapsed or refractory (R / R) CLL / SLL.

12. The composition described in claim 7, wherein the B cell malignancy is treatment-naïve (TN) CLL / SLL.

13. The composition described in claim 6, wherein the B cell malignant tumor is mantle cell lymphoma (MCL).

14. The composition described in claim 6, wherein the B cell malignant tumor is Waldenstrom's macroglobulinemia (WM).

15. The composition described in claim 6, wherein the B cell malignant tumor has a low risk of tumor lysis syndrome (TLS).

16. The composition of claim 6, wherein the B cell malignant tumor has Bcl-2 Gly101Val mutation expression.

17. The composition of claim 1, wherein the composition is orally administered according to a daily ramp-up schedule including a first dose on day 1 of about 10, 20, 40, 80, or 160 mg / day, a second dose on day 2 of about 20, 40, 80, 160, or 320 mg / day, and daily doses from day 3 onwards of about 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg / day.

18. The composition of claim 1, wherein the composition is orally administered on a weekly ramp-up schedule lasting 5, 6, 7, 8, or 9 weeks.

19. The composition of claim 18, wherein the composition is orally administered according to a weekly ramp-up schedule lasting five weeks.

20. The composition of claim 18, wherein the weekly ramp-up schedule is about 1 mg QD in week 1, about 2 mg QD in week 2, about 5 mg QD in week 3, about 10 mg QD in week 4, about 20 mg QD in week 5, about 40 mg QD in week 6, about 80 mg QD in week 7, about 160 mg QD in week 8, and about 320 mg QD from week 9 onwards.

21. The composition of claim 1, wherein the composition is administered in combination with a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) or a pharma- ceutically acceptable salt thereof.

22. The composition according to claim 20, characterized in that (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) or a pharma- ceutically acceptable salt thereof is orally administered at a dose of 160 mg twice daily or 320 mg once daily.

23. The composition of claim 21, wherein (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound B) or a pharma- ceutically acceptable salt thereof is orally administered for 8 to 12 weeks before the Bcl-2 inhibitor is administered.

Images