B-cell malignancies treatment using bcl-2 inhibitor

Abstract

FIELD: pharmaceuticals.SUBSTANCE: method for treating a B-cell malignancy in a patient is provided, comprising administering to the patient a therapeutically effective amount of a Bcl-2 inhibitor at a daily dose of 320 mg or 640 mg, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof.EFFECT: productive treatment of B-cell malignancies.23 cl, 16 dwg, 12 tbl, 6 ex

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATION

[0002] This application claims priority and benefit from U.S. Provisional Patent Application Nos. 63 / 340,642, filed May 11, 2022, and 63 / 195,892, filed June 2, 2021, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

[0003] FIELD OF INVENTION

[0004] Disclosed herein are methods of treating a B-cell malignancy in a subject using 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 combination thereof with 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.

[0005] STATE OF THE ART

[0006] Distorted apoptosis plays a central role in tumor development, tumor maintenance, and therapeutic resistance. Apoptosis can be triggered by two main pathways: the extrinsic or death receptor-mediated pathway and the intrinsic or mitochondrial pathway (Czabotar et al 2014). It is the intrinsic pathway that is most frequently deregulated in lymphoid malignancies. Cell death mediated by this pathway is regulated by members of the B-cell lymphoma-associated protein-2 (Bcl-2) family, which is thought to contain three subfamilies. The pro-survival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1 / Bfl-1, and possibly Bcl-B) promotes cell survival by inhibiting their pro-apoptotic relatives. Proapoptotic BAX / BAK-like proteins, including BOK, are the major effectors of apoptosis, while BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are the initiators of apoptosis (Anderson et al 2014).In healthy cells, pro-survival Bcl-2 proteins bind and inhibit BAX and BAK after their partial activation, reducing the ability of BAX / BAK to oligomerize and form pores that permeabilize the mitochondrial outer membrane. BH3-only proteins are induced transcriptionally or post-transcriptionally in response to various stresses and induce apoptosis either by binding pro-survival Bcl-2 proteins, thereby releasing BAX / BAK, or by directly activating these apoptotic effectors. Different Bcl-2 family proteins have different binding specificities for each other, resulting in a complex yet ordered network of interactions that determine cell fate (Roberts 2016).

[0007] Bcl-2 is the first anti-apoptotic protein discovered in the 1980s as a result of the t(14;18) chromosomal translocation and a hallmark of FL. The Bcl-2 gene is located on chromosome 18q21.33. The Bcl-2 protein contains 239 amino acids and has a molecular mass of 26 kDa (Schenk et al 2017). Bcl-2 is widely expressed during development and becomes restricted during maturation in many tissues (Kondo et al 2008). Mice lacking Bcl-2 die from polycystic kidney disease early in life, since Bcl-2 is critical for the survival of renal epithelial progenitor cells during embryogenesis (Veis et al 1993). Bcl-2-deficient mice also have abnormally reduced numbers of mature, resting B and T lymphocytes and prematurely gray hair due to aberrant melanocyte death (Veis et al 1993, Yamamura et al 1996).Although initially thought to act as a classic growth-promoting oncogene, Bcl-2 was later shown to promote malignant cell survival by attenuating apoptosis. Transgenic mice expressing Bcl-2 panhematopoietically (VavP-BCL-2) preferentially develop follicular lymphoma, preceded by marked germinal center hyperplasia (Egle et al 2004). Mice coexpressing the BCL-2 and MYC transgenes developed lymphomas significantly faster than littermates expressing only one of these transgenes, confirming the role of BCL-2 as an oncogene (Adams and Cory 2007).

[0008] High Bcl-2 expression is almost universal in CLL, FL, MCL, and Waldenström's macroglobulinemia (WM); in contrast, Bcl-2 expression levels are somewhat more variable among multiple myeloma (MM) and significantly more variable among DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang 2017). When Bcl-2 is overexpressed, the ratio of pro- and anti-apoptotic Bcl-2 family members is disrupted, and apoptotic cell death can be prevented. Moreover, Bcl-2 protein is closely associated with chemoresistance in hematological tumors. Since Bcl-2-mediated resistance to intrinsic apoptosis is considered a key to pathogenesis, targeting Bcl-2 may improve apoptosis and overcome drug resistance in cancer therapy. Thus, Bcl-2 has become an attractive target for therapeutic strategies in cancer.

[0009] Venetoclax (ABT-199) was approved for the treatment of patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, despite high clinical activity and a favorable safety profile, patients may develop acquired resistance to venetoclax over time with chronic treatment. Blombery et al. demonstrated that the Gly101Val mutation (G101V mutation) in Bcl-2 mediates acquired refractoriness by reducing the binding affinity of venetoclax without disrupting 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 occurs primarily in patients after prolonged exposure to venetoclax monotherapy (Tausch et al 2019).

[0010] WO 2019 / 210828 A discloses a series of compounds characterized by the following formulas (III-B), (III-C), (III-D) or (III-E), or a stereoisomer or a pharmaceutically acceptable salt thereof, as Bcl-2 inhibitors.

[0011] (III-B) (III-C) (III-D) (III-E)

[0012] The compounds disclosed in WO 2019 / 210828 A are potent and selective inhibitors of the Bcl-2 protein.

[0013] BRIEF DESCRIPTION OF THE INVENTION

[0014] The inventors of the present invention found that a Bcl2 inhibitor characterized by the formula (III-B), (III-C), (III-D) or (III-E), particularly 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (compound 1) or a pharmaceutically acceptable salt thereof, exhibited potent activity in killing cells of various lymphoma and leukemia cell lines, including MV4-11 (acute myeloid leukemia, AML), OCI-LY10 (B-cell non-Hodgkin's lymphomas, B-NHL), Toledo (diffuse large B-cell lymphomas, DLBCL), DOHH2 (follicular lymphomas, FL), DHL-4 (germinal center-like B-cell diffuse large B-cell lymphomas, GCB-DLBCL), and MAVER-1 (mantle cell lymphomas, MCL). It was found that the IC values 50 are in the range from 0.6 nM to 13 nM.

[0015] The inventors of the present invention also found that a Bcl2 inhibitor characterized by formula (III-B), (III-C), (III-D) or (III-E), in particular compound 1 or a pharmaceutically acceptable salt thereof, showed significant tumor growth inhibition in cancers with high safety, including B-cell malignancies selected from non-Hodgkin's lymphoma (NHL) with an expected low risk of tumor lysis syndrome, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) with a low tumor burden, CLL / SLL with a high tumor burden, mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia (WM) or acute lymphoblastic leukemia (ALL).

[0016] Furthermore, the inventors of the present invention have found that a Bcl2 inhibitor characterized by formula (III-B), (III-C), (III-D) or (III-E), in particular compound 1 or a pharmaceutically acceptable salt thereof, in combination with a BTK inhibitor disclosed in WO2014 / 173289A, in particular (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (zanubrutinib, Compound B), causes significant inhibition of tumor growth in cancer types compared to the efficacy of each therapeutic agent as a separate agent. Furthermore, combination therapy demonstrated significant tumor growth inhibition in cancers with a high safety margin, including B-cell malignancies selected from chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) or mantle cell lymphoma (MCL).

[0017] In a first aspect, this document discloses a method for treating B-cell malignancies using a Bcl-2 inhibitor, wherein the Bcl-2 inhibitor is a compound represented by the following formulas (III-B), (III-C), (III-D) or (III-E),

[0018] (III-B), (III-C), (III-D), (III-E),

[0019] or its pharmaceutically acceptable salt or its stereoisomer,

[0020] where

[0021] R 2 in each case is independently selected from the group consisting of hydrogen, halogen and -C 1-8 alkyl optionally substituted with halogen;

[0022] R 1d in each case independently represents a halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR Ba , -SO2R Ba , -COR Ba , -CO2R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb R Bc , -NRBa R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc , -NR Ba CO2R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO2NR Bb R Bc or -NR Ba SO2R Bb ; where each specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with 1 to 4 R substituents Bd ;

[0023] each R Ba , R Bb and R Bc independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, hydroxy, -NH2 or -N(C 1-6 alkyl)2, -C 1-8alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0024] R Bd in each case independently represents hydrogen, halogen, oxo, -CN, -NO2, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0025] m represents an integer 1-4;

[0026] R 5 represents -L 5 -CyC,

[0027] where L 5 represents a direct connection, -(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 Rb ) v-1 -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a -, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -, -SO2NR a -, -NR a SO2-, -NR a S(O)2NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO- or -C(=NR a )NR b -, where t and v in each case independently represent purely 1 to 7 and one or two fragments of CR a R b in -(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 - are unsubstituted or substituted by one or more moieties selected from O, S, SO, SO2, C(O) or NR a ;

[0028] CyC is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or two R substituents 5a ;

[0029] R 5a in each case is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C(=O)OR 5b , -C(=O)NR 5b R 5c , -C(=NR 5b )NR 5c R 5d , -N(R 5b )C(=O)R 5c , -N(R 5b )C(=O)OR 5c , -N(R 5b )C(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -N(R 5b )S(O)2NR 5c R 5d , -NR 5b SO2R 5c , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or two substituents R 5e ;

[0030] where each R 5b , R 5c and R 5d independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or two substituents R 5e ;

[0031] R 5e in each case is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO2R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR5g R 5h , -N(R 5f )S(O)NR 5g R 5h , -N(R 5f )S(O)2NR 5g R 5h , -NR 5f SO2R 5g , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0032] each R 5f , R 5g and R 5h independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0033] or two adjacent R 5 on the phenyl ring together with the phenyl ring form a benzene ring, said ring is optionally substituted with halogen, oxo, cyano, -NO2, -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO2R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O)2NR 5j R 5k , -NR 5i SO2R 5k , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0034] R 5i , R 5j and R 5k independently represent hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy or -C 1-8 alkoxy;

[0035] R a , R b , R c and R d in each case independently represent hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each indicated -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently substituted with -CN, halogen, -NO2, -NR e R f , oxo, -OR e or -SR e ; And

[0036] where each R e and R f independently represents hydrogen, C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, C 2-8 alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.

[0037] In a second aspect, this document discloses a Bcl-2 inhibitor of formula (III-B), (III-C), (III-D) or (III-E) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof for use in the treatment of B-cell malignancies.

[0038] In a third aspect, this document discloses a method for treating B-cell malignancies in a subject, said 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.

[0039] In a fourth aspect, this document discloses a method for treating B-cell malignancies 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 pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B) or a pharmaceutically acceptable salt thereof.

[0040] In a fifth aspect, this document discloses the use of a pharmaceutical composition in the manufacture of a medicament for use in the treatment of B-cell malignancies, said pharmaceutical combination comprising a Bcl-2 inhibitor of formulas (III-B), (III-C), (III-D) or (III-E) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

[0041] In a sixth aspect, the present document discloses the use of a pharmaceutical combination in the manufacture of a medicament for use in treating cancer, said pharmaceutical combination comprising a Bcl-2 inhibitor or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B, zanubrutinib) or a pharmaceutically acceptable salt thereof.

[0042] In an embodiment of each of the above aspects, the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1) or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment of each of the above aspects, the B-cell malignancies are relapsed / refractory.

[0044] 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).

[0045] In one 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 (DLBCL), marginal zone lymphoma (MLZ), or transformed NHL.

[0046] In one preferred embodiment of each of the above aspects, the B-cell malignancy is chronic lymphocytic leukemia / small cell lymphocytic lymphoma (CLL / SLL) with a low tumor burden or CLL / SLL with a high tumor burden.

[0047] In one preferred embodiment of each of the above aspects, the B-cell malignancy is mantle cell lymphoma (MCL).

[0048] In one preferred embodiment of each of the above aspects, the B-cell malignancy is Waldenstrom's macroglobulinemia (WM).

[0049] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally at a dose of 1 mg once a day (1 time per day) to 640 mg 1 time per day or 20 mg 1 time per day to 640 mg 1 time per day according to a dose escalation schedule.

[0050] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally in a dose according to a daily dose escalation schedule. Preferably, the daily dose escalation schedule provides a first dose on day 1, a second dose on day 2, and a recommended dose on day 3 and onward, where the second dose on day 3 and onward is higher than the second dose on day 2, and the second dose on day 2 is 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 administered orally according to a daily dose escalation schedule that provides 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 day 3 and onward 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 day 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 day 3 and thereafter is about 40 mg, 80 mg, 160 mg, 320 mg, or 640 mg daily. Specifically, the first dose on day 1 is approximately 160 mg / day, the second dose on day 2 is approximately 320 mg / day, and the daily dose on day 3 and thereafter is approximately 640 mg daily. In some embodiments, the period of the daily dose escalation schedule lasts for two days. In some embodiments, the administration period lasts for three days or more.In some embodiments, a B-cell malignancy has a lower risk of developing TLS. In some embodiments, the B-cell malignancy is NHL (except MCL). In some preferred embodiments, the B-cell malignancy is FL, DLBCL, LMZ, or transformed NHL.

[0051] In one embodiment of each of the above aspects, the Bcl-2 inhibitor is administered orally at a dose according to a weekly dose escalation schedule. Preferably, the weekly dose escalation 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, a subsequent weekly dose escalation schedule, and a recommended dose in a given week and beyond, wherein the dose in the subsequent week is at least twice the dose of the dose in the previous week until the recommended weekly dose is reached, and the subsequent weekly dose escalation schedule is a weekly dose escalation schedule for 0, 1, 2, 3, or 4 weeks.

[0052] In some embodiments, the Bcl-2 inhibitor is administered orally in a dose according to a weekly dose escalation 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 administered orally in a weekly dose escalation schedule providing a dose step of 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, 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 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 and thereafter 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 and thereafter 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 in week 10 and thereafter is about 640 mg / day. In some embodiments, the period of the weekly dose escalation schedule lasts for five, six, seven, eight, or nine weeks. In some embodiments, the administration period lasts for six, seven, eight, nine, or ten weeks or more. In some embodiments, the B-cell malignancy is selected from CLL / MLL, MCL, or MB.In some embodiments, the B-cell malignancy is selected from low tumor burden CLL / MLL, high tumor burden CLL / MLL, or CLL / MLL with prior treatment with venetoclax, MCL, or MB.

[0053] In one embodiment of the above aspects, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B) is administered orally at a dose of 320 mg / day (160 mg twice a day or 320 mg once a day) and the Bcl-2 inhibitor is administered orally on a weekly dose escalation schedule. Preferably, compound B is administered orally starting from 8 to 12 weeks before administration of compound 1.Preferably, the weekly dose escalation schedule provides for the first dose in week 1, the second dose in week 2, the third dose in week 3, the fourth dose in week 4, the fifth dose in week 5, the subsequent weekly dose escalation schedule and the recommended dose in a given week and thereafter, wherein the dose in the subsequent week is at least double the dose of the dose in the previous week until the recommended weekly dose is reached, and the subsequent weekly dose escalation schedule is a weekly dose escalation schedule for 0, 1, 2, 3 or 4 weeks.

[0054] In some embodiments, the Bcl-2 inhibitor is administered orally in a dose according to a weekly dose escalation 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 administered orally in a weekly dose escalation schedule providing a dose step of 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, 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 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 and thereafter 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 and thereafter 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 in week 10 and thereafter is about 640 mg / day. In some embodiments, the period of the weekly dose escalation schedule lasts for five, six, seven, eight, or nine weeks. In some embodiments, the administration period lasts for six, seven, eight, nine, or ten weeks or more.In some embodiments, the B-cell malignancy is CLL / MLL, including R / R CLL / MLL or naive CLL / MLL or MCL.

[0055] In monotherapy, among patients with R / R NHL, significant reduction in SPD from baseline was observed in most patients, two of 20 (10%) patients demonstrated a response, including 1 PR at 160 mg and 1 CR at 320 mg, and 23 patients discontinued treatment due to disease progression (n=20), adverse events (n=1), and other reasons or physician's decision (n=2); among patients with R / R CF, one of 2 (50%) achieved a minor response at 80 mg. In combination therapy, among patients with R / R MCL, five of 10 (50%) patients achieved a PR or better at 80 or 100 mg, including 1 CR at each dose level, and 1 R / R MCL was discontinued due to disease progression. In addition, among patients with CLL / MLL, a significant decrease in absolute lymphocyte count (ALC) was observed in all CLL patients during the dose escalation period in both monotherapy and combination therapy, with a decrease in lymphocyte count observed as early as the 1 mg dose level.With monotherapy, four of 6 (67%) patients achieved a partial response with lymphocytosis (PR-L) or improvement at 80 or 160 mg of compound 1. With combination therapy, sixteen of 20 (80%) patients with R / R CLL / MLL achieved PR-L or improvement at dose levels ranging from 40 to 320 mg, and 1 patient with R / R CLL / MLL was discontinued due to disease progression.

[0056] Results obtained in 78 patients indicate that compound 1 is well tolerated in patients with CLL or NHL at the dose levels tested. Dose escalation was completed for patients receiving NHL monotherapy, with only 1 DLT observed and MTD not reached, and among patients receiving CLL monotherapy, only 1 DLT was observed. Grade ≥3 adverse events were infrequent and manageable.

[0057] The data obtained indicate 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 observed in only 1 patient with CLL at high risk of TLS receiving monotherapy.

[0058] Furthermore, transient neutropenia was the most common grade ≥3 AE, and significant reduction in ALC was observed during dose escalation in CLL patients, with promising early response rates in R / R CLL patients.

[0059] In one embodiment, each of the above aspects of Bcl-2 is orally administered once a day (1 time per day).

[0060] In one embodiment of each of the above aspects, the B-cell malignancy has Bcl-2 expression.

[0061] In one embodiment of each of the above aspects, the B-cell malignancy has expression of the Bcl-2 Gly101Val mutation.

[0062] BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0063] Fig. 1A and 1B show the efficacy of Bcl-2 inhibitors in the RS4;11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model. ####p< 0.0001 compared with vehicle medium by one-way ANOVA (Dunnett's multiple comparison test).

[0064] *p< 0.05, ****p< 0.0001 compared with venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; once a day, once a day; twice a day, twice a day; orally, orally via tube.

[0065] Fig. 2A and 2B show the efficacy of Bcl-2 inhibitors in the MAVER-1 subcutaneous mantle cell lymphoma (MCL) xenograft model. ##p< 0.01, ####p< 0.0001 compared with vehicle by one-way ANOVA (Dunnett's multiple comparison test). ****p< 0.0001 compared with vehicle by one-way ANOVA (Tukey's multiple comparison test).

[0066] Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; 1 time per day, once a day; 2 times per day, twice a day; orally, orally through a tube.

[0067] Figures 3A and 3B show the efficacy of Bcl-2 inhibitors in the Toledo subcutaneous xenograft model of diffuse large cell lymphoma (DLBCL). ###p< 0.001, ####p< 0.0001 compared with vehicle by one-way ANOVA (Dunnett's multiple comparison test).

[0068] **p< 0.01, ****p< 0.0001 compared with venetoclax by one-way ANOVA (Tukey's multiple comparison test). Abbreviations: ANOVA, analysis of variance; SEM, standard error of the mean; once daily, once a day; twice daily, twice a day; orally, orally via tube.

[0069] Fig. 4A and 4B show the efficacy of Bcl-2 inhibitors in the RS4;11 Bcl-2G101V KI subcutaneous xenograft model of acute lymphoblastic leukemia (ALL). ## p< 0.01, #### p< 0.0001 compared with vehicle by one-way ANOVA; **** p< 0.0001 compared with venetoclax by one-way ANOVA.

[0070] Fig. 5A-5D show the effects of compound 1 (Bcl-2 inhibitor) and compound B (BTK inhibitor) on tumor growth in the human JeKo-1 MCL xenograft model. *p< 0.05, ***p< 0.001, ****p< 0.0001 compared with the combination treatment group by one-way ANOVA test.

[0071] Figure 6A shows treatment-emergent AEs, regardless of causality, that occurred in at least 2 patients receiving (A) monotherapy (N=25) or (B) combination therapy (N=11). In Figure 6A: a Neutropenia combines "decreased neutrophil count" and "neutropenia"; b Thrombocytopenia combines "decreased platelet count" and "thrombocytopenia"; and ALT=alanine transaminase.

[0072] Fig. 6B shows the treatment duration and best response. Fig. 6B: a Treatment duration is 8-12 weeks of zanubrutinib monotherapy before starting Compound 1+zanubrutinib; nPR=nodular partial response; PD=disease progression; PR=partial response; PR-L=PR with lymphocytosis; and SD=stable disease.

[0073] Fig. 6C shows the change in SPD among patients with NHL a . In Fig. 6C, aAll patients in cohort 1A who had a post-baseline CT scan at the time of data cutoff were included (n=11); CT=computed tomography; DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; LMZ=marginal zone lymphoma; and SPD=sum of the product of the perpendicular diameters.

[0074] Fig. 6D shows the decrease in ALC during the increase in patients with CLL a . In Fig. 6D, aThe metrics reflect the recovery of ALC above the ULN (4 x 109 / L) from baseline before Compound 1 administration before the next dose escalation (or 1 week after the target dose) on a per-dose basis. Patients received each Compound 1 dose level for 1 week before escalating to the next dose. Patients receiving combination therapy also received zanubrutinib during the Compound 1 dose escalation, beginning 8-12 weeks before the first Compound 1 dose (note: one patient with normal baseline ALC values ​​was excluded from the monotherapy data).

[0075] Definitions

[0076] Unless otherwise defined in this document, all other technical and scientific terms used in this document have the meaning generally understood by a person of ordinary skill in the technical field.

[0077] As used in this document, including the appended claims, the singular forms "a," "an," and "the" include their corresponding plural forms unless the context clearly dictates otherwise.

[0078] The term "or" is used to mean the term "and / or" and is used interchangeably with the term "and / or" unless the context clearly requires otherwise.

[0079] As used herein, the term "anti-cancer agent" refers to any agent that can be used to treat a cellular proliferative disorder such as cancer, including, but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.

[0080] As used herein, the terms "administering," "administering," "treating," and "treating" when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid mean contacting an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treating a cell includes contacting a reagent with the cell, as well as contacting a reagent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also mean treating in vitro and ex vivo, for example, a cell, with a reagent, diagnostic agent, binding compound, or another cell. The term "subject" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., a rat, mouse, dog, cat, rabbit), and most preferably a human.Treating any disease or disorder refers, in one aspect, to ameliorating the disease or disorder (i.e., slowing, halting, or reducing the progression of the disease or at least one of its clinical symptoms). In another aspect, "treating," "treating," or "treating" refers to alleviating or improving at least one physical parameter, including those that may not be perceptible to the patient. In yet another aspect, "treating," "treating," or "treating" refers to modulating the disease or disorder, either physically (e.g., stabilizing a noticeable symptom), physiologically (e.g., stabilizing a physical parameter), or both physically and physiologically. In yet another aspect, "treating," "treating," or "treating" refers to preventing or delaying the onset, development, or progression of the disease or disorder.

[0081] As used herein, the term "subject" is a mammal, such as a primate, preferably a higher primate, such as a human (e.g., a patient suffering from or at risk of developing a disease described herein). In some embodiments, the subject is a human or a patient.

[0082] The terms "cancer" or "tumor" as used herein have the broadest meaning, as understood in the art, and refer to a physiological condition in mammals typically characterized by unregulated cell growth. In the context of the present invention, cancer is not limited to a specific type or location.

[0083] As used herein, the term "therapeutically effective amount" refers to an amount of a Bcl-2 inhibitor that, when administered to a subject for the treatment of a disease or at least one clinical symptom of the disease or disorder, is sufficient to provide such treatment of the disease, disorder, or symptom. A "therapeutically effective amount" may vary depending on the agent, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any particular case may be obvious to those skilled in the art or can be determined by routine experimentation.In the case of combination therapy, "therapeutically effective amount" refers to the total number of entities of the combination to effectively treat a disease, disorder, or condition.

[0084] As used herein, the term "dose escalation regimen" or "dose escalation schedule" refers to a dosing regimen or schedule wherein the active ingredient of interest is administered at a dose increased on a regular basis, such as daily or weekly, over a period of time, such as over several days or several weeks, and then administered at the recommended dose (daily or weekly).

[0085] DETAILED DESCRIPTION OF THE ESSENCE OF THE INVENTION

[0086] The present invention relates to a method for treating B-cell malignancy in a subject using 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 pharmaceutically acceptable salt thereof.

[0087] The present invention also relates to a method for treating B-cell malignancies 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 pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B) or a pharmaceutically acceptable salt thereof.

[0088] Bcl-2 inhibitor

[0089] The Bcl-2 inhibitor in the present invention is a compound represented by the following formulas (III-B), (III-C), (III-D) or (III-E),

[0090] (III-B), (III-C), (III-D), (III-E),

[0091] or its pharmaceutically acceptable salt or its stereoisomer,

[0092] where

[0093] R 2 in each case is independently selected from the group consisting of hydrogen, halogen and -C 1-8 alkyl optionally substituted with halogen;

[0094] R 1d in each case independently represents a halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO2, -OR Ba , -SO2R Ba , -COR Ba , -CO2R Ba , -CONR Ba R Bb , -C(=NR Ba )NR Bb R Bc , -NR Ba R Bb , -NR Ba COR Bb , -NR Ba CONR Bb R Bc, -NR Ba CO2R Bb , -NR Ba SONR Bb R Bc , -NR Ba SO2NR Bb R Bc or -NR Ba SO2R Bb ; where each specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with 1 to 4 R substituents Bd ;

[0095] each R Ba , R Bb and R Bc independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with halogen, hydroxy, -NH2 or -N(C 1-6 alkyl)2, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0096] R Bdin each case independently represents hydrogen, halogen, oxo, -CN, -NO2, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy, -C 1-8 alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0097] m represents an integer 1-4;

[0098] R 5 represents -L 5 -CyC,

[0099] where L 5 represents a direct connection, -(CR a R b ) t -, -(CR a R b ) t-1 -(CR c =CR d )-(CR a R b ) v-1 -, -(CR a R b ) t-1 -(C≡C)-(CR a R b ) v-1 -, -O-, -S-, -S(O)-, -SO2-, -C(O)-, C(O)O-, -OC(O)-, -NR a-, -C(O)NR a -, -NR a C(O)-, -NR a C(O)O-, -NR a C(O)NR b -, -SO2NR a -, -NR a SO2-, -NR a S(O)2NR b -, -NR a S(O)NR b -, -C(O)NR a SO2-, -C(O)NR a SO- or -C(=NR a )NR b -, where t and v in each case independently represent purely 1 to 7 and one or two fragments of CR a R b in -(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 - are unsubstituted or substituted by one or more moieties selected from O, S, SO, SO2, C(O) or NR a ;

[0100] CyC is cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is optionally substituted with one or two R substituents 5a ;

[0101] R 5a in each case is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR 5b , -SR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C(=O)OR 5b , -C(=O)NR 5b R 5c , -C(=NR 5b )NR 5c R 5d , -N(R 5b )C(=O)R 5c , -N(R 5b )C(=O)OR 5c , -N(R 5b )C(O)NR 5c R 5d , -N(R 5b )S(O)NR 5c R 5d , -N(R 5b )S(O)2NR 5c R 5d , -NR 5b SO2R 5c , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or two substituents R 5e ;

[0102] where each R 5b , R 5c and R 5d independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or two substituents R 5e ;

[0103] R 5e in each case is independently selected from hydrogen, halogen, cyano, oxo, -NO2, -OR 5f , -SR 5f , -NR 5f R 5g , -COR 5f , -SO2R 5f , -C(=O)OR 5f , -C(=O)NR 5f R 5g , -C(=NR 5f )NR 5g R 5h , -N(R 5f )C(=O)R 5g , -N(R 5f )C(=O)OR 5g , -N(R 5f )C(O)NR5g R 5h , -N(R 5f )S(O)NR 5g R 5h , -N(R 5f )S(O)2NR 5g R 5h , -NR 5f SO2R 5g , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0104] each R 5f , R 5g and R 5h independently represents hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0105] or two adjacent R 5 on the phenyl ring together with the phenyl ring form a benzene ring, said ring is optionally substituted with halogen, oxo, cyano, -NO2, -OR 5i , -SR 5i , -NR 5i R 5j , -COR 5i , -SO2R 5i , -C(=O)OR 5i , -C(=O)NR 5i R 5j , -C(=NR 5i )NR 5j R 5k , -N(R 5i )C(=O)R 5j , -N(R 5i )C(=O)OR5j , -N(R 5i )C(O)NR 5j R 5k , -N(R 5i )S(O)NR 5j R 5k , -N(R 5i )S(O)2NR 5j R 5k , -NR 5i SO2R 5k , -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0106] R 5i , R 5j and R 5k independently represent hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of the specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with halogen, hydroxy or -C 1-8 alkoxy;

[0107] R a , R b , R c and R d in each case independently represent hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each indicated -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is independently substituted with -CN, halogen, -NO2, -NR e R f , oxo, -OR e or -SR e ; And

[0108] where each R e and R f independently represents hydrogen, C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, C 2-8 alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl.

[0109] In some embodiments, R 2 is hydrogen.

[0110] In some embodiments, R 1d, if substituted on the phenyl group at position 2 of ring B (including aziridin-1-yl, azetedin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl or azocan-1-yl, preferably pyrrolidin-1-yl group), independently represents halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , -SO2R Ba , -CONR Ba R Bb , -NO2, -NR Ba R Bb , -NR Ba COR Bb or -NR Ba SO2R Bb ; where each specified -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is independently optionally substituted with 1 to 4 R substituents Bd , as defined in formulas (III-B), (III-C), (III-D) or (III-E), preferably 1 or 2 substituents R Bd , as defined in formulas (III-B), (III-C), (III-D), or (III-E). In another aspect, one R1d is located in position 2 of the phenyl ring in position 2 of ring B.

[0111] In some embodiments, R 1d represents methyl, ethyl, isopropyl, propyl or methoxymethyl or two methyls in position of the phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.

[0112] In some embodiments, the 2-(2-substituted phenyl)pyrrolidin-1-yl moiety in formulas (III-B), (III-C), (III-D), or (III-E) is selected from the group consisting of:

[0113]

[0114] And

[0115] In some embodiments, m is 1; and L 5 represents a direct connection, -(CR a R b ) t - or -NR a-, where t is a number from 1 to 7 and one or two CR a R b fragment in -(CR a R b ) t - are unsubstituted or substituted by one or more moieties selected from O or NR a , where R a and R b defined in formulas (III-B), (III-C), (III-D) or (III-E).

[0116] In some embodiments, L 5 represents a direct connection, -(CR a R b ) 1-4 -, -O-(CR a R b ) 1-3 -, -NH-(CR a R b ) 1-3 or -NH-, where R a and R b are defined in formulas (III-B), (III-C), (III-D) or (III-E), thus, -L 5 -CyC fragment is CyC, -(CR a R b ) 1-4 -CyC, -O-(CR a R b ) 1-3 -CyC, -NH-(CR a R b ) 1-3 -CyC or -NH-CyC, respectively. More preferably, L 5represents a direct bond, -(CH2) 1-4 -, -O-(CH2) 1-3 -, -NH-(CR a R b )-(CH2)2- or -NH-, where R a represents hydrogen and R b represents C 1-8 alkyl, optionally substituted by phenyl-S-, thus -L 5 -CyC fragment is CyC, -(CH2) 1-4 -CyC, -O-(CH2) 1-3 -CyC, -NH-(CR a R b )-(CH2)2-CyC or -NH-CyC, respectively. More preferably, L 5 represents a direct bond, -CH2-, -O-CH2-, -NH-CH2-, or -NH-, thus -L 5 The -CyC moiety is CyC, -CH2-CyC, -O-CH2-CyC, -NH-CH2-CyC, or -NH-CyC, respectively.

[0117] In some embodiments, CyC is cycloalkyl or heterocyclyl, each of which is optionally substituted with one or two R substituents 5a ;

[0118] R 5a independently selected from hydrogen, halogen, cyano, oxo, -OR 5b , -NR5b R 5c , -COR 5b , -SO2R 5b , -C 1-8 alkyl, -C 2-8 alkynyl, -cycloalkyl or heterocyclyl, each of the specified -C 1-8 alkyl and heterocyclyl optionally substituted with one or two substituents R 5e , which are selected from hydrogen, halogen, cyano, -OR 5f , -C 1-8 alkyl, -cycloalkyl or heterocyclyl;

[0119] where R 5b and R 5c each independently represents hydrogen, -C 1-8 alkyl or heterocyclyl indicated by -C 1-8 alkyl optionally substituted with one or two substituents R 5e , which represent hydrogen, -NR 5f R 5g or -cycloalkyl;

[0120] each R 5f and R 5g independently represents hydrogen or -C 1-8 alkyl;

[0121] or two adjacent R 5on the phenyl ring together with the phenyl ring form a benzene ring, said ring optionally substituted with heteroaryl.

[0122] In some embodiments, CyC is a cycloalkyl selected from monocyclic C 3-8 cycloalkyl or bridged cycloalkyl ( ), each of them is optionally substituted with one or two substituents R 5a . Preferably, CyC is cyclopentyl or cyclohexyl, each optionally substituted with one or two substituents R 5a .

[0123] In some embodiments, CyC is a heterocyclyl selected from:

[0124] monocyclic 4- to 9-membered heterocyclyl groups containing one nitrogen, or oxygen, or sulfur heteroatom as ring members;

[0125] monocyclic 4- to 9-membered heterocyclyl groups containing two heteroatoms selected from oxygen, sulfur or nitrogen as ring members; or

[0126] 5-20 membered spiroheterocyclyl containing one or two heteroatoms selected from nitrogen, sulfur or oxygen as ring members,

[0127] each of which is optionally substituted with one or two R 5a .

[0128] In some embodiments, CyC is a monocyclic 4-6-membered heterocyclyl group containing one nitrogen, or oxygen, or sulfur heteroatom as ring members. 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.

[0129] 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 piperazinyl. Even more preferably, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl.

[0130] In some embodiments, R 5a independently selected from hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO2R 5b , -C 1-8 alkyl, -C 2-8 alkynyl, monocyclic C 3-8 cycloalkyl or a monocyclic 4-9-membered heterocyclyl group containing one or two heteroatoms selected from a nitrogen, or oxygen, or sulfur heteroatom as ring members, each of the said -C 1-8alkyl and a monocyclic 4-9-membered heterocyclyl group optionally substituted with one or two substituents R 5e ; preferably cycloalkyl as R 5a represents C 3-6 cycloalkyl; more preferably cyclopropyl; preferably heterocyclyl as R 5a represents 4- to 6-membered heterocyclyl groups containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatom as ring members; more preferably heterocyclyl as R 5a represents oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or morpholinyl; even more preferably heterocyclyl as R 5a is oxetan-3-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl or morphin-4-yl.

[0131] In some embodiments, heterocyclyl as R 5eis a monocyclic 4- to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen, oxygen, or sulfur heteroatoms as ring members.

[0132] In some embodiments, heterocyclyl as R 5e is tetrahydropyran-4-yl.

[0133] In some embodiments, R 5a represents -NR 5b R 5c , where R 5b represents hydrogen and R 5c is a heterocyclyl.

[0134] In some embodiments, R 5a represents -NR 5b R 5c , where R 5b represents hydrogen and R 5c is tetrahydropyran-4-yl.

[0135] In some embodiments, R 5a represents -NR 5b R 5c , where each R 5b and R 5c independently represents hydrogen or -C 1-6alkyl substituted by cycloalkyl, preferably -C 1-6 alkyl substituted by monocyclic C 3-8 cycloalkyl.

[0136] In some embodiments, R 5a represents -OR 5b or -SO2R 5b , where R 5b represents hydrogen or C 1-8 alkyl, preferably methyl.

[0137] In some embodiments, R 5a represents -COR 5b , where R 5b represents hydrogen or C 1-8 alkyl, optionally substituted with -NR 5f R 5g , where each R 5f and R 5g independently represents hydrogen or C 1-8 alkyl, preferably methyl.

[0138] In some embodiments, two adjacent R 5 on the phenyl ring together with the phenyl ring form indazolyl, which is substituted by tetrahydropyranyl.

[0139] In some embodiments, m is 1 and R 5represents -L 5 -CyC selected from the group consisting of:

[0140]

[0141]

[0142]

[0143] In some embodiments, m is 1 and R 5 represents , , , .

[0144] In some embodiments, the Bcl-2 inhibitor in the present invention is selected from the group consisting of the following:

[0145] 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;

[0146] (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;

[0147] (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;

[0148] (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;

[0149] (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;

[0150] 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;

[0151] (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;

[0152] (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;

[0153] 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;

[0154] (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;

[0155] (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;

[0156] (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;

[0157] (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;

[0158] (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;

[0159] (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;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] (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;

[0164] (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;

[0165] 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;

[0166] 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;

[0167] (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;

[0168] 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;

[0169] 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;

[0170] (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;

[0171] (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;

[0172] 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;

[0173] 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;

[0174] 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;

[0175] 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;

[0176] 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;

[0177] (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;

[0178] 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;

[0179] (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;

[0180] (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;

[0181] (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;

[0182] (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;

[0183] (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;

[0184] (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;

[0185] (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;

[0186] (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;

[0187] (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;

[0188] 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;

[0189] 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;

[0190] 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;

[0191] (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;

[0192] (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;

[0193] (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;

[0194] (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;

[0195] 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;

[0196] 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;

[0197] (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;

[0198] (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;

[0199] 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;

[0200] (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;

[0201] (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;

[0202] 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;

[0203] 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;

[0204] 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;

[0205] 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;

[0206] 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;

[0207] 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;

[0208] 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;

[0209] 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;

[0210] 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;

[0211] 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;

[0212] 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;

[0213] 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;

[0214] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((4-(((((1s,4s) or (1r,4r))-4-((dimethyl(oxo)-l6-sulfaneylidene)amino)cyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;

[0215] 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-((S)-2-(2-cyclopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-(methyl(3-nitro-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)(oxo)-l6-sulfaneylidene)benzamide;

[0216] 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;

[0217] (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;

[0218] 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;

[0219] 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;

[0220] 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;

[0221] 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;

[0222] 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;

[0223] 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;

[0224] 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;

[0225] 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;

[0226] 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;

[0227] 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;

[0228] 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;

[0229] 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;

[0230] N-((4-((((S)-1,4-dioxan-2-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-((1H-pyrrolo[2,3-b]p iridin-5-yl)oxy)-4-(6-((S)-2-(2-ethylphenyl)pyrrolidin-1-yl)-2-azaspiro[3.3]heptan-2-yl)benzamide;

[0231] (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;

[0232] (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;

[0233] (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;

[0234] 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;

[0235] 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;

[0236] (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;

[0237] 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;

[0238] 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;

[0239] 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;

[0240] 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;

[0241] 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;

[0242] (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;

[0243] 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;

[0244] 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

[0245] 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;

[0246] or a pharmaceutically acceptable salt or stereoisomer thereof.

[0247] In some embodiments, the Bcl-2 inhibitor in the present invention is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (Compound 1) or a pharmaceutically acceptable salt thereof.

[0248] Obtaining Bcl-2 inhibitors

[0249] All Bcl-2 inhibitors of 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 produced by the method disclosed in International Publication WO2019 / 210828A1.

[0250] Getting connection 1

[0251] Step 1: 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride

[0252] 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 conc. HCl (350 mL, 4.18 mol) at room temperature, and stirred for 4 h. After concentration in vacuo, MeOH (750 mL) was added to the residue, and then the resulting mixture was concentrated in vacuo (this treatment was repeated twice). The brown residue was suspended in EA (1250 mL) and stirred for 1 h. The solid residue was filtered and dried in vacuo to give the title product as an off-white powder (350 g, yield: 76.0%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 3.03 (s, 6 H), 2.96-2.89 (m, 4 H), 1.93 (s, 4 H), 1.74-1.67 (m, 4 H). MS (EIR, m / e) [M+1] + 186.0.

[0253] 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

[0254] A mixture of methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoate (100 g), 2,2-dimethoxy-7-azaspiro[3.5]nonane hydrochloride (116 g, 1.5 equiv), and DBU (160 g, 3.0 equiv) in NMP (500 mL) was stirred for 16 h at 85°C. After completion of the reaction, the mixture was cooled to 50 ± 5°C, and citric acid in water (2%, 5 L) was added dropwise to the system under stirring. After filtration, the precipitate was collected and dissolved in DCM (1.5 L). The crude product solution was washed with citric acid in water (2%, 1.5 L), saturated aq. NaHCO3 (1.5 L) and 15% aq. NaCl (1.5 L) were added and then dried over anhydrous Na2SO4. Silica gel (100 g) was added to the crude product solution with stirring and then filtered. The filtrate was concentrated to 300 mL. MTBE (500 mL) was poured into the system. After stirring for 2 h, the precipitate was collected by filtration and dried under vacuum to give an off-white solid (192 g, yield: 72.1%). 1H NMR (400 MHz, DMSO-d6) δ m. d.: 11.63 (s, 1H), 8.00 (d,J=2.4 Hz, 1H), 7.76 (d,J=9.2 Hz, 1H), 7.47 (t,J=3.2 Hz, 1H), 7.42 (d,J=2.4 Hz, 1H, 1H), 4.42 (d,J=2.4 Hz, 1H, 799), Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). MS (EIR, m / e) [M+1] + 451.9.

[0255] Step 3: Methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate

[0256] 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 the mixture was stirred overnight. After completion of the reaction, the mixture was cooled to 10 °C and adjusted to pH 8-9 with aqueous NaOH (4 M) under stirring. The organic phase was separated and washed with 15% aq. NaCl (1 L), then washed with H2O (1 L). Then, the organic phase was concentrated to 500 mL, MTBE (1 L) was poured into the solution, and then the system was concentrated to 500 mL (this treatment was repeated 3 times). The resulting system was stirred for 0.5 h. After filtration, the precipitate was collected and then dried under vacuum to yield the title product as a white solid (152 g, yield: 96.23%). 1H NMR (400 MHz, DMSO-d6) δ m. d.: 11.64 (s, 1H), 8.02 (d,J=2.4 Hz, 1H), 7.78 (d,J=9.2 Hz, 1H), 7.47 (t,J=3.2 Hz, 1H), 7.44 (d,J=2.4 Hz, 1H, 83), Hz, 1H), 6.43 (d,J=2.4 Hz, 1H), 6.38-6.36 (m, 1H), 3.65 (s, 3H), 3.24-3.21 (m, 4H), 2.80 (s, 4H), 1.70-1.67 (m, 4H). MS (EIR, m / e) [M+1] + 405.9.

[0257] Step 4: (S)-tert-butyl-2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate

[0258] To a mixture of (S)-tert-butyl 2-(2-bromophenyl)pyrrolidine-1-carboxylate (50 g, 153.3 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (38.6 g, 229.9 mmol) in dioxane (500 mL) and H2O (50 mL) were added Cs2CO3 (100 g, 305 mmol) and Pd(dppf)Cl2 (6.6 g, 7.5 mmol). The mixture was stirred at 100°C for 8 h. TLC showed that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE / EA (v / v)=100 / 1-10 / 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.

[0259] Step 5: (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate

[0260] To a solution of (S)-tert-butyl 2-(2-(prop-1-en-2-yl)phenyl)pyrrolidine-1-carboxylate (30 g, 104.39 mmol) in MeOH (500 mL) was added Pd / C (10 g, 10%), and the mixture was stirred at 20°C under H2 (15 psi) for 12 h. TLC showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to give (S)-tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (60 g, crude), which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm: 7.39-6.90 (m, 4H), 5.36-5.04 (m, 1H), 3.77-3.52 (m, 2H), 3.20-3.17 (m, 1H), 2.47-2.24 (m, 1H), 1.96-1.65 (m, 3H), 1.54-1.38 (m, 2H), 1.31-1.22 (m, 8H), 1.17 (s, 7H).

[0261] Step 6: (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride

[0262] To a solution of tert-butyl 2-(2-isopropylphenyl)pyrrolidine-1-carboxylate (55 g, 190 mmol) in DCM (50 mL) was added dropwise HCl in 1,4-dioxane (4 M, 142 mL, 570 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting residue was suspended with EA (100 mL), filtered, and dried in vacuo to give (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride 26 g (yield: 60.4%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.93 (s, 1H), 8.81 (s, 1H), 7.63-7.57 (m, 1H), 7.41-7.34 (m, 2H), 7.32-7.24 (m, 1H), 4.91-4.75 (m, 1H), 3.47-3.35 (m, 1H), 3.31-3.25 (m, 1H), 2.40-2.21 (m, 1H), 2.19-1.86 (m, 3H), 1.25 (d, J=6.7 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). MS (EIR, m / e) [M+1] + 190.0.

[0263] 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

[0264] A mixture of (S)-2-(2-isopropylphenyl)pyrrolidine hydrochloride (120 g, 0.535 mol) and methyl 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-oxo-7-azaspiro[3.5]nonan-7-yl)benzoate (218 g, 0.509 mol) in DCM (2.2 L) was charged into a reactor. The temperature was controlled below 30°C, and NaBH(OAc)3 (216 g, 1.018 mol) was added into the reactor in 5-6 portions. The reaction mixture was then stirred at room temperature and monitored by TLC. After complete consumption of the ketone starting material, the mixture was adjusted to pH 4~5 with dilute HCl (0.5 M). The separated organic phase was washed with H2O (600 mL × 2), and then washed with aq. NaHCO3 (600 mL × 2), saturated aq. NaCl (600 mL). The organic phase was collected, then dried over anhydrous Na2SO4 and concentrated. 256 g of an off-white solid was obtained as a crude product, which was used directly in the next step. MS (EIR, m / e) [M+1] + 579.0.

[0265] Step 8: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0266] To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aq. NaOH (3.5 M). It was stirred at room temperature overnight. After removing THF and MeOH in vacuo, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH=5~6 with 3 N HCl acid at room temperature with stirring. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%). 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d,J=8.0 Hz, 1H), 7.56-7.40 (m, 2H), 7.35 (s, 1H), 7.27-7.04 (m, 3H), 6.68 (d,J=8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32-3.26 (m, 1H), 3.10-3.04 (m, 4H), 2.35-2.30 (m, 1H), 2.9-2.15 (m, 1 H), 1.74-1.64 (m, 4H), 1.52-1.37 (m, 6H), 1.28-1.06 (m, 6H). MS (EIR, m / e) [M+1] + 564.9.

[0267] 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

[0268] A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol), and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After complete consumption of the starting material (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, the reaction mixture was heated to ~35°C and N 1 ,N 1-dimethylethane-1,2-diamine (17.2 g, 195 mmol) was added in one portion. The reaction mixture was stirred for another 12 h. The mixture was washed twice with 10 wt % aq. AcOH solution (300 mL × 2) and then washed with saturated aq. NaHCO3 (300 mL × 2). The organic layer was collected and concentrated to about 90 mL. 22 g of silica gel was added and stirred for 2 h. After filtration, 180 mL of EA was added to the filtrate with reflux and stirred for 5 h. After cooling the mixture to room temperature, the precipitated substances were filtered, and then the wet cake was washed twice with EA (180 mL). After drying in vacuo at 80-90 °C, the desired compound (48 g, yield: 69.5%) was obtained. 1H NMR (DMSO-d6) δ m. d.: 11.65 (s, 1H), 11.11 (width, 1H), 8.58-8.39 (m, 2H), 8.00 (d,J=2.8 Hz, 1H), 7.74 (d,J=8.8 Hz, 1H), 7.57-7.37 (m, 7.30 Hz), 3H), 7.00 (d,J=9.2 Hz, 1H), 6.65 (d,J=1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.8-8, 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.44-1.26 (m, 7H), 1.19 (d,J=8.0 Hz, 3H), 1.14 (d,J=8.0 Hz, 3H), 1.10 (s, 4H). MS (EIR, m / e) [M+1] + 889.9.

[0269] Treatment Methods

[0270] In one aspect, the present invention provides a method for treating cancer. In certain aspects, the method comprises administering to a patient in need an effective amount of compound 1. The cancer is a B-cell malignancy selected from the group consisting of non-Hodgkin's lymphoma (NHL) with an expected low risk of tumor lysis syndrome, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) with a low tumor burden, CLL / SLL with a high tumor burden, mantle cell lymphoma (MCL), and Waldenstrom's macroglobulinemia (WM). In some embodiments, the B-cell malignancies are relapsed / refractory.

[0271] Compound 1 can be administered by any suitable route, including oral, parenteral, pulmonary, and intranasal administration, and, if needed for local treatment, intralesional administration. Dosing can be carried out by any suitable route. Various dosing regimens are contemplated herein, including, but not limited to, single or multiple administrations at different time points, bolus administration, and pulse infusion.

[0272] Compound 1 will be formulated, dosed, and administered in accordance with good medical practice. Factors to be considered in this context include the specific disease 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 agent, the route of administration, the regimen of administration, and other factors known to practitioners. Compound 1 is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of compound 1 in the formulation, the type of disorder or treatment, and other factors discussed above.

[0273] For the prevention or treatment of a disease, the appropriate dosage of Compound 1 will depend on the type of disease to be treated, the severity and course of the disease, whether Compound 1 is administered for prophylactic or therapeutic purposes, the previous therapy, the patient's condition, the 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 treatment courses.

[0274] EXAMPLES

[0275] The present invention is further disclosed without limitation by the following examples illustrating the same.

[0276] Case 1: Study on the efficacy of Bcl-2 inhibitors in the RS4;11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model

[0277] 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). The cells were grown in RPMI 1640 medium (Corning, Cat. No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Cat. No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Cat. No. 15140-122). RS4;11 cells were maintained as cell suspension cultures at 37ºC in a 5% CO2 atmosphere. Five- to six-week-old female NCG mice were purchased from the Gempharmatech Information Technology Center. All animals were maintained under specific pathogen-free (SPF) conditions with full barrier conditions and free access to food and water. Mice were housed in groups under a 12-hour light-dark cycle (lights on at 8:00 a.m.), at a temperature of 20-26ºC and a humidity of 37-62% in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.).Mice were fed with complete pelleted feed sterilized by Co60 irradiation (Beijing Ke Ao Xie Li Feed Co., Ltd.).

[0278] On the day of implantation, RS4;11 cells were harvested and resuspended in an appropriate volume of cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to a final concentration of 5×10 7 cells / ml. Before inoculation, resuspended cells were placed on ice. Before cell inoculation, the right anterior lateral region of each mouse was cleaned with 75% ethanol. Each animal was injected subcutaneously with 1×10 7 cells in 200 μl of cell suspension into the right anterior phalanx. After implantation, the primary tumor volume was measured in two dimensions using calipers.

[0279] The animals were randomly divided into 10 groups of 10 mice per group depending on body weight and tumor volume (100 mm 3 -200 mm 3). The groups consisted of vehicle, 5, 15, 50 mg / kg venetoclax once daily, 5, 15, 50 mg / kg compound 1 once daily, and 2.5, 7.5, 25 mg / kg compound 1 twice daily. The drugs were administered orally through a gavage tube (PO) at a volume of 10 ml / kg body weight. Body weight was determined immediately before dosing, and the dosing volume was adjusted accordingly.

[0280] Individual body weights were recorded twice weekly, and mice were observed daily for clinical signs of toxicity throughout the study period. Mice were euthanized using carbon dioxide when tumor volume reached 2000 mm. 3 , the tumor ulcerated or body weight loss exceeded 20%.

[0281] The tumor volume was calculated using the formula: V=0.5 × (a × b 2 ), where a and b represent the long and short diameters of the tumor, respectively.

[0282] The in vivo efficacy of compound 1 was examined and compared with 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 and 15 mg / kg, compound 1 demonstrated significantly higher efficacy than venetoclax. In the clinic, venetoclax was administered at a dose of 400 mg daily. Its clinically relevant dose in mice is approximately 15 mg / kg once daily, based on the unbound AUC. The compound 12.5 mg / kg twice daily was more active than venetoclax at a dose of 15 mg / kg once daily. Moreover, at identical total daily doses of 15 and 50 mg / kg, compound 1 exhibited equivalent antitumor activity with once-daily and twice-daily dosing. These results are presented in Figures 1A-1B.

[0283] All treatment groups had no significant effect on the body weight of animals throughout the study.

[0284] Table 1

[0285] Means Dose (mg / kg) Administration scheme Route of administration Mean tumor volume (day 42) (mm 3 ±SEM) Carrier medium Carrier medium 2 times a day × 21 Orally >2000 Compound 1 2,5 2 times a day × 42 Orally 512,5±115,9 Compound 1 7,5 2 times a day × 42 Orally 252,8±48,3 Compound 1 25 2 times a day × 42 Orally 136,6±2,2 Compound 1 5 1 time per day × 42 Orally 820,9±140,2 Compound 1 15 1 time per day × 42 Orally 312,6±57,9 Compound 1 50 1 time per day × 42 Orally 141,8±5,1 Venetoclax 5 1 time per day × 35 Orally >2000 Venetoclax 15 1 time per day × 42 Orally 1070,6±181,1 Venetoclax 50 1 time per day × 42 Orally 288,4±37,8

[0286] Case 2: Study of the Efficacy of Bcl-2 Inhibitors in the MAVER-1 Subcutaneous Xenograft Model of Mantle Cell Lymphoma (MCL)

[0287] 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). The cells were grown in RPMI 1640 medium (Corning, Cat. No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Cat. No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Cat. No. 15140-122). MAVER-1 cells were maintained as cell suspension cultures at 37ºC in a 5% CO2 atmosphere. Five- to six-week-old female NCG mice were purchased from the Gempharmatech Information Technology Center. All animals were maintained under specific pathogen-free (SPF) conditions with full barrier conditions and free access to food and water. Mice were housed in groups under a 12-hour light-dark cycle (lights on at 8:00 a.m.), at a temperature of 21-26ºC and a humidity of 44-61% in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.).Mice were fed with complete pelleted feed sterilized by Co60 irradiation (Beijing Ke Ao Xie Li Feed Co., Ltd.).

[0288] On the day of implantation, MAVER-1 cells were harvested and resuspended in an appropriate volume of cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to a final concentration of 1.5×10 7 cells / ml. Before inoculation, resuspended cells were placed on ice. Before cell inoculation, the right anterior lateral region of each mouse was cleaned with 75% ethanol. Each animal was injected subcutaneously with 3×10 6 cells in 200 μl of cell suspension into the right anterior phalanx. After implantation, the primary tumor volume was measured in two dimensions using calipers.

[0289] The animals were randomly divided into 7 groups of 10 mice per group depending on body weight and tumor volume (100 mm 3 -200 mm 3). The groups consisted of vehicle, 5, 15 mg / kg venetoclax once daily, 5, 15 mg / kg compound 1 once daily, and 2.5, 7.5 mg / kg compound 1 twice daily. The drugs were administered orally through a gavage tube (PO) at a volume of 10 ml / kg per body weight. Body weight was determined immediately before dosing, and the dosing volume was adjusted accordingly.

[0290] Individual body weights were recorded twice weekly, and mice were observed daily for clinical signs of toxicity throughout the study period. Mice were euthanized using carbon dioxide when tumor volume reached 2000 mm. 3 , the tumor ulcerated or body weight loss exceeded 20%.

[0291] The tumor volume was calculated using the formula: V=0.5 × (a × b 2), where a and b represent the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: % TGI=100 × [1- (treated t -processed t0 ) / (carrier environment t -carrier environment t0 )] (treated t=tumor volume treated at time t, treated t0=tumor volume treated at time 0, vehicle t=tumor volume treated with vehicle at time t, and vehicle t0=tumor volume treated with vehicle at time 0)

[0292] The in vivo efficacy of Compound 1 was also examined and compared with venetoclax in MAVER-1 ALL xenografts grown subcutaneously in NCG mice. Compound 1 potently suppressed tumor growth in a dose-dependent manner. The tumor growth inhibition (TGI) at day 14 for Compound 1 at 2.5 and 7.5 mg / kg twice daily and 5 and 15 mg / kg once daily was 77%, 103%, and 86%, 103%, respectively. Venetoclax at 5 and 15 mg / kg once daily achieved 38% and 91% of the TGI, respectively. At identical total daily doses of 5 and 15 mg / kg, compound 1 exhibited greater antitumor activity than venetoclax. Compound 1 at 115 mg / kg once daily and 7.5 mg / kg twice daily were equally active. These results are presented in Figures 2A–2B and Table 2.

[0293] All treatment groups had no significant effect on the body weight of animals throughout the study.

[0294] Table 2

[0295] Means Dose (mg / kg) Administration scheme Route of administration Mean tumor volume (day 14) (mm 3 ±SEM) TGI (Day 14) Carrier medium Carrier medium 2 times a day × 17 Orally 1637,7±143,0 - Compound 1 2,5 2 times a day × 17 Orally 511,5±49,9 77% Compound 1 7,5 2 times a day × 17 Orally 136,2±2,6 103% Compound 1 5 1 time per day × 17 Orally 383,5±29,6 86% Compound 1 15 1 time per day × 17 Orally 140,5±5,3 103% Venetoclax 5 1 time per day × 17 Orally 1082,1±109,4 38% Venetoclax 15 1 time per day × 17 Orally 315,4±23,1 91%

[0296] Case 3: Study of the efficacy of Bcl-2 inhibitors in the Toledo subcutaneous xenograft model of diffuse large cell lymphoma (DLBCL)

[0297] Toledo cells are of diffuse large cell lymphoma (DLBCL) origin and were obtained from the American Type Culture Collection (ATCC CRL-2631, Manassas, VA, DC, USA). The cells were grown in RPMI 1640 medium (Corning, Cat. No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Cat. No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Cat. No. 15140-122). Toledo cells were maintained as cell suspension cultures at 37ºC in an atmosphere of 5% CO2. Five- to six-week-old female NCG mice were purchased from the Gempharmatech Information Technology Center. All animals were maintained under specific pathogen-free (SPF) conditions with full barrier conditions and free access to food and water. Mice were housed in groups under a 12-hour light-dark cycle (lights on at 8:00 a.m.), at a temperature of 21-26ºC and a humidity of 35-61% in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.).Mice were fed with complete pelleted feed sterilized by Co60 irradiation (Beijing Ke Ao Xie Li Feed Co., Ltd.).

[0298] On the day of implantation, Toledo cells were harvested and resuspended in an appropriate volume of cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to a final concentration of 1.5×10 7 cells / ml. Before inoculation, resuspended cells were placed on ice. Before cell inoculation, the right anterior lateral region of each mouse was cleaned with 75% ethanol. Each animal was injected subcutaneously with 3×10 6 cells in 200 μl of cell suspension into the right anterior phalanx. After implantation, the primary tumor volume was measured in two dimensions using calipers.

[0299] Transplanted animals were randomly divided into 10 groups of 10 mice per group on day 0 according to the transplantation sequence and body weight. The groups consisted of a vehicle group, 5, 15, 50 mg / kg venetoclax at a once-daily dose, 5, 15, 50 mg / kg compound 1 at a once-daily dose, and 2.5, 7.5, 25 mg / kg compound 1 at a twice-daily dose. The drugs were administered orally through a gavage (PO) at a volume of 10 ml / kg body weight. Body weight was determined immediately before dosing, and the dosing volume was adjusted accordingly.

[0300] Individual body weights were recorded twice weekly, and mice were observed daily for clinical signs of toxicity throughout the study period. Mice were euthanized using carbon dioxide when tumor volume reached 2000 mm. 3 , the tumor ulcerated or body weight loss exceeded 20%.

[0301] The tumor volume was calculated using the formula: V=0.5 × (a × b 2 ), where a and b represent the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: % TGI=100 × [1- (treated t -processed t0 ) / (carrier environment t -carrier environment t0 )] (treated t=tumor volume treated at time t, treated t0=tumor volume treated at time 0, vehicle t=tumor volume treated with vehicle at time t, and vehicle t0=tumor volume treated with vehicle at time 0)

[0302] The in vivo efficacy of compound 1 was further examined and compared with venetoclax in the Toledo subcutaneous DLBCL xenograft model. After daily oral administration at well-tolerated doses of 2.5, 7.5, and 25 mg / kg twice daily or 5, 15, and 50 mg / kg once daily, compound 1 induced dose-dependent antitumor effects. At the same total daily doses of 5 and 15 mg / kg, compound 1 demonstrated significantly higher efficacy than venetoclax. These results are presented in Figures 3A–3B and Table 3.

[0303] All treatment groups had no significant effect on the body weight of animals throughout the study.

[0304] Table 3

[0305] Means Dose (mg / kg) Administration scheme Route of administration Mean tumor volume (day 31) (mm 3 ±SEM) TGI (Day 31) Carrier medium Carrier medium 2 times a day × 31 Orally 1703,1±190,9 - Compound 1 2,5 2 times a day × 31 Orally 515,7±79,1 70% Compound 1 7,5 2 times a day × 31 Orally 230,5±25,9 86% Compound 1 25 2 times a day × 31 Orally 182,5±15,9 89% Compound 1 5 1 time per day × 31 Orally 679,3±63,2 60% Compound 1 15 1 time per day × 31 Orally 267,4±30,4 84% Compound 1 50 1 time per day × 31 Orally 214,8±19,4 87% Venetoclax 5 1 time per day × 31 Orally 1256,5±136,5 26% Venetoclax 15 1 time per day × 31 Orally 847,8±109,4 50% Venetoclax 50 1 time per day × 31 Orally 258,3±22,6 85%

[0306] Case 4: Study on the Efficacy of Bcl-2 Inhibitors in RS4;11 Bcl-2G101V KI Acute Lymphoblastic Leukemia (ALL) Subcutaneous Xenograft Model

[0307] RS4;11 Bcl-2G101V KI cells are of acute lymphoblastic leukemia (ALL) origin and were screened in the laboratory. The cells were grown in RPMI 1640 medium (Corning, Cat. No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Cat. No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Cat. No. 15140-122). RS4;11 Bcl-2G101V KI cells were maintained as cell suspension cultures at 37ºC in an atmosphere of 5% CO2. Five- to six-week-old female NCG mice were purchased from GemPharmatech Co., Ltd, Jiangsu, China. All animals were maintained under specific pathogen-free (SPF) conditions with full barrier conditions and free access to food and water. Mice were housed in groups under a 12-hour light-dark cycle (lights on at 8:00 a.m.), at a temperature of 20-26ºC and humidity of 37-62% in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.). Mice were fed a complete pelleted diet sterilized with Co60 irradiation (Beijing Ke Ao Xie Li Feed Co., Ltd.).

[0308] On the day of implantation, RS4;11 Bcl-2G101V KI cells were harvested and resuspended in an appropriate volume of cold DPBS and the same volume of Matrigel (Corning, Cat. No. 356237) to a final concentration of 5×10 7 cells / ml. Before inoculation, resuspended cells were placed on ice. Before cell inoculation, the right anterior lateral region of each mouse was cleaned with 75% ethanol. Each animal was injected subcutaneously with 1×10 7 cells in 200 μl of cell suspension into the right anterior phalanx. After implantation, the primary tumor volume was measured in two dimensions using calipers.

[0309] The animals were randomly divided into 7 groups of 8 mice per group depending on body weight and tumor volume (about 300 mm 3). The groups consisted of a vehicle group, 15, 50, and 100 mg / kg venetoclax at a once-daily dose, and 15, 50, and 100 mg / kg compound 1 at a once-daily dose. The drugs were administered orally through a gavage tube (PO) at a volume of 10 ml / kg per body weight. Body weight was determined immediately before dosing, and the dosing volume was adjusted accordingly.

[0310] Individual body weights were recorded twice weekly, and mice were observed daily for clinical signs of toxicity throughout the study period. Mice were euthanized using carbon dioxide when tumor volume reached 2000 mm. 3 , the tumor ulcerated or body weight loss exceeded 20%.

[0311] The tumor volume was calculated using the formula: V=0.5 × (a × b 2 ), where a and b represent the long and short diameters of the tumor, respectively.

[0312] The in vivo efficacy of compound 1 was examined and compared with venetoclax in RS4;11 Bcl-2G101V KI xenografts grown subcutaneously in NCG mice. Venetoclax showed little efficacy even at a higher dose, while compound 1 potently and dose-dependently inhibited tumor growth. These results are presented in Figures 4A–4B and Table 4. The curves for compound 1 at 50 mg / kg orally once daily and 100 mg / kg orally once daily are pooled.

[0313] All treatment groups had no significant effect on the body weight of animals throughout the study.

[0314] Table 4

[0315] Means Dose (mg / kg) Administration scheme Route of administration Mean tumor volume (day 10) (mm 3 ±SEM) TGI (Day 10) Carrier medium N / A 1 time per day x 10 Orally 1515,4±84,2 N / A Compound 1 15 1 time per day x 10 Orally 554,2±70,3 78% Compound 1 50 1 time per day x 10 Orally 155,1±4,3 110% Compound 1 100 1 time per day x 10 Orally 144,5±3,5 111% Venetoclax 15 1 time per day x 10 Orally 976,6±64,0 44% Venetoclax 50 1 time per day x 10 Orally 711,8±49,7 65% Venetoclax 100 1 time per day x 10 Orally 530,4±75,4 80%

[0316] Example 5: Evaluation of the efficacy of Bcl-2 inhibitors in combination with BTK inhibitors in the JeKo-1 mantle cell lymphoma (MCL) subcutaneous xenograft model

[0317] 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). The cells were grown in RPMI 1640 medium (Corning, Cat. No. 10-040-CVR) supplemented with 10% (v / v) fetal bovine serum (Gibco, Cat. No. 10099-141C) and 100 μg / mL penicillin and streptomycin (Gibco, Cat. No. 15140-122). JeKo-1 cells were maintained as suspension cell cultures at 37ºC in a 5% CO2 atmosphere. Five- to six-week-old female NCG mice were purchased from the Gempharmatech Information Technology Center. All animals were maintained under specific pathogen-free (SPF) conditions with full barrier conditions and free access to food and water. Mice were housed in groups under a 12-hour light-dark cycle (lights on at 8:00 a.m.), at a temperature of 23-27ºC and a humidity of 28-51% in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd.).Mice were fed a complete pelleted diet sterilized by Co60 irradiation (Beijing Ke Ao Xie Li Feed Co., Ltd.). All experiments were conducted in accordance with the IACUC BeiGene.

[0318] On the day of implantation, JeKo-1 cells were harvested and resuspended in an appropriate volume of cold PBS and the same volume of Matrigel (Corning, Cat. No. 356237) to a final concentration of 5×10 7 cells / ml. Before inoculation, resuspended cells were placed on ice. Before cell inoculation, the right anterior lateral region of each mouse was cleaned with 75% ethanol. Each animal was injected subcutaneously with 1×10 7 cells in 200 μl of cell suspension into the right anterior phalanx. After implantation, the primary tumor volume was measured in two dimensions using calipers.

[0319] The transplanted animals were randomly divided into 8 groups of 10 mice per group on day 0 according to the transplantation sequence and body weight. The groups consisted of the vehicle group, 5, 15, 50 mg / kg compound 1 (Bcl-2 inhibitor) at a once-daily dose, and 20 mg / kg compound B (BTK inhibitor, zanubrutinib, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide) at a twice-daily dose, and their combinations. The drugs were administered orally through a gavage (po) at a volume of 10 ml / kg body weight. The body weight was determined immediately before dosing, and the dosing volume was adjusted accordingly.

[0320] Individual body weights were recorded twice weekly, and mice were observed daily for clinical signs of toxicity throughout the study period. Mice were euthanized using carbon dioxide when tumor volume reached 2000 mm. 3, the tumor ulcerated or body weight loss exceeded 20%.

[0321] Tumor volume (TV) was calculated using the formula: TV=0.5 × (a × b 2 ), where a and b represent the long and short diameters of the tumor, respectively. Tumor growth inhibition (TGI) was calculated using the following formula: % TGI=100 × [1- (treated t ) / (carrier environment t )] (treated t=tumor volume treated at time t, vehicle t=tumor volume treated with vehicle at time t)

[0322] The in vivo efficacy of Compound 1 and Compound B was examined in a subcutaneous JeKo-1 MCL xenograft model grown subcutaneously in NCG mice. The results are shown in Figures 5A, 5B, 5C, and 5D. At day 21, Compound 1 at 5, 15, and 50 mg / kg once daily and Compound B at 20 mg / kg twice daily resulted in tumor growth inhibition (TGI) of 29%, 49%, 49%, and 56%, respectively. Combinations of Compound B at 20 mg / kg twice daily with Compound 1 at 5, 15, or 50 mg / kg once daily resulted in TGI of 62%, 74%, and 71%, respectively (see Table 1). Combinations of compound 1 at 15 or 50 mg / kg once daily with compound B at 20 mg / kg twice daily demonstrated higher antitumor activity than either agent alone (Figures 1C and 1D). All treatment groups had no significant effect on animal body weight throughout the study.

[0323] Table 5

[0324] Group Mean tumor volume (D21) (mm 3 ±SEM) TGI (%) Carrier medium 1820,9±125,7 N / A Compound B, 20 mg / kg orally twice daily 799,8±73,2 56% Compound 1, 5 mg / kg orally once daily 1293,3±100,0 29% Compound 1, 15 mg / kg orally once daily 929,5±73,6 49% Compound 1, 50 mg / kg orally once daily 927,5±100,6 49% Compound B, 20 mg / kg in combination with Compound 1 5 mg / kg 687,2±90,2 62% Compound B, 20 mg / kg in combination with Compound 1 15 mg / kg 475,7±28,8 74% Compound B, 20 mg / kg in combination with Compound 1 50 mg / kg 530,5±37,7 71%

[0325] Example 6: Clinical trial

[0326] 1. Method

[0327] Research Plan / Objectives

[0328] Phase 1 (dose escalation and safety extension) studies were conducted to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of compound 1 in patients with R / R B-cell malignancies. (Table 6-1A).

[0329] Dose escalation (Part 1) occurs in independent cohorts stratified by patient disease type. These cohorts continue until the recommended phase 2 dose (RP2D) is determined, which is then used in the corresponding expansion cohorts (Part 2).

[0330] Part 1 Dose escalation schedule for monotherapy and dose selection

[0331] 1) Cohort 1A: Cohort 1A consists of patients with relapsed / refractory B-cell non-Hodgkin's lymphoma (R / R B-cell NHL), excluding mantle cell lymphoma (MCL). These patients are considered to be at low risk of developing tumor lysis syndrome (low risk TLS) and are treated with a short dose escalation schedule, reaching the target dose on day 3. Patients in this cohort receive escalating doses of compound 1 monotherapy: 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg (unless adjusted based on the recommendation of the safety monitoring committee [SMC]).

[0332] 2) Cohort 1B is open if ≥1 tolerated dose level was identified in cohort 1A. It consists of patients with low tumor burden R / R CLL / MLL. Dose titration was performed in this cohort, including assessment of the dose escalation schedule and target dose. Patients received weekly dose escalation steps until the target dose for this cohort was reached. The escalation 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 based on SMC recommendations). Dosing in this cohort was not performed before SMC.

[0333] 3) Cohort 1C: This cohort includes patients with R / R chronic lymphocytic leukemia / small lymphocytic lymphoma (R / R CLL / SLL) with a high tumor burden. This cohort will not be dosed until the RP2D for cohort 1B is established. The purpose of this cohort is to confirm the safety of the dose escalation schedule for monotherapy and the RP2D established in patients with low tumor burden CLL / SLL in patients with a high tumor burden.

[0334] 4) Cohort 1D: This cohort consists of patients with R / R MCL. This cohort will not be dosed until the RP2D for cohort 1B is established. The purpose of this cohort is to confirm the safety of the dose escalation schedule for monotherapy and the RP2D established in patients with CLL / MLL with low tumor burden in patients with R / R MCL.

[0335] --Cohort 1D: This cohort includes patients with R / R MCL. The target doses are 160 and 320 mg.

[0336] 5) Cohort 1E: This cohort consists of patients with R / R Waldenström's macroglobulinemia (R / R MB). This cohort will not be dosed until the RP2D for cohort 1B is established. The purpose of this cohort is to confirm the safety of the dose escalation schedule for monotherapy and the RP2D established in patients with CLL / MLL with low tumor burden in patients with R / R MB.

[0337] All dose cohorts will be reviewed by a safety monitoring committee (SMC) before opening subsequent dose levels or MTD / RP2D statement.

[0338] Part 2 Expansion Cohorts in Monotherapy

[0339] 1) Cohort 2A: R / R indolent NHL (follicular lymphoma [FL] and marginal zone lymphoma [MLZ]).

[0340] 2) Cohort 2B: R / R aggressive NHL (diffuse large B-cell lymphoma [DLBCL] and transformed B-cell NHL).

[0341] 3) Cohort 2C:R / R CLL / MLL with low tumor burden.

[0342] 4) 2D cohort: R / R CLL / MLL with high tumor burden.

[0343] 5) Cohort 2E: R / R CLL / MLL with prior treatment with venetoclax (ven).

[0344] 6) Cohort 2F:R / R MKL.

[0345] 7) Cohort 2G:P / P MV.

[0346] The study also includes dose escalation and expansion cohorts for the combination of Compound 1 and the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in patients with selected B-cell malignancies such as CLL / MLL and mantle cell lymphoma (MCL). (Table 6-2A). Patients in the combination cohort received zanubrutinib 320 mg daily (160 mg twice daily [bid] or 320 mg once daily [OD]), starting 8-12 weeks before Compound 1 administration. The corresponding dose escalation and expansion were performed in Part 3 and Part 4.)

[0347] Part 3 Dose escalation schedule for combination and dose selection

[0348] In cohort 3A and cohort 3B, patients with R / R CLL / MLL or R / R MCL, respectively, were studied to determine the RP2D and MTD or MAD for compound 1 in combination with zanubrutinib 320 mg daily.

[0349] Dose titration was continued in patients with R / R CLL / MLL or R / R MCL who were Bcl-2 inhibitor-naive and had not progressed on a BTK inhibitor, including evaluation of the dose escalation schedule and target dose of Compound 1 when used in combination with zanubrutinib. The dose of Compound 1 is variable, while the dose of zanubrutinib is fixed at 320 mg / day (160 mg twice daily or 320 mg once daily). Dose escalations were performed weekly to achieve the target dose for this cohort. The escalation steps for Compound 1 are 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg (unless adjusted based on SMC recommendation).

[0350] In cohort 3A, dosing was continued until the SMC determined a safe starting dose for this disease with an increased risk of TLS (based on Part 1 data) and established an initial target dose after the target dose+1 was determined to be safe in the Part 1 cohorts. Patients in cohort 3B are expected to have a similar risk of TLS compared with CLL / MLL, and patients in this cohort can initiate dose titration at or below the current highest tolerated dose (or RP2D, if established) for CLL / MLL patients during combination dose titration (cohort 3A).

[0351] Part 4 Expansion Cohorts in Combination

[0352] 1) Cohort 4A studied patients with R / R CLL / MLL with a dose escalation schedule and the target dose of Compound 1 determined in Cohort 3A in combination with zanubrutinib 320 mg / day (administered as 160 mg twice daily or 320 mg once daily) to expand the safety assessment of the treatment dose and dose escalation schedule.

[0353] 2) Cohort 4B studied treatment-naive (TN) CLL / MLL patients and used the same doses and regimens as cohort 4A unless modified by SMC.

[0354] 3) Cohort 4C studied patients with R / R MCL and used the RP2D reported in cohort 3B unless they were modified by SMC.

[0355] In all cohorts of the Phase 1 study, Compound 1 was administered orally once daily (OD).

[0356] Table 6-1A Study Design (Monotherapy Cohorts)

[0357] Part 1: Dose Selection RP2D Part 2: Expansion Cohort Population Disease Planned N The RP2D for each disease type will be determined based on the SMC review of available safety and activity data. Cohort Population Disease Planned N 1A R / R NHL (FL, DWKKL, LMZ or transformed NHL) 15-30 2A R / R (Food intake effect) Slow-moving NHL (FL, LMZ) 10 1B R / R (low risk TLS) HLL / MLL 15-30 2B R / R (Food intake effect) Aggressive NHL (Aggressive NHL, Transformed NHL) 10 1C R / R (high risk of TLS*) HLL / MLL 3-6 2C R / R (low risk TLS) HLL / MLL 20 1D R / R MKL 3-6 2D R / R (high risk of TLS*) HLL / MLL 10 1E R / R MV 3-6 2E R / R (before ven) HLL / MLL 10 2F R / R MKL 20 2G R / R MV 20

[0358] Table 6-2A Study design (combination cohorts)

[0359] Part 3: Dose Selection RP2D Part 4: Expansion Cohort Population Disease Planned N The RP2D for the cohort will be determined based on the SMC review of available safety and activity data. Cohort Population Disease Planned N 3A R / R HLL / MLL 15-30 4A R / R HLL / MLL 30 3B R / R MKL 3-6 4B TN HLL / MLL 20 4C R / R MKL 20

[0360] Data for cohorts 1A, 1B, 3A, and 3B are presented in this description.

[0361] *High risk TLS is defined as the presence of any lymph node ≥10 cm or the presence of any lymph node ≥5 cm with simultaneous absolute lymphocyte count (ALC) ≥25 × 109 / L.

[0362] Main selection criteria

[0363] Each patient eligible to participate in this study must meet all of the following criteria.

[0364] 1. Age 18 years or older

[0365] 2. Confirmed diagnosis of one of the following:

[0366] NHL cohorts

[0367] a.LMZ,i.) R / R extranodal, splenic or nodal LMZ, defined as disease that has relapsed after or was refractory to at least 1 prior therapy; ii.) Active disease requiring treatment.

[0368] b.FL, i). R / R FL (grade 1, 2 or 3a according to the 2008 WHO classification for tumours of the hematopoietic and lymphoid tissue), defined as disease that has relapsed after or is refractory to at least 1 previous systemic therapy; ii.) Active disease requiring treatment.

[0369] c. DLBCL, i.) R / R DLBCL (including all subtypes of DLBCL) defined as disease that has recurred after

[0370] or refractory to at least 1 prior systemic therapy and progresses after autologous stem cell transplantation or is not a candidate for autologous stem cell transplantation (due to comorbidities or lack of response to salvage chemotherapy); ii.) Active disease requiring treatment.

[0371] d. Transformed indolent B-cell NHL,i.) Any lymphoma that meets the other conditions of Part 1 that has transformed to a more aggressive lymphoma. Patients with transformation from CLL or MLL (Richter's transformation) are not covered by Part 1.ii.) Active disease requiring treatment.

[0372] MKL Cohorts

[0373] e. WHO-defined MCL i.) R / R MCL, defined as disease that has relapsed after, or was refractory to, at least 1 prior systemic therapy; ii.) Requiring treatment according to the investigator.

[0374] CLL / MLL cohorts:

[0375] f. Diagnosis of CLL / MLL meeting the criteria of the International Workshop on Chronic Lymphocytic Leukemia (Hallek et al 2008).

[0376] i. Meet the following prior treatment criteria: (1) For the P / P cohorts (cohorts 1C, 2C, 2D, 2E, 3A, and 4A), disease that has relapsed after or was refractory to at least 1 prior therapy; (2) For the venetoclax-treated cohort (cohort 2E), prior therapy must include disease progression after therapy with venetoclax for 2 months or more (monotherapy or combination); (3) For the treatment-naive cohort (cohort 4B), patients must not have received prior CLL / MLL treatment (except for 1 interrupted regimen of less than 2 weeks duration and more than 4 weeks duration before study entry).

[0377] ii. Treatment required

[0378] MV Cohorts:

[0379] g. CF as defined by WHO (clinical and final histological diagnosis), i.) R / R disease, defined as disease that has relapsed after or is refractory to at least 1 prior therapy; ii.) Meeting at least 1 criterion for treatment according to the consensus committee criteria of the Seventh International Workshop on Waldenström Macroglobulinemia (Dimopoulos et al 2014).

[0380] Measurable disease by computed tomography / magnetic resonance imaging, defined as:

[0381] a. CLL: at least 1 lymph node with the longest diameter > 1.5 cm and measurable in 2 perpendicular dimensions or clonal lymphocytes by flow cytometry.

[0382] b. DLBCL, FL, LMZ, MCL, or MLL: at least 1 lymph node with the longest diameter > 1.5 cm OR 1 extranodal lesion with the longest diameter > 1.0 cm, measured in 2 perpendicular dimensions. For LMZ, isolated splenomegaly is considered measurable for this study.

[0383] c. MB: serum IgM level> 0.5 g / dL.

[0384] 3. Measurable disease based on computed tomography (CT) / magnetic resonance imaging (MRI).

[0385] 4. Eastern Cooperative Oncology Group (ECOG) performance status score from 0 to 2.

[0386] 6. Sufficient function of the pancreas, as evidenced by:

[0387] Serum amylase ≤ 1.5 x upper limit of normal (ULN)

[0388] Serum lipase ≤ 1.5 x ULN

[0389]

[10] Key exclusion criteria:

[0390] • Known involvement of the central nervous system in lymphoma / leukemia

[0391] • Known plasma cell neoplasms, prolymphocytic leukemia, history of or current suspicion of Richter syndrome.

[0392] Increasing the dose

[0393] For dose escalation, patients were enrolled in 1 of 5 planned daily oral dose levels of Compound 1 in cohorts of at least 3 patients: 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg daily.

[0394] Increasing the dose

[0395] To protect against possible tumor lysis syndrome (TLS), all patients received dose escalation to the target level, and the target doses were 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg daily for both monotherapy and combination therapy (Table 5-1B).

[0396] 1) Patients with NHL (excluding MCL) included in cohorts 1A, 2A, and 2B received 2-day dose escalations (day 1, 25% of target dose; day 2, 50% of target dose) to reach the target daily dose (day 3+, 100%).

[0397] 2) Patients with CLL / MLL, MCL, or CF included in cohorts 1B, 1C, 1D, 1E, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 4A, 4B, and 4C received weekly dose escalation (starting with 1 mg daily, doubling the dose weekly to reach the target dose). The dose increments are 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, and 640 mg.

[0398]

[11] Other types of TLS prevention included

[0399] 1) Hydration: Orally or intravenously 1.5-2 L / day from ≥1 day before to ≥1 day after each new dose level;

[0400] 2) Antihyperuricemic drugs (allopurinol; rasburicase if needed): starting ≥2 days before the first dose and up to 1 week after reaching the final target dose level; and

[0401] 3) Hospitalization for observation: Laboratory parameters of TLS and PK were frequently monitored.

[0402] ---NHL: Required during dose escalation for at least the first 3 escalated doses; and

[0403] ---CLL: Required on day 1 of each week for at least the first 3 increased doses.

[0404] Table 5-1B Dose Escalation Schedules (Example Target Dose 80 mg)

[0405] Two-day dose escalation regimens for patients with diseases at lower risk of developing TLS (cohorts 1A, 2A, and 2B) 20 mg once a day D1 40 mg once a day D2 80 mg once a day D3+ Weekly dose escalation schedule for patients with CLL / MLL, MCL, or CF (cohorts 1B, 1C, 1D, 1D', 1E, 2C, 2D, 2E, 2F, 2G, 3A, 3B, 4A, 4B, and 4C) 1 mg 1 time per day H1 2 mg 1 time per day H2 5 mg 1 time per day H3 10 mg 1 time per day H4 20 mg 1 time per day H5 40 mg 1 time per day H6 80 mg once a day H7+ →

[0406] D, day; 1 time per day, once a day; W, week.

[0407] Reporting, etc.

[0408] Adverse events (AEs) were recorded according to CTCAE v5.0 (msCLL for selection of hematological toxicities in 7 patients with CLL)

[0409] NP Terminology Criteria v5.0 (International Workshop on CLL [IWCCL] for the Selection of Hematological Toxic Manifestations in Patients with CLL). Treatment response was assessed using the Lugano classification 12 for patients with NHL and the IWCCL guidelines 13 for patients with CLL.

[0410] Dose-limiting toxicities (DLTs) were assessed during dose escalation up to day 21 at the target dose per patient. To find the target dose, a Bayesian logistic regression model was used to model the relationship between dose levels and the incidence of dose-limiting toxicities (DLTs) across dose-level cohorts.

[0411] 2. Results

[0412] Distribution and baseline

[0413] In monotherapy, cohort 1A treated 7 patients with R / R NHL, and cohort 1B treated 2 patients with R / R CLL. Then, cohorts 1A, 1B, 3A, and 3B included a total of 36 patients (Table 5-2A): 1) in monotherapy, cohort 1A treated 19 patients with R / R NHL, and cohorts 1B and 1C treated 6 and 10 patients with R / R CLL; and 2) in combination therapy, cohort 3A treated 10 patients with R / R CLL, and cohort 3B treated 1 patient with R / R MCL.

[0414] Table 5-2A Patient Distribution

[0415] Monotherapy N=25, median follow-up: 2.6 months (range 0.1-15.7) Cohorts 1A R / R NHL (FL, DLBCL, tNHL, LMZ) n=19 Median follow-up: 2.6 months (range 0.1-15.7) With treatment: n=8; Without treatment n=11 (PD: n=8, NP: n=1, Other*: n=1). Cohorts 1B R / R CLL / MLL n=2 Median follow-up: 4.0 months (range 3.3-4.6) With treatment: n=2. Combination therapy N=11 Median follow-up: 3.3 months (range 0.1-6.6) Cohorts 3A R / R CLL / MLL n=10 Median follow-up: 3.9 months (range 0.1-6.6) Cohorts 3B R / R MKL n=1 Observation: 0.5 months * Includes "other" or "physician's decision."

[0416] Table 6-2B Patient and disease characteristics

[0417] Characteristic Monotherapy N=25 Combination therapy N=11 Age, median (range), y 76 (55-86) 60 (41-75) ECOG performance status, n (%) 0 10 (40) 7 (63,6) 1 13 (52) 4 (36,4) 2 2 (8) 0 Disease types, n (%) HLL 6 (24) 10 (90,9) DVCKL 12 (48) -- FL 4 (16) -- LMZ 3 (12) -- MKL 0 1 (9,1) Number of prior lines of therapy, mean (range) 2 (1-5) 1 (1-2) Time from end of last systemic therapy to first dose, average (range), months 7,7 (9-49,7) 45,5 (1,6-194,4)

[0418] Safety

[0419] The safety data of 36 patients (monotherapy [N=25], combination therapy [N=11]) who received compound 1 are shown in Table 6-3A and Figure 6A. In addition, the safety data of 58 patients who received compound 1 are shown in Table 6-3B. Of the 58 patients who received monotherapy, 26 with R / R non-Hodgkin lymphoma (NHL; 17 DLBCL, 6 FL, and 3 LMZ) received compound 1 ≤640 mg, and 6 with R / R CLL / MLL received compound 1 ≤160 mg. Of the 58 patients who received combination therapy, 19 with R / R CLL / MLL received compound 1 ≤160 mg, and 7 with R / R MCL received compound 1 ≤80 mg. The MTD has not yet been reached. The median follow-up was 3.9 months (range 0.1–20.4). Twenty of 58 patients discontinued treatment (17 due to disease progression; 1 due to NP; 2 due to other reasons).

[0420] With monotherapy, the most common adverse events (AEs) emerging after initiation of treatment included nausea. The patient experienced grade 3 or higher AEs: abdominal pain, enteritis, small bowel obstruction, increased alkaline phosphatase, increased GGT, increased platelet count, cachexia, pyrexia, back pain, and laboratory TLS. In one high-risk patient with CLL receiving monotherapy, laboratory TLS resolved without intervention (laboratory TLS <2%). Two deaths were reported due to disease progression.

[0421] In combination therapy, 2 grade ≥3 AEs (1 neutropenia, 1 autoimmune hemolytic anemia) were reported.

[0422] Table 5-3A. Common adverse events (N=36)

[0423] NP, n (%) Monotherapy N=25 Combination therapy N=11 Total 22 (88) 9 (82) NP grade ≥3 11 (44) 0 Serious NP 9 (36) 0 Leads to death 2 (8) a 0 NP, which lead to the suspension of the intake of compound 1 4 (16) b 0 NP, which lead to a decrease in the dose of compound 1 0 0 NP, which lead to discontinuation of compound 1 1 (4) c 0

[0424] a-None of these were related to the study drug; 1 death due to disease progression and 1 gastrointestinal bleeding after bowel surgery. B- - increased ALT and GGT; neutropenia, pyrexia and febrile neutropenia; gastrointestinal bleeding and small bowel obstruction; neutropenia. c - gastrointestinal bleeding after intestinal surgery.

[0425] Table 6-3B. Common adverse events (N=58)

[0426] Compound 1 monotherapy (n=32) Any adverse event in >10% of patients n (%) Degree ≥3 All degrees Nausea 0 12 (37,5) Diarrhea 0 8 (25,0) Fatigue 0 8 (25,0) Neutropenia 6 (18,8) 8 (25,0) Fever 1 (3,1) 6 (18,8) Constipation 0 5 (15,6) Dizziness 0 5 (15,6) Fall 2 (6,3) 5 (15,6) Headache 0 5 (15,6) Abdominal pain 2 (6,3) 4 (12,5) Peripheral edema 0 4 (12,5) Thrombocytopenia 2 (6,3) 4 (12,5) Urinary tract infection 0 4 (12,5) Combination of compound 1 + zanubrutinib (n=26) Any adverse event in >10% of patients n (%) Degree ≥3 All degrees Closed trauma 0 6 (23,1) Nausea 0 6 (23,1) Diarrhea 0 5 (19,2) Fatigue 0 4 (15,4) Back pain 0 3 (11,5) Headache 0 3 (11,5) Petechial hemorrhage 0 3 (11,5)

[0427] Dose escalation status

[0428] NHL Cohort 1A: The 40-mg (n=3; 1 LMZ, 2 DLBCL), 80-mg (n=4; 1 FL, 3 DLBCL), and 320-mg (n=3) dose cohorts were completed without disease-limiting toxicities (DLTs); one DLT of grade 3 febrile neutropenia was observed in the 160-mg dose cohort (n=3+1); and all dose cohorts, including the 320-mg and 640-mg dose cohorts, were completed with the MTD not reached until 640 mg.

[0429] Cohort 1B R / R CLL: Dose escalation was initiated from a target dose of 80 mg (n=4) after it was deemed tolerable in cohort 1A, with one DLT of grade 4 neutropenia observed. The study continued with dose cohorts of 160 mg, 320 mg, and 640 mg. Although cohort 1B only included patients with low risk of TLS, a patient with high risk of TLS was erroneously included. Based on retrospective review of the baseline CT by a radiologist, the largest nodule was enlarged to 6.5 × 2.4 cm with an absolute lymphocyte count (ALC) of 37.4 × 10 9 / L (n=2, target dose level 80 mg).

[0430] 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); and the 320-mg and 640-mg dose cohorts were continued.

[0431] Cohort 3B R / R MCL: The 80 mg dose cohorts were completed without disease-limiting toxicities (DLTs); the 160 mg, 320 mg, and 640 mg dose cohorts were ongoing.

[0432] Cohort 4B TN CLL: Cohorts with 160 mg dose were opened, tolerability and promising activity were noted.

[0433] Adverse events of BCL2 inhibitor of interest

[0434] TLS: A patient with a high baseline risk of TLS who was erroneously enrolled developed laboratory TLS and developed a tumor flare with lactate dehydrogenase 1500, the largest nodule up to 5-10 cm, ALC 135.9 × 109 / L during discontinuation of the BTK inhibitor during early dose escalation. This patient also had baseline hyperuricemia and a history of it. During dose escalation, the patient met the criteria for laboratory TLS according to the Howard 8 criteria at the late dose increase at both the 40 mg and 80 mg levels. Baseline urate: 430 mmol / L; peak urate: 570 mmol / L; baseline phosphate: 0.35 mmol / L; peak phosphate: 2.16 mmol / L. The patient had no complications following laboratory TLS, which resolved the following day and did not require continued retention of Compound 1.

[0435] In monotherapy, neutropenia was observed in 6 patients (5 patients experienced neutropenia ≥ grade 3) and 2 patients recovered with early treatment with compound 1.

[0436] One patient receiving monotherapy with a high baseline risk of TLS experienced a significant tumor flare upon discontinuation of the BTK inhibitor, and in the late stages of increased risk, laboratory TLS developed. The patient experienced no complications following the laboratory TLS; it resolved the following day and did not require continued withholding of compound 1.

[0437] Efficiency

[0438] Most patients showed a reduction in the sum of the product of the perpendicular diameters. In patients with CLL / MLL, a significant reduction in the absolute lymphocyte count was observed already at doses up to 1 mg. Early efficacy data from 36 patients (monotherapy [N=25], combination therapy [N=11]) are presented below.

[0439] NHL: No NHL patient achieved a response to compound 1 (Figure 6B). Two patients (both 80 mg with DLBCL) experienced nodule shrinkage and continued therapy, and five patients experienced disease progression. With continuous treatment (treatment duration of approximately 5 months), two patients achieved a response to compound 1, including one complete response (CR). A reduction in the sum of the product of the perpendicular diameters (SPD) was observed at all dose levels tested.

[0440] CLL / MLL: In monotherapy, 1 in 4 patients with CLL achieved a first response assessment and a partial response at the 80 mg dose level (Figure 6C) and had del (17p) CLL, where 2 responses (partial response or better) were observed with continued treatment. While in combination therapy, some patients experienced a partial response with lymphocytosis or better (n=2 at both 40 mg and 80 mg).

[0441] A significant decrease in absolute lymphocyte count (ALC) was observed in all patients during the dose escalation period, with one patient responding after overcoming the initial tumor flare and another patient experiencing a decrease even at the 1 mg dose level (Figure 6D). A significant decrease in absolute ALC was observed in all CLL patients during the dose escalation period, with a decrease in lymphocyte count observed as early as the 1 mg dose level.

[0442] 3. Conclusion

[0443] Early Phase 1 results from 9 patients (monotherapy [N=9]) indicate that compound 1 is well tolerated at the dose levels tested. No dose-limiting toxicities (DLTs) were observed across the 2 dose levels. Grade ≥3 AEs were infrequent and manageable, and only 2 patients experienced neutropenia. The risk of TLS appears limited and manageable, with only 1 case of laboratory TLS observed in a patient at high risk for TLS. Preliminary activity in this patient population was assessed as accrual and follow-up increased, and inclusion of patients with R / R CLL has only recently begun, but a decrease in absolute lymphocyte count (ALC) was observed with an initial dose increase of 1 mg.

[0444] Results from a study of 36 patients (monotherapy [N=25], combination therapy [N=11]) indicate that compound 1 is well tolerated in patients with, for example, CLL or NHL at the dose levels tested:

[0445] Only 1 dose-limiting toxicity (DLT) was observed across the 4 dose levels tested in the NHL cohort and 1 DLT was observed in the CLL cohort;

[0446] Grade ≥3 adverse reactions were uncommon and manageable, and only 2 patients experienced neutropenia;

[0447] The risk of TLS appears to be limited and manageable, and was not observed in combined cohorts; The risk of TLS appears to be limited and manageable, and only 1 case of laboratory TLS was observed in a CLL patient at high risk of TLS;

[0448] Neutropenia was the most common grade ≥3 AE, but was transient and poorly correlated with treatment dose, and preliminary activity in this patient population is assessed with increasing patient numbers and follow-up. A significant decrease in ALC was observed during CLL dose escalation in patients, and a decrease in absolute lymphocyte count (ALC) was observed with the initial 1 mg dose escalation; and

[0449] Evaluation of patients with MCL not receiving treatment for CLL or CF is planned in future cohorts.

[0450]

[12] Based on the results of a study of 58 patients, treatment with Compound 1 demonstrated promising efficacy and an improved safety profile, particularly in the combined cohorts. Grade ≥3 neutropenia was rare. Compound 1 was tolerated at doses up to 640 mg as monotherapy and up to 160 mg in combination with zanubrutinib. Dose escalation was continued, as the MTD had not yet been reached in any of the dose escalation cohorts. Enrollment is ongoing, and data from the treatment-naive Waldenström macroglobulinemia and CLL / MLL cohorts will be available soon.

[0451] Furthermore, a larger number of patients were included in the studies. A total of 78 patients were dosed in the following distribution and evaluated for corresponding efficacy.

[0452] (1) Patients with R / R NHL (n=26, median follow-up=6.0 months [range 1.7-22.0]), R / R CLL / MLL (n=6, median follow-up=8.2 months [range 5.2-15.0]), and R / R MB (n=2, median follow-up=2.6 months [range 2.0-3.2]) were enrolled in monotherapy (N=34), and among the patients with R / R NHL, there were patients with FL (n=6), DLBCL (n=17), and LMZ (n=3). Among patients with R / R NHL, a significant reduction in SPD from baseline was observed in the majority of patients, with two of 20 (10%) patients demonstrating a response, including one PR at 160 mg and one CR at 320 mg, and 23 patients discontinuing treatment due to disease progression (n=20), adverse events (n=1), and other reasons or physician's decision (n=2). Among patients with R / R CF, one of two (50%) achieved a minor response at 80 mg.

[0453] (2) Combination therapy (N=44) included patients with R / R CLL / MLL (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 / MLL (expansion cohort at 160 mg daily, n=14, median follow-up=2.1 months [range 0.0-2.8]). Among patients with R / R MCL, five of 10 (50%) patients achieved a PR or better at 80 or 100 mg, including 1 CR at each dose level, and 1 R / R MCL was discontinued due to disease progression.

[0454] (3) Among CLL / MLL patients, significant reductions in absolute lymphocyte count (ALC) were observed in all CLL patients during the dose escalation period in both monotherapy and combination therapy, with lymphocyte count reductions observed as early as 1 mg. In monotherapy, four of 6 (67%) patients achieved partial response with lymphocytosis (PR-L) or improvement at 80 or 160 mg of Compound 1. In combination therapy, sixteen of 20 (80%) R / R CLL / MLL patients achieved PR-L or improvement at dose levels ranging from 40 to 320 mg, and 1 R / R CLL / MLL patient was discontinued due to disease progression. Results obtained in 78 patients indicate that compound 1 is well tolerated in patients with CLL or NHL at the dose levels tested. Dose escalation was completed with monotherapy in NHL patients who experienced only one DLT and did not reach the MTD, and only one DLT was observed among CLL patients receiving monotherapy. Grade 3 or higher adverse events were infrequent and manageable.

[0456] The data obtained indicate 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 observed in only 1 patient with CLL at high risk of TLS receiving monotherapy.

[0457] Furthermore, transient neutropenia was the most common grade ≥3 AE, and significant reduction in ALC was observed during dose escalation in CLL patients, with promising early response rates in R / R CLL patients.

[0458] Furthermore, CR and PR were observed in patients with CLL with monotherapy or combination therapy with zanubrutinib (compound B), and significant reductions in SPD were observed at all dose levels. All doses from 40 mg to 640 mg were safe, and the incidence of adverse events did not increase significantly with increasing dose. Doses of 40 mg and 80 mg are likely less optimal, as they reduce ALC to a lesser extent; negative changes in minimal residual disease (MRD) in blood were observed in the 160 mg cohorts after 6 months of treatment, but not in the 40 mg and 80 mg cohorts. The 640 mg dose appears safe but requires a large number of tablets. Therefore, 320 mg is likely the recommended dose for phase 2 studies in CLL, as it likely provides the best balance between efficacy, safety, and convenience.

[0459] The above examples and description of certain embodiments should be considered as illustrative and not as limiting the present invention in accordance with the claims. As can be readily appreciated, numerous variations and combinations of the features described above can be used without departing from the present invention, as set forth in the claims. All such variations are intended to be within the scope of the present invention. All references cited herein are hereby incorporated by reference in their entirety.

[0460] REFERENCE MATERIAL

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[0462] Anderson, M.A., Huang, D., and Roberts, A. (2014) Targeting BCL2 for the treatment of lymphoid malignancies. Semin Hematol 51, 219-227

[0463] Czabotar, P. E., Lessene, G., Strasser, A., and Adams, J. M. (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15, 49-63

[0464] Egle, A., Harris, A. W., Bath, M. L., O'Reilly, L., and Cory, S. (2004) VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276- 2283

[0465] 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

[0466] Roberts, A. W. (2016) Targeting apoptotic pathways to treat lymphoid malignancies. Rinsho Ketsueki 57, 2054-2058

[0467] 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

[0468] 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

[0469] 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.

[0470] 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.

[0471] 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.

[0472] 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.

[0473] 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 U S A, 1986. 83(14): p. 5214-8.

[0474] 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.

[0475] Roberts, A.W., et al., Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med, 2016. 374(4): p. 311-22.

[0476] 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.

[0477] 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.

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[0479] 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 method of treating a B-cell malignancy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a Bcl-2 inhibitor at a daily dose of 320 mg or 640 mg, wherein the Bcl-2 inhibitor is 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the Bcl-2 inhibitor is administered at a daily dose of 320 mg.

3. The method according to claim 1, wherein the Bcl-2 inhibitor is administered at a daily dose of 640 mg.

4. The method according to any one of claims 1-3, wherein the Bcl-2 inhibitor is administered once daily (QD) or twice daily (BID).

5. The method of claim 4, wherein the Bcl-2 inhibitor is administered at a dose of 320 mg or 640 mg once daily (QD).

6. The method of claim 4, wherein the Bcl-2 inhibitor is administered at a dose of 160 mg or 320 mg twice daily (BID).

7. The method of claim 5, wherein the Bcl-2 inhibitor is administered orally at a dose of 320 mg once daily (QD).

8. The method according to any one of claims 1-7, wherein the B-cell malignancy is non-Hodgkin's lymphoma (NHL), acute lymphoblastic leukemia (ALL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MLZ), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL) or Waldenstrom's macroglobulinemia (WM).

9. The method of claim 8, wherein the B-cell malignancy is chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).

10. The method of claim 9, wherein the B-cell malignancy is low-tumor-burden chronic lymphocytic leukemia / small cell lymphoma (CLL / SLL).

11. The method according to claim 9, wherein the malignant neoplasm is B-leukemia / small cell lymphoma (CLL / SLL) with a high tumor load.

12. The method of claim 9, wherein the B-cell malignancy is relapsed or refractory (R / R) CLL / MLL.

13. The method of claim 9, wherein the B-cell malignancy is previously untreated CLL / MLL.

14. The method of claim 8, wherein the B-cell malignancy is mantle cell lymphoma (MCL).

15. The method of claim 8, wherein the B-cell malignancy is Waldenstrom's macroglobulinemia (WM).

16. The method of claim 8, wherein the B-cell malignancy has a lower risk of developing tumor lysis syndrome (TLS).

17. The method of claim 8, wherein the B-cell malignancy expresses the Bcl-2 Gly101Val mutation.

18. The method according to claim 6, wherein the patient has previously been treated with venetoclax.

19. The method of any one of claims 9-13, wherein the Bcl-2 inhibitor is administered according to a weekly dose escalation schedule for nine weeks.

20. The method of claim 19, wherein the weekly dose escalation schedule is about 1 mg QD on week 1, about 2 mg QD on week 2, about 5 mg QD on week 3, about 10 mg QD on week 4, about 20 mg QD on week 5, about 40 mg QD on week 6, about 80 mg QD on week 7, about 160 mg QD on week 8, and about 320 mg QD on week 9.

21. The method of claim 20, further comprising administering to the patient in need 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 pharmaceutically acceptable salt thereof.

22. The method according to claim 21, wherein (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B) or a pharmaceutically acceptable salt thereof is administered orally at a dose of 160 mg twice a day or 320 mg once a day.

23. The method of claim 22, wherein (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide (compound B) or a pharmaceutically acceptable salt thereof is administered orally for 8-12 weeks prior to administration of the BCL-2 inhibitor.

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