WO2021110102A1 - Procédés de traitement du cancer utilisant un inhibiteur de bcl-2 - Google Patents

Procédés de traitement du cancer utilisant un inhibiteur de bcl-2 Download PDF

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WO2021110102A1
WO2021110102A1 PCT/CN2020/133636 CN2020133636W WO2021110102A1 WO 2021110102 A1 WO2021110102 A1 WO 2021110102A1 CN 2020133636 W CN2020133636 W CN 2020133636W WO 2021110102 A1 WO2021110102 A1 WO 2021110102A1
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azaspiro
methyl
pyrrolo
pyridin
oxy
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Nan HU
Yin GUO
Yunhang GUO
Zhiwei Wang
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BeOne Medicines Ltd
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Beigene Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Bcl-2 inhibitor in particularly 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide or a pharmaceutically acceptable salt thereof.
  • a Bcl-2 inhibitor in particularly 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl
  • Impaired apoptosis plays a central role in tumor development, tumor maintenance, and therapeutic resistance.
  • Apoptosis can be triggered via two main pathways: the extrinsic or death-receptor-mediated pathway, and the intrinsic or mitochondrial pathway (Czabotar et al 2014) . It is the intrinsic pathway that is more commonly perturbed in lymphoid malignancies. Cell death mediated through this pathway is regulated by members of a family of proteins related to B-cell lymphoma-2 (Bcl-2) , which is considered to contain three subfamilies.
  • Bcl-2 B-cell lymphoma-2
  • the pro-survival subgroup (Bcl-2, Bcl-xL, Bcl-W, Mcl-1, A1/Bfl-1, and possibly Bcl-B) promotes cell survival by inhibiting their pro-apoptotic relatives.
  • the pro-apoptotic BAX/BAK-like proteins, including BOK, are the essential effectors of apoptosis, and the BH3-only proteins (BIM, PUMA, BID, NOXA, BMF, BIK, and HRK) are the initiators of apoptosis (Anderson et al 2014) .
  • the pro-survival Bcl-2 proteins bind and inhibit BAX and BAK after they have been partially activated, impairing the ability of BAX/BAK to oligomerize and form pores to induce mitochondrial outer membrane permeabilization.
  • the BH3-only proteins are induced transcriptionally or post-transcriptionally in response to diverse stresses and initiate apoptosis by either binding the pro-survival Bcl-2 proteins, thereby unleashing BAX/BAK, or by directly activating these effectors of apoptosis.
  • the various Bcl-2 family proteins have differential specificity of binding to one another, resulting in a complex but ordered network of interactions governing cell fate (Roberts 2016) .
  • Bcl-2 was the first anti-apoptotic protein discovered in 1980s as a consequence of t (14; 18) chromosomal translocation and the hallmark of FL.
  • BCL-2 gene resides on chromosome 18q21.33.
  • the Bcl-2 protein has 239 amino acids and a molecular weight of 26 kDA (Schenk et al 2017) .
  • Bcl-2 is widely expressed during development and becomes restricted upon maturation in many tissues (Kondo et al 2008) .
  • Mice lacking Bcl-2 succumb to polycystic kidney disease early in life because Bcl-2 is critical for the survival of renal epithelial progenitor cells during embryogenesis (Veis et al 1993) .
  • mice also have abnormally reduced numbers of mature, resting B and T lymphocytes, and gray prematurely because of the aberrant death of melanocytes (Veis et al 1993, Yamamura et al 1996) . Although originally believed to act as a classical growth-driving oncogene, it was later shown that Bcl-2 instead promotes malignant cell survival by attenuating apoptosis.
  • Transgenic mice with pan-hematopoietic Bcl-2 expression (VavP-BCL-2) preferentially develop follicular lymphoma, preceded by florid germinal center hyperplasia (Egle et al 2004) . Mice co-expressing BCL-2 and MYC transgenes developed lymphomas markedly faster than littermates expressing either transgene alone, validating BCL-2 as an oncogene (Adams and Cory 2007) .
  • High Bcl-2 expression is almost universal in CLL, FL, MCL, and Waldenstrom macroglobulinemia (WM) ; in contrast, the levels of Bcl-2 expression are somewhat more variable among multiple myeloma (MM) and substantially more variable among DLBCL and B-lineage acute lymphoblastic leukemia (Roberts and Huang 2017) .
  • MM multiple myeloma
  • DLBCL B-lineage acute lymphoblastic leukemia
  • Bcl-2 protein is closely related to chemoresistance in hematological tumors.
  • Bcl-2-mediated resistance to intrinsic apoptosis is considered as a key to pathogenesis
  • targeting Bcl-2 can improve apoptosis and overcome drug resistance to cancer therapy.
  • Bcl-2 has become an attractive target for therapeutic strategy in cancer.
  • Venetoclax (ABT-199) was approved for treating patients with chronic lymphocytic leukemia (CLL) and acute myeloblastic leukemia (AML) .
  • CLL chronic lymphocytic leukemia
  • AML acute myeloblastic leukemia
  • Blombery et al demonstrated that the Gly101Val mutation (G101V mutation) in BCL-2 confers acquired refractoriness by reducing the binding affinity of venetoclax without disrupting the binding of pro-apoptotic proteins to Bcl-2.
  • the novel Gly101Val mutation in Bcl-2 was identified at progression in 7 of 15 patients. This mutation is mainly found in patients after long-term exposure to venetoclax monotherapy (Tausch et al 2019) .
  • WO2019/210828A disclosed a series of compounds having following Formulas (III-B) , (III-C) , (III-D) or (III-E) , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as Bcl-2 inhibitors,
  • the compounds disclosed in WO2019/210828A are potent and selective Bcl-2 protein inhibitor.
  • a Bcl2 inhibitor having Formulas (III-B) , (III-C) , (III-D) or (III-E) in particularly 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (Compound 1) or a pharmaceutically acceptable salt thereof, exhibited potent cell killing activity against a variety of lymphoma and leukemia cell lines, including MV4-11 (acute myeloid leukemias, AML) , OCI-LY10 (B-cell non-Hodgkin's lymphom
  • Bcl2 inhibitor having Formulas (III-B) , (III-C) , (III-D) or (III-E) , in particularly Compound 1 or a pharmaceutically acceptable salt thereof, demonstrated significant inhibition of tumor growth in cancer with high safety, including B-cell malignancies selected from acute lymphoblastic leukemia (ALL) , mantle cell lymphomas (MCL) and diffuse large B-cell lymphomas (DLBCL) .
  • ALL acute lymphoblastic leukemia
  • MCL mantle cell lymphomas
  • DLBCL diffuse large B-cell lymphomas
  • a method of treating cancer with a Bcl-2 inhibitor wherein the Bcl-2 inhibitor is a compound represented by the following Formulas (III-B) , (III-C) , (III-D) or (III-E) ,
  • R 2 at each occurrence, is independently selected from the group consisting of hydrogen, halogen, or -C 1-8 alkyl optionally substituted with halogen;
  • R Ba , R Bb , and R Bc are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -NH 2 or -N (C 1-6 alkyl) 2 , -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R Bd is independently hydrogen, halogen, oxo, -CN, -NO 2 , -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 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • n is an integer of 1-4;
  • R 5 is –L 5 -CyC
  • CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or two substituents R 5a ;
  • R 5b , R 5c , and R 5d are each independently hydrogen, -C 1-8 alkyl, -C 2- 8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or two substituents R 5e ;
  • R 5f , R 5g , and R 5h are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 5i , R 5j , and R 5k are independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2- 8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy or -C 1-8 alkyoxy;
  • R a , R b , R c , and R d at each occurrence are independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently substituted with –CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or –SR e ; and
  • R e and R f are each independently hydrogen, C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, C 2-8 alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.
  • a method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a Bcl-2 inhibitor of Formulas (III-B) , (III-C) , (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition in the manufacture of a medicament for use in the treatment of cancer, said pharmaceutical combination comprising a Bcl-2 inhibitor of Formulas (III-B) , (III-C) , (III-D) or (III-E) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the cancer is B-cell malignancies.
  • the cancer is lymphoma or leukemia.
  • the cancer is selected from the group consisting of acute myeloid leukemias (AML) , B-cell non-Hodgkin's lymphoma (B-NHL) , indolent B-cell Non-Hodgkin Lymphoma (NHL) , diffuse large B-cell lymphomas (DLBCL) , Germinal center B-cell like diffuse large B-cell lymphomas (GCB-DLBCL) , follicular lymphomas (FL) , mantle cell lymphomas (MCL) , acute lymphoblastic leukemia (ALL) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL) .
  • AML acute myeloid leukemias
  • B-NHL B-cell non-Hodgkin's lymphoma
  • NHL indolent B-cell Non-Hodgkin Lymphoma
  • DLBCL diffuse large B-cell lympho
  • the cancer is relapsed/refractory, or transformed.
  • the Bcl-2 inhibitor is orally administrated at a dose of 20 mg/per day to 700 mg/per day.
  • the cancer has Bcl-2 expression.
  • the cancer has Bcl-2 Gly101Val mutation expression.
  • Figure 1 shows efficacy of Bcl-2 inhibitors in RS4; 11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model.
  • ALL acute lymphoblastic leukemia
  • ANOVA analysis of variance
  • SEM standard error of the mean
  • QD once daily
  • BID twice daily
  • p.o. oral gavage.
  • Figure 2 shows efficacy of Bcl-2 inhibitors in MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model.
  • ANOVA analysis of variance
  • SEM standard error of the mean
  • QD once daily
  • BID twice daily
  • p.o. oral gavage.
  • Figure 3 shows efficacy of Bcl-2 inhibitors in Toledo diffuse large B cell lymphoma (DLBCL) subcutaneous xenograft model.
  • DLBCL diffuse large B cell lymphoma
  • ANOVA analysis of variance
  • SEM standard error of the mean
  • QD once daily
  • BID twice daily
  • p.o. oral gavage.
  • Figure 4 shows efficacy of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model.
  • ALL acute lymphoblastic leukemia
  • anti-cancer agent refers to any agent that can be used to treat a cell proliferative disorder such as cancer, including but not limited to, cytotoxic agents, chemotherapeutic agents, radiotherapy and radiotherapeutic agents, targeted anti-cancer agents, and immunotherapeutic agents.
  • administering when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, means contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, rabbit) and most preferably a human. Treating any disease or disorder refer in one aspect, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) . In another aspect, “treat, " “treating, “ or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treat, “treating, “ or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom) , physiologically, (e.g., stabilization of a physical parameter) , or both.
  • “treat, “ “treating, “ or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • subject in the context of the present disclosure is a mammal, e.g., a primate, preferably a higher primate, e.g., a human (e.g., a patient having, or at risk of having, a disorder described herein) .
  • the subject is a human or a patient.
  • cancer or “tumor” herein has the broadest meaning as understood in the art and refers to the physiological condition in mammals that is typically characterized by unregulated cell growth. In the context of the present disclosure, the cancer is not limited to certain type or location.
  • terapéuticaally effective amount refers to the amount of a Bcl-2 inhibitor that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to effect such treatment for the disease, disorder, or symptom.
  • the “therapeutically effective amount” can vary with the agent, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • the “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • the present disclosure provides a method of treating cancer in a subject with Bcl-2 inhibitor, in particularly 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (Compound 1) or a pharmaceutically acceptable salt thereof.
  • Bcl-2 inhibitor in particularly 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2
  • the Bcl-2 inhibitor in present disclosure is a compound represented by the following Formulas (III-B) , (III-C) , (III-D) or (III-E) ,
  • R 2 at each occurrence, is independently selected from the group consisting of hydrogen, halogen, or -C 1-8 alkyl optionally substituted with halogen;
  • R Ba , R Bb , and R Bc are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -NH 2 or -N (C 1-6 alkyl) 2 , -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R Bd is independently hydrogen, halogen, oxo, -CN, -NO 2 , -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 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy, -C 1-8 alkyoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • n is an integer of 1-4;
  • R 5 is –L 5 -CyC
  • CyC is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or two substituents R 5a ;
  • R 5b , R 5c , and R 5d are each independently hydrogen, -C 1-8 alkyl, -C 2- 8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2-8 alkenyl, C 2-8 alkynyl, -cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or two substituents R 5e ;
  • R 5f , R 5g , and R 5h are each independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 5i , R 5j , and R 5k are independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said -C 1-8 alkyl, -C 2- 8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with halogen, hydroxy or -C 1-8 alkyoxy;
  • R a , R b , R c , and R d at each occurrence are independently hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl are each independently substituted with –CN, halogen, -NO 2 , -NR e R f , oxo, -OR e , or –SR e ; and
  • R e and R f are each independently hydrogen, C 1-8 alkyl, C 1-8 alkoxy-C 1-8 alkyl-, C 2- 8 alkenyl, C 2-8 alkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.
  • R 2 is hydrogen
  • R 1d when substituted on the phenyl group at position 2 of ring B (including the aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-1-yl, azepan-1-yl, or azocan-1-yl, preferably the pyrrolidin-1-yl group) , is independently halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR Ba , - SO 2 R Ba , -CONR Ba R Bb , -NO 2 , -NR Ba R Bb , -NR Ba COR Bb , or -NR Ba SO 2 R Bb ; wherein said -C 1- 8 alkyl, -C 2-8 alkenyl,
  • R 1d is methyl, ethyl, isopropyl, propyl or methoxymethyl, or two methyl at position of the phenyl ring; or propenyl; or cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or ethoxy or isopropoxy; or amino or dimethylamino.
  • 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:
  • m is 1; and L 5 is a direct bond, - (CR a R b ) t -or -NR a -, wherein t is a number of 1 to 7, and one or two CR a R b moieties in - (CR a R b ) t -are un-replaced or replaced with one or more moieties selected from O and NR a , wherein R a and R b are defined with Formulas (III-B) , (III-C) , (III-D) or (III-E) .
  • L 5 is a direct bond, - (CR a R b ) 1-4 -, -O- (CR a R b ) 1-3 -, -NH- (CR a R b ) 1- 3 , or -NH-, wherein R a and R b are defined as with Formulas (III-B) , (III-C) , (III-D) or (III-E) , so that the –L 5 -CyC moiety is CyC, - (CR 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.
  • L 5 is a direct bond, - (CH 2 ) 1-4 -, -O- (CH 2 ) 1- 3 -, -NH- (CR a R b ) - (CH 2 ) 2 -, or -NH-, wherein R a is hydrogen and R b is C 1-8 alkyl optionally substituted with phenyl-S-so that the –L 5 -CyC moiety is CyC, - (CH 2 ) 1-4 -CyC, -O- (CH 2 ) 1-3 -CyC, -NH- (CR a R b ) - (CH 2 ) 2 -CyC, or -NH-CyC, respectively.
  • L 5 is a direct bond, -CH 2 -, -O-CH 2 -, -NH-CH 2 -, or -NH-so that the –L 5 -CyC moiety is CyC, -CH 2 -CyC, -O-CH 2 -CyC, -NH-CH 2 -CyC, or -NH-CyC, respectively.
  • CyC is cycloalkyl, or heterocyclyl, each of which is optionally substituted with one or two substituents R 5a ;
  • R 5a is independently selected from hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 alkyl, -C 2-8 alkynyl, -cycloalkyl, or heterocyclyl, each of said -C 1- 8 alkyl, and heterocyclyl is optionally substituted with one or two substituents R 5e which is selected from hydrogen, halogen, cyano, -OR 5f , -C 1-8 alkyl, -cycloalkyl, or heterocyclyl;
  • R 5b , and R 5c are each independently hydrogen, -C 1-8 alkyl or heterocyclyl, said -C 1-8 alkyl is optionally substituted with one or two substituents R 5e which is hydrogen, -NR 5f R 5g , or -cycloalkyl;
  • R 5f and R 5g are each independently hydrogen or -C 1-8 alkyl
  • CyC is cycloalkyl selected from monocyclic C 3-8 cycloalkyl or bridged cycloalkyl each of which is optionally substituted with one or two substituents R 5a .
  • CyC is cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two substituents R 5a .
  • CyC is heterocyclyl selected from:
  • CyC is monocyclic 4 to 6-membered heterocyclyl groups containing one nitrogen or oxygen or sulfur heteroatom as ring member. More preferably, Cyc is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, and piperdinyl.
  • CyC is selected from oxetan-2-yl, Oxetan-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, azetidin-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperdin-4-yl, piperdin-2-yl, and piperdin-3-yl.
  • CyC is monocyclic 6-membered heterocyclyl group containing two heteroatoms selected from oxygen and nitrogen as ring members. More preferably, CyC is dioxanyl, morpholino, morpholinyl, or piperzinyl. Even more preferably 1, 3-dioxan-2-yl, 1, 3-dioxan-4-yl, 1, 4-dioxan-2-yl, morpholin-1-yl, morpholin-2-yl, or morpholin-3-yl.
  • R 5a is independently selected from hydrogen, halogen, cyano, oxo, -OR 5b , -NR 5b R 5c , -COR 5b , -SO 2 R 5b , -C 1-8 alkyl, -C 2-8 alkynyl, monocyclic C 3-8 cycloalkyl, or monocyclic 4 to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatom as ring members, each of said -C 1-8 alkyl and monocyclic 4 to 9-membered heterocyclyl group is optionally substituted with one or two substituents R 5e ; preferably, cycloalkyl as R 5a is C 3-6 cycloalkyl; more preferably cyclopropyl; preferably, heterocyclyl as R 5a is 4 to 6-membered heterocyclyl groups containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatom as ring members;
  • heterocyclyl as R 5e is monocyclic 4 to 9-membered heterocyclyl group containing one or two heteroatoms selected from nitrogen or oxygen or sulfur heteroatom as ring members.
  • heterocyclyl as R 5e is tetrahydro-pyran-4-yl.
  • R 5a is -NR 5b R 5c , wherein R 5b is hydrogen, and R 5c is heterocyclyl.
  • R 5a is -NR 5b R 5c , wherein R 5b is hydrogen, and R 5c is tetrahydro-pyran-4-yl.
  • R 5a is -NR 5b R 5c , wherein R 5b and R 5c are each independently hydrogen or –C 1-6 alkyl substituted with cycloalkyl, preferably –C 1-6 alkyl substituted with monocyclic C 3-8 cycloalkyl.
  • R 5a is -OR 5b or -SO 2 R 5b , wherein R 5b is hydrogen or C 1-8 alkyl, preferably methyl.
  • R 5a is -COR 5b , wherein R 5b is hydrogen or C 1-8 alkyl optionally substituted with -NR 5f R 5g , wherein R 5f and R 5g are each independently hydrogen or C 1-8 alkyl, preferably methyl.
  • two adjacent R 5 on the phenyl ring together with the phenyl ring form indazolyl which is substituted with tetrahydropyranyl.
  • m is 1, and R 5 is -L 5 -CyC selected from the group consisting of:
  • m is 1 and R 5 is
  • the Bcl-2 inhibitor in present disclosure is selected form the group consist of:
  • the Bcl-2 inhibitor in present disclosure is 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -N- ( (4- ( ( ( (1r, 4r) -4-hydroxy-4-methylcyclohexyl) methyl) amino) -3-nitrophenyl) sulfonyl) -4- (2- ( (S) -2- (2-isopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonan-7-yl) benzamide (Compound 1) or a pharmaceutically acceptable salt thereof.
  • 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
  • Step 3 methyl 2- ( (1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4- (2-oxo-7-azaspiro [3.5] nonan- 7-yl) benzoate
  • Step 4 (S) -tert-butyl 2- (2- (prop-1-en-2-yl) phenyl) pyrrolidine-1-carboxylate
  • Step 5 (S) -tert-butyl 2- (2-isopropylphenyl) pyrrolidine-1-carboxylate
  • Step 6 (S) -2- (2-isopropylphenyl) pyrrolidine hydrochloride
  • 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
  • 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
  • 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
  • the present disclosure provides a method of treating cancer.
  • the method comprises administering to a patient in need an effective amount of Compound 1.
  • the cancer can include, without limitation, B-cell malignancies, lymphoma or leukemia, selected from the group consisting of acute myeloid leukemias (AML) , B-cell non-Hodgkin's lymphoma (B-NHL) ) , indolent B-cell Non-Hodgkin Lymphoma (NHL) , diffuse large B-cell lymphomas (DLBCL) , Germinal center B-cell like diffuse large B-cell lymphomas (GCB-DLBCL) , follicular lymphomas (FL) , mantle cell lymphomas (MCL) , acute lymphoblastic leukemia (ALL) , chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and marginal zone lymphoma (MZL) .
  • AML acute myeloid
  • Compound 1 can be administered by any suitable means, including oral, parenteral, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Dosing can be by any suitable route. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.
  • Compound 1 would be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. Compound 1 is optionally formulated with one or more agents currently used to prevent or treat the disorder in question. The effective amount of such other agents depends on the amount of Compound 1 in the formulation, the type of disorder or treatment, and other factors discussed above.
  • Compound 1 For the prevention or treatment of disease, the appropriate dosage of Compound 1 will depend on the type of disease to be treated, the severity and course of the disease, whether Compound 1is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to Compound 1, and the discretion of the attending physician. Compound 1 is suitably administered to the patient at one time or over a series of treatments.
  • Example 1 Efficacy study of Bcl-2 inhibitors in RS4; 11 acute lymphoblastic leukemia (ALL) subcutaneous xenograft model
  • the RS4; 11 cells are of acute lymphoblastic leukemia (ALL) origin and were obtained from American Type Culture Collection (ATCC CRL-1873, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 ⁇ g/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . RS4; 11 cells were maintained as suspension cell cultures at 37 °C in a 5%CO 2 atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center.
  • ALL acute lymphoblastic leukemia
  • mice were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water.
  • SPF pathogen free
  • Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 20-26 °C and 37-62%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .
  • RS4 11 cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 5 ⁇ 10 7 cells/mL.
  • Re-suspended cells were placed on ice prior to inoculation.
  • the right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation.
  • Each animal was injected subcutaneously with 1 ⁇ 10 7 cells in 200 ⁇ L of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.
  • mice were randomly assigned into 10 groups with 10 mice per group according to body weight and tumor volume (100 mm 3 -200 mm 3 ) .
  • the groups consisted of vehicle group, 5, 15, 50 mg/kg of venetoclax with QD dosing, 5, 15, 50 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5, 25 mg/kg of Compound 1with BID dosing.
  • Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.
  • Agent Dose (mg/kg) Schedule Route Mean Tumor volume (Day 42) (mm 3 ⁇ SEM) Vehicle Vehicle BID ⁇ 21 p.o. >2000 Compound 1 2.5 BID ⁇ 42 p.o. 512.5 ⁇ 115.9 Compound 1 7.5 BID ⁇ 42 p.o. 252.8 ⁇ 48.3 Compound 1 25 BID ⁇ 42 p.o. 136.6 ⁇ 2.2 Compound 1 5 QD ⁇ 42 p.o. 820.9 ⁇ 140.2 Compound 1 15 QD ⁇ 42 p.o. 312.6 ⁇ 57.9 Compound 1 50 QD ⁇ 42 p.o. 141.8 ⁇ 5.1 Venetoclax 5 QD ⁇ 35 p.o. >2000 Venetoclax 15 QD ⁇ 42 p.o. 1070.6 ⁇ 181.1 Venetoclax 50 QD ⁇ 42 p.o. 288.4 ⁇ 37.8
  • Example 2 Efficacy study of Bcl-2 inhibitors in MAVER-1 mantle cell lymphoma (MCL) subcutaneous xenograft model
  • MAVER-1 cells are of mantle cell lymphoma (MCL) origin and were obtained from American Type Culture Collection (ATCC CRL-3008, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 ⁇ g/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . MAVER-1 cells were maintained as suspension cell cultures at 37 °C in a 5%CO 2 atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center.
  • mice were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water.
  • SPF pathogen free
  • Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 21-26 °C and 44-61%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .
  • MAVER-1 cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 1.5 ⁇ 10 7 cells/mL.
  • Re-suspended cells were placed on ice prior to inoculation.
  • the right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation.
  • Each animal was injected subcutaneously with 3 ⁇ 10 6 cells in 200 ⁇ L of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.
  • mice were randomly assigned into 7 groups with 10 mice per group according to body weight and tumor volume (100 mm 3 -200 mm 3 ) .
  • the groups consisted of vehicle group, 5, 15 mg/kg of venetoclax with QD dosing, 5, 15 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5 mg/kg of Compound 1 with BID dosing.
  • Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.
  • Example 3 Efficacy study of Bcl-2 inhibitors in Toledo diffuse large B cell lymphoma (DLBCL) subcutaneous xenograft model
  • Toledo cells are of diffuse large B cell lymphoma (DLBCL) origin and were obtained from American Type Culture Collection (ATCC CRL-2631, Manassas, VA, DC, USA) . Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 ⁇ g/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . Toledo cells were maintained as suspension cell cultures at 37 °C in a 5%CO 2 atmosphere. Five to six-week-old female NCG mice were purchased from Gempharmatech of Information Technology Center.
  • DLBCL diffuse large B cell lymphoma
  • mice were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water.
  • SPF pathogen free
  • Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 21-26 °C and 35-61%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radiosterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .
  • Transplanted animals were randomized into 10 groups with 10 mice per group on day 0 according to transplantation sequence and body weight.
  • the groups consisted of vehicle group, 5, 15, 50 mg/kg of venetoclax with QD dosing, 5, 15, 50 mg/kg of Compound 1 with QD dosing, and 2.5, 7.5, 25 mg/kg of Compound 1 with BID dosing.
  • Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.
  • Example 4 Efficacy study of Bcl-2 inhibitors in RS4; 11 Bcl-2G101V KI acute lymphoblastic leukemia (ALL) subcutaneous xenograft model
  • the RS4; 11 Bcl-2G101V KI cells are of acute lymphoblastic leukemia (ALL) origin and were screened in house. Cells were grown in RPMI 1640 medium (Corning, Cat#10-040-CVR) , supplemented with 10% (v/v) fetal bovine serum (Gibco, Cat#10099-141C) , and 100 ⁇ g/mL of penicillin and streptomycin (Gibco, Cat#15140-122) . RS4; 11 Bcl-2G101V KI cells were maintained as suspension cell cultures at 37 °C in a 5%CO 2 atmosphere. Five to six-week-old female NCG mice were supplied by GemPharmatech Co., Ltd, Jiangsu, China.
  • ALL acute lymphoblastic leukemia
  • mice were maintained under specific pathogen free (SPF) “full barrier” condition with free access to food and water.
  • SPF pathogen free
  • Mice were group-housed under a 12 h light: dark cycle (lights on at 08: 00 h) , at a temperature of 20-26 °C and 37-62%humidity in IVC cages (Lingyunboji (Beijing) Technology Co., Ltd. ) . Mice were fed with complete granulated feed with Co60 radio sterilization (Beijing Ke Ao Xie Li Feed Co., Ltd. ) .
  • RS4; 11 Bcl-2G101V KI cells were harvested and re-suspended with appropriate volume of ice cold DPBS and same volume of Matrigel (Corning, Cat#356237) to give a final concentration of 5 ⁇ 10 7 cells/mL.
  • Re-suspended cells were placed on ice prior to inoculation.
  • the right front flank region of each mouse was cleaned with 75%ethanol prior to cell inoculation.
  • Each animal was injected subcutaneously with 1 ⁇ 10 7 cells in 200 ⁇ L of cell suspension in the right front flank via a 26-gauge needle. After implantation, primary tumor volume was measured in two dimensions using a caliper.
  • mice were randomly assigned into 7 groups with 8 mice per group according to body weight and tumor volume (around 300 mm 3 ) .
  • the groups consisted of vehicle group, 15, 50 and 100 mg/kg of venetoclax with QD dosing, 15, 50 and 100 mg/kg of Compound 1 with QD dosing.
  • Treatments were administered by oral gavage (p.o. ) in a volume of 10 mL/kg body weight. Body weight was assessed immediately before dosing and volume dosed was adjusted accordingly.
  • VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood 103, 2276-2283
  • Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.
  • Cell 75, 229–240.

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Abstract

L'invention concerne des méthodes de traitement du cancer chez un sujet avec un inhibiteur de Bcl-2, en particulier du 2-(1H-pyrrolo[2, 3-b]pyridin-5-yl)oxy)-N-(4-((((1r, 4r)-4-hydroxy-4-méthylcyclohexyl)méthyle) amino)-3-nitrophényle)sulfonyl)-4-(2-((S)-2-(2-isopropylphényl)pyrrolidin-1-yl)-7-azaspiro[3,5]nonan-7-yl) benzamide ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/133636 2019-12-02 2020-12-03 Procédés de traitement du cancer utilisant un inhibiteur de bcl-2 Ceased WO2021110102A1 (fr)

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WO2021223736A1 (fr) * 2020-05-08 2021-11-11 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
CN115490708A (zh) * 2021-06-18 2022-12-20 苏州亚盛药业有限公司 磺酰胺类大环衍生物及其制备方法和用途
WO2023030363A1 (fr) * 2021-08-31 2023-03-09 Beigene, Ltd. Formes solides d'inhibiteurs de bcl-2, procédé de préparation et utilisation correspondante
WO2023218410A1 (fr) * 2022-05-12 2023-11-16 Beigene Switzerland Gmbh Méthodes de traitement de malignités myéloïdes à l'aide d'un inhibiteur de bcl-2
WO2023231777A1 (fr) * 2022-06-01 2023-12-07 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
WO2024017354A1 (fr) * 2022-07-21 2024-01-25 Beigene, Ltd. Méthodes de traitement du myélome multiple à l'aide d'un inhibiteur de bcl-2
WO2024140690A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Intermédiaires de sonrotoclax et leur procédé de préparation
WO2024140678A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Intermédiaire protégé par cétal pour sonrotoclax et son procédé de préparation
WO2024140692A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Sels et formes solides d'un intermédiaire de sonrotoclax
US12077536B2 (en) 2018-04-29 2024-09-03 Beigene, Ltd. BCL-2 inhibitors
EP4351542A4 (fr) * 2021-06-02 2025-04-09 BeiGene Switzerland GmbH Méthodes de traitement de la malignité des lymphocytes b au moyen d'un inhibiteur de bcl-2
US12286430B2 (en) 2020-04-15 2025-04-29 Beigene, Ltd. Bcl-2 inhibitor
US12516053B2 (en) 2019-10-28 2026-01-06 Beone Medicines I Gmbh Bcl-2 inhibitors

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US12077536B2 (en) 2018-04-29 2024-09-03 Beigene, Ltd. BCL-2 inhibitors
US12516053B2 (en) 2019-10-28 2026-01-06 Beone Medicines I Gmbh Bcl-2 inhibitors
US12286430B2 (en) 2020-04-15 2025-04-29 Beigene, Ltd. Bcl-2 inhibitor
WO2021223736A1 (fr) * 2020-05-08 2021-11-11 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
EP4351542A4 (fr) * 2021-06-02 2025-04-09 BeiGene Switzerland GmbH Méthodes de traitement de la malignité des lymphocytes b au moyen d'un inhibiteur de bcl-2
CN115490708A (zh) * 2021-06-18 2022-12-20 苏州亚盛药业有限公司 磺酰胺类大环衍生物及其制备方法和用途
WO2023030363A1 (fr) * 2021-08-31 2023-03-09 Beigene, Ltd. Formes solides d'inhibiteurs de bcl-2, procédé de préparation et utilisation correspondante
WO2023218410A1 (fr) * 2022-05-12 2023-11-16 Beigene Switzerland Gmbh Méthodes de traitement de malignités myéloïdes à l'aide d'un inhibiteur de bcl-2
WO2023231777A1 (fr) * 2022-06-01 2023-12-07 Fochon Pharmaceuticals, Ltd. Composés en tant qu'inhibiteurs de bcl-2
WO2024017354A1 (fr) * 2022-07-21 2024-01-25 Beigene, Ltd. Méthodes de traitement du myélome multiple à l'aide d'un inhibiteur de bcl-2
WO2024140692A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Sels et formes solides d'un intermédiaire de sonrotoclax
WO2024140678A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Intermédiaire protégé par cétal pour sonrotoclax et son procédé de préparation
WO2024140690A1 (fr) * 2022-12-27 2024-07-04 Beigene (Suzhou) Co., Ltd. Intermédiaires de sonrotoclax et leur procédé de préparation

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