WO2023122000A1 - Inhibiteurs de bcl-2 - Google Patents

Inhibiteurs de bcl-2 Download PDF

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Publication number
WO2023122000A1
WO2023122000A1 PCT/US2022/053328 US2022053328W WO2023122000A1 WO 2023122000 A1 WO2023122000 A1 WO 2023122000A1 US 2022053328 W US2022053328 W US 2022053328W WO 2023122000 A1 WO2023122000 A1 WO 2023122000A1
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tetrahydro
heterocyclic
oxazin
alkyl
nitro
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English (en)
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Yi Chen
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Guangzhou Lupeng Pharmaceutical Co Ltd
Newave Pharmaceutical Inc
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Guangzhou Lupeng Pharmaceutical Co Ltd
Newave Pharmaceutical Inc
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Priority claimed from PCT/US2021/064278 external-priority patent/WO2022140224A1/fr
Priority claimed from PCT/US2022/034518 external-priority patent/WO2023121713A1/fr
Application filed by Guangzhou Lupeng Pharmaceutical Co Ltd, Newave Pharmaceutical Inc filed Critical Guangzhou Lupeng Pharmaceutical Co Ltd
Priority to US18/721,999 priority Critical patent/US20250114374A1/en
Publication of WO2023122000A1 publication Critical patent/WO2023122000A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Apoptosis or programmed cell death, is a conserved and regulated process that is the primary mechanism for the removal of aged, damaged and unnecessary cells.
  • the ability to block apoptotic signaling is a key hallmark of cancer and is thus important for oncogenesis, tumor maintenance and chemoresistance [Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57-70 (2000).].
  • BCL-2-associated X protein for example, BCL-2-associated X protein (BAX), BCL-2 antagonist/killer 1 (BAK), BCL-2- associated agonist of cell death (BAD), BC L-2— like 11 (BIM), NOXA and BCL-2 binding component 3 (PUMA)
  • prosurvival BCL-2, BCL-XL, BCL-2— like 2 (BCL-W), myeloid cell leukemia sequence 1 (MCL-1) and BCL-2- related protein A1 (BFL-1 ) proteins in the BCL-2 family control commitment to programmed cell death. Altering the balance among these opposing factions provides one means by which cancer cells undermine normal apoptosis and gain a survival advantage [Youle, R.J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 9, 47-59 (2008)].
  • BCL-2 the first identified apoptotic regulator, was originally cloned from the breakpoint of a t(14; 18) translocation present in human B cell lymphomas [Tsujimoto, Y., et al. Science 228, 1440-1443 (1985); Cleary, M.L., et al Cell 47, 19-28 (1986); Boise, L.H. et al. Cell 74, 597-608 (1993)].
  • This protein has since been shown to have a dominant role in the survival of multiple lymphoid malignancies [Vaux, D.L., et al pre-B cells. Nature 335, 440-442 (1988)].
  • Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers and disorders of the immune system.
  • Bcl-2 inhibitors such as ABT-737, ABT-263, and ABT-199 as shown below have been identified and entered human clinical trials for cancers treatment.
  • ABT-737 is discovered by nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure based fragment drug design [Tillman Oltersdorf, et al, Nature, Vol 435, 2005, p 677], ABT-737 a smallmolecule inhibitor of the anti-apoptotic proteins Bd-2, Bcl-XL and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation.
  • NMR nuclear magnetic resonance
  • ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumors, and produces cures in a high percentage of the mice.
  • ABT-737 is not orally bioavailable, and its formulation for intravenous delivery is hampered by its low aqueous solubility.
  • ABT-263 (Navitoclax) has been developed [Cheol-Min Park, et al J. Med. Chem. 2008, 51, 6902-6915].
  • ABT-263 is a potent inhibitor of Bcl-xL, Bcl-2 and Bcl-w with Ki of ⁇ 0.5 nM, ⁇ 1 nM and ⁇ 1 nM.
  • ABT -263 has an IC50 of 110 nM against SCLC H146 cell line.
  • ABT-263 When ABT-263 is administered at 100 mg/kg/day in the H345 xenograft model, significant antitumor efficacy is observed with 80% TGI and 20% of treated tumors indicating at least a 50% reduction in tumor volume.
  • Oral administration of ABT-263 alone causes complete tumor regressions in xenograft models of smallcell lung cancer and acute lymphoblastic leukemia [Tse C, et al. Cancer Res. 2008, 68(9), 3421-3428].
  • the inhibition of BCL-XL by ABT-263 navitoclax
  • This mechanism-based thrombocytopenia is the dose-limiting toxicity of single-agent navitoclax treatment in patients and limits the ability to drive drug concentrations into a highly efficacious range.
  • a BCL-2 selective (BCL-XL sparing) inhibitor would culminate in substantially reduced thrombocytopenia while maintaining efficacy in lymphoid malignancies.
  • the resulting increase in the therapeutic window should allow for greater BCL-2 suppression and clinical efficacy in BCL-2-dependent tumor types.
  • ABT-199 GDC-0199
  • ABT-199 is a Bcl-2-selective inhibitor with Ki of ⁇ 0.01 nM, >4800-fold more selective versus Bd-xL and Bcl-w, and no activity to Mcl-1.
  • ABT-199 potently inhibits RS4; 11 cells with EC50 of 8 nM.
  • ABT-199 induces a rapid apoptosis in RS4; 11 cells with cytochrome c release, caspase activation, and the accumulation of sub-G0/G1 DNA.
  • Quantitative immunoblotting reveals that sensitivity to ABT-199 correlated strongly with the expression of Bcl-2, including NHL, DLBCL, MOL, AML and ALL cell lines.
  • ABT-199 also induces apoptosis in CLL with an average EC50 of 3.0 nM.
  • a single dose of 100 mg/kg of ABT-199 causes a maximal tumor growth inhibition of 95% and tumor growth delay of 152% in RS4;11 xenografts.
  • ABT-199 also inhibits xenograft growth (DoHH2, Granta-519) as a single agent or in combination with Bendamustine and other agents.
  • Human Phase I and II data showed that ABT-199 is highly efficacious for CLL who have 17p deletion, and was approved by FDA in 2016.
  • WO/2017/132474, WO/2019/040550, and WO/2019/040573 disclosed a novel class of BCL-2 inhibitors. However, there is still a strong need for continuing search in this field of art for more potent BCL-2 inhibitor.
  • this invention provides compounds of the Formula (1) or an N-oxide thereof, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug of said compound of Formula (1) or N-oxide thereof:
  • G is C(O), S(O 2 ), P(O)(R a ), or S(O)(NR a );
  • E is S(O 2 ), P(O)(R a ), S(O)(NR a ) or C(O);
  • Qi is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Q 2 is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Q3 is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Q4 is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Q5 is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Qs is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Q? is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents;
  • Qs is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents; one or more (e.g., both) border ring atom(s) between ring Qs and the ring with Z 2 can be carbon or heteroatom(s);
  • Q x is a cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or heteroaryl, each of the aforementioned is optionally substituted with one or more independently selected Rd substituents; each R1 is independently H, D, halo, cyano, nitro, alkyl, alkylene-R a , alkylene-P(O)RbR c , alkenyl, alkynyl, -C(O)R a , -C(O)NR b R c , -C(O)OR a , -NH(CH 2 ) p R a , -NR b R c , -NR b C(O)
  • R5 and Rs taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rd substituents; each R?
  • each R x is independently H, D, halo, cyano, nitro, alkyl, alkylene-R a , alkylene-P(O)RbR c , alkenyl, alkynyl, NRbS(O) 2 R c , -N S(O) 2 NRbR c , cycloalkyl, cycloalkenyl, spirocycloalkyl, fused-carbocyclic, bridged-carbocyclic, heterocycloalkyl, heterocycloalkenyl, spiro-heterocyclic, fused-heterocyclic, bridged-heterocyclic, aryl, or hetero
  • R4 and R x taken together with the atom(s) to which they are attached, independently form a cycloalkyl or heterocycloalkyl, wherein each cycloalkyl or heterocycloalkyl is optionally and independently substituted with one or more independently selected Rd substituents;
  • Z1 is a bond, (CR a Rb) P , a bivalent alkenyl group, or a bivalent alkynyl group, N(R a ), 0, S, C(0), S(0 2 ), -O(CR a R b )p-, -N(R a )(CR a R b )p-, 0C(0), C(0)0, 0S0 2 , S(0 2 )0, C(O)S, SC(O), C(0)C(0), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), 0C(0)0, OC(O)S, OC(O)N(R a ), N(R a )C(O)O, N(R a )C(O)S, N(R a )C(O)N(R a ), (CR a
  • Z 2 is a bond, (CR a Rb) P , a bivalent alkenyl group, or a bivalent alkynyl group, N(R a ), 0, S, C(0), S(0 2 ), -O(CR a R b )p-, -N(R a )(CR a R b )p-, 0C(0), C(0)0, 0S0 2 , S(0 2 )0, C(O)S, SC(O), C(0)C(0), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), 0C(0)0, OC(O)S, OC(O)N(R a ), N(R a )C(O)O, N(R a )C(O)S, N(R a )C(O)N(R a ), (CR a
  • Z4 is a bond, (CR a Rb) P , a bivalent alkenyl group, or a bivalent alkynyl group, N(R a ), 0, S, C(0), S(0 2 ), -O(CR a R b )p-, -N(R a )(CR a R b )p-, 0C(0), C(0)0, 0S0 2 , S(0 2 )0, C(O)S, SC(O), C(0)C(0), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), 0C(0)0, OC(O)S, OC(O)N(R a ), N(R a )C(O)O, N(R a )C(O)S, N(R a )C(O)N(R a ), (CRaR
  • Z5 is a bond, (CR a R b ) P , a bivalent alkenyl group, or a bivalent alkynyl group, N(R a ), 0, S, C(O), S(O 2 ), -O(CR a R b )p-, -N(Ra)(CR a R b )p-, OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(R a ), N(R a )C(O), S(O 2 )N(R a ), N(R a )S(O 2 ), OC(O)O, OC(O)S, OC(O)N(R a ), N(R a )C(O)O, N(R a )C(O)S, N(Ra)C(O)N(R a ), (
  • L is absent, a bond, (CR a R b ) P , N(R C ), 0, S, C(O), S(O 2 ), -O(CR a R b ) P -, -N(R c )(CR a R b ) P -, OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(R c ), N(R c )C(O), S(O 2 )N(R C ), N(R C )S(O 2 ), OC(O)O, OC(O)S, OC(O)N(R c ), N(R c )C(O)O, N(R c )C(O)S, N(R c )C(O)N(R c ), (CRaR b )pN(R c )(CR
  • the invention provides a compound represented by Formula (2):
  • the invention provides a compound represented by Formula (3):
  • W 4 is C(R a ) or N.
  • the invention provides a compound represented by Formula (4):
  • the invention provides a compound represented by Formula (5):
  • the invention provides a compound represented by Formula (6):
  • the invention provides a compound represented by Formula (7):
  • W 7 is N, or C(R a ).
  • the invention provides a compound represented by Formula (8):
  • W 7 is N, or C(Ra);
  • Z 3 is a bond, (CH 2 ) P , N(H), 0, S, C(O), S(O 2 ), OC(O), C(O)O, OSO 2 , S(O 2 )O, C(O)S, SC(O), C(O)C(O), C(O)N(H), N(H)C(O), S(O 2 )N(H), N(H)S(O 2 ), OC(O)O, OC(O)S, OC(O)N(H), N(H)C(O)O, N(H)C(O)S, N(H)C(O)N(H), (CH 2 ) P N(H)(CH 2 ) q , (CH 2 ) P N(H)C(O)(CH 2 ) q , (CH 2 ) P C(O)N(H)(CH 2 ) q , or OC(O)N(H)(CH 2 ) p+ iN(H)
  • a modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability, and/or therapeutic index as compared to the unmodified compound is also contemplated.
  • exemplary modifications include (but are not limited to) applicable prodrug derivatives, and deuterium-enriched compounds.
  • a pharmaceutical composition containing one or more of the compounds (such as any one of those in Formulae (1-7), (A-E), (l-VIII), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof or an N-oxide thereof), modifications, and/or salts thereof described herein, and a pharmaceutically acceptable diluent or carrier, for use in treating a neoplastic disease, therapeutic uses thereof, and use of the compounds for the manufacture of a medicament for treating the disease / disorder.
  • the compounds such as any one of those in Formulae (1-7), (A-E), (l-VIII), or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof or an N-oxide thereof
  • a pharmaceutically acceptable diluent or carrier for use in treating a neoplastic disease, therapeutic uses thereof, and use of the compounds for
  • This invention also relates to a method of treating a neoplastic disease, an autoimmune disease, or a neorodegenerative disease, comprising administering to a subject in need thereof an effective amount of one or more compounds of the invention (such as any one of those in Formulae (1-7), (A-E), (l-VIII),, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof or an N-oxide thereof), modifications, and/or salts thereof described herein, or a pharmaceutical composition comprising the compound(s) of the invention.
  • compounds of the invention such as any one of those in Formulae (1-7), (A-E), (l-VIII),, or a pharmaceutically acceptable salt, solvate, polymorph, tautomer, stereoisomer, an isotopic form, or a prodrug thereof or an N-oxide thereof
  • modifications, and/or salts thereof described herein or a pharmaceutical composition comprising the
  • the neoplastic disease, autoimmune disease, or neorodegenerative disease is characterized by abnormal (e.g., enhanced or increased) Bcl-2 activity.
  • the neoplastic disease can be a hematological malignancy or cancer including solid tumor; the autoimmune disease can be type I diabetes; and the neorodegenerative disease can be schizophrenia.
  • the neoplastic disease is myeloma, multiple myeloma, lymphoma, follicular lymphoma (FL), non-Hodgkin’s lymphoma, leukemia, acute leukemia, acute lymphoblastic leukemia (ALL) (such as BCL-2-dependent ALL and pediatric ALL), chronic lymphoblastic leukemia (CLL) (such as relapsed/refractory CLL, del(17p) CLL), chronic myeloid leukemia (CML) (such as blast-crisis CML), mantle cell lymphoma (MOL), diffuse large B-cell lymphoma, lung cancer such as small cell lung cancer (SCLC), melanoma, breast cancer, or prostate cancer, including drug-resistant cancer thereof.
  • ALL acute leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukemia
  • CML chronic myeloid leukemia
  • MOL mantle cell lymphoma
  • the method further comprises administering one or more further treatment(s) effective to treat the neoplastic disease, such as surgery, radiation therapy, a chemotherapeutic agent (such as bendamustine, NL-101 (7-(5-(bis(2-chloroethyl)amino)-1-methyl-1 H-benzo[d]imidazol-2-yl)-N- hydroxyheptanamide), cisplatin, carboplatin, etoposide, topotecan), a target thearpy (e.g., an anti-CD20 antibody such as rituximab, a Bruton's tyrosine kinase inhibitor such as ibrutinib and acalabrutinib (ACP-196), a PI3K5 inhibitor such as idelalisib); an antibody-drug conjugate or ADC (such as anti-CD30 ADC brentuximab vedotin), an immunotherapeutic agent (
  • Also provided herein is the use of one or more compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds of the invention, for the preparation of a medicament for the treatment of the above-referenced diseases or conditions.
  • the compounds of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more of the disclosed compounds are for use in treating the above-referenced diseases or conditions.
  • Exemplary compounds described herein include, but are not limited to, the following:
  • Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof.
  • the syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art.
  • Each of the asymmetric carbon atoms may be in the R or S configuration, and both of these configurations are within the scope of the invention.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
  • geometric isomer refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans).
  • a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geomeric isomers in the mixture.
  • Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic ) of the compound.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • a modified compound of any one of such compounds including a modification having an improved (e.g., enhanced, greater) pharmaceutical solubility, stability, bioavailability and/or therapeutic index as compared to the unmodified compound is also contemplated.
  • the examples of modifications include but not limited to the prodrug derivatives, and the deuterium-enriched compounds. For example:
  • Prodrug derivatives prodrugs, upon administration to a subject, will converted in vivo into active compounds of the present invention [Nature Reviews of Drug Discovery, 2008, Volume 7, p255]. It is noted that in many instances, the prodrugs themselves also fall within the scope of the range of compounds according to the present invention.
  • the prodrugs of the compounds of the present invention can be prepared by sta dard organic reaction, for example, by reacting with a carbamylating agent (e.g., 1 , 1 -acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, or the like) or an acylating agent. Further examples of methods and strategies of making prodrugs are described in Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985.
  • deuterium-enriched compounds deuterium (D or 2 H) is a stable, non-radioactive isotope of hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as a mixture of the isotopes X H (hydrogen or protium), D ( 2 H or deuterium), and T ( 3 H or tritium). The natural abundance of deuterium is 0.015%.
  • the H atom actually represents a mixture of H and D, with about 0.015% being D.
  • compounds with a level of deuterium that has been enriched to be greater than its natural abundance of 0.015% should be considered unnatural and, as a result, novel over their nonenriched counterparts.
  • the compounds of the present invention may be present and optionally administered in the form of salts, and solvates.
  • the invention encompasses any pharmaceutically acceptable salts and solvates of any one of the above-described compounds and modifications thereof.
  • the compounds of the present invention possess a free base form
  • the compounds can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids such as sulfate, nitrate, phosphate, etc.; and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • a pharmaceutically acceptable inorganic or organic acid e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids such as sulfate, nitrate, phosphate, etc.
  • Further acid addition salts of the present invention include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenz
  • a pharmaceutically acceptable base addition salt can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • bases include alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine.
  • aluminum salts of the compounds of the present invention are alkali metal hydroxides including potassium, sodium and lithium hydroxides; alkaline earth metal hydroxides such as barium and calcium hydroxides; alkali metal alkoxides, e.g., potassium ethanolate and sodium propanolate; and various organic bases such as ammonium hydroxide, piperidine, diethanolamine and N-methylglutamine.
  • aluminum salts of the compounds of the present invention are also included.
  • Organic base salts of the present invention include, but are not limited to: copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium and zinc salts.
  • Organic base salts include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g., arginine, betaine, caffeine, chloroprocaine, choline, N.N’-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine, N-methyl-
  • a pharmaceutically acceptable salt is a hydrochloride salt, hydrobromide salt, methanesulfonate, toluenesulfonate, acetate, fumarate, sulfate, bisulfate, succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, biocarbonate, carbonate, sodium hydroxide salt, calcium hydroxide salt, potassium hydroxide salt, tromethamine salt, or mixtures thereof.
  • Compounds of the present invention that comprise tertiary nitrogen-containing groups may be quaternized with such agents as (CM) alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di-(Cu) alkyl sulfates, e.g., dimethyl, diethyl and diamyl sulfates; alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (CM) alkyl halides, e.g., benzyl chloride and phenethyl bromide.
  • Such salts permit the preparation of both water- and oil-soluble compounds of the invention.
  • Amine oxides also known as amine-W-oxide and W-oxide, of anti-cancer agents with tertiary nitrogen atoms have been developed as prodrugs [Mol Cancer Therapy. 2004 Mar; 3(3) :233-44]
  • Compounds of the present invention that comprise tertiary nitrogen atoms may be oxidized by such agents as hydrogen peroxide (H2O2), Caro’s acid or peracids like meta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.
  • H2O2 hydrogen peroxide
  • Caro Caro’s acid or peracids like meta-Chloroperoxybenzoic acid (mCPBA) to from amine oxide.
  • mCPBA meta-Chloroperoxybenzoic acid
  • the compounds disclosed therein are bcl-2 inhibitors.
  • the pharmaceutical composition of the present invention comprises one or more bcl-2 inhibitors, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCI, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • compositions of the present invention optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • pharmaceutically acceptable carriers and/or diluents therefor such as lactose, starch, cellulose and dextrose.
  • Other excipients such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes.
  • compositions of the present invention may further comprise other conventional pharmaceutically inactive agents.
  • Any inert excipient that is commonly used as a carrier or diluent may be used in compositions of the present invention, such as sugars, polyalcohols, soluble polymers, salts and lipids.
  • Sugars and polyalcohols which may be employed include, without limitation, lactose, sucrose, mannitol, and sorbitol.
  • Illustrative of the soluble polymers which may be employed are polyoxyethylene, poloxamers, polyvinylpyrrolidone, and dextran.
  • Useful salts include, without limitation, sodium chloride, magnesium chloride, and calcium chloride.
  • Lipids which may be employed include, without limitation, fatty acids, glycerol fatty acid esters, glycolipids, and phospholipids.
  • compositions of the present invention may further comprise binders (e.g., acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e.g., tris-HCL, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g., glycerol
  • the pharmaceutical compositions are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.
  • the invention encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the invention.
  • the compounds can be in a crystalline form, in amorphous form, and have any particle size.
  • the particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.
  • solubilizing the compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, pH adjustment and salt formation, using co-solvents, such as ethanol, propylene glycol, polyethylene glycol (PEG) 300, PEG 400, DMA (10-30%), DMSO (10-20%), NMP (10-20%), using surfactants, such as polysorbate 80, polysorbate 20 (1-10%), cremophor EL, Cremophor RH40, Cremophor RH60 (5-10%), Pluronic F68/Poloxamer 188 (20-50%), Solutol HS15 (20-50%), Vitamin E TPGS, and d-a-tocopheryl PEG 1000 succinate (20-50%), using complexation such as HP
  • co-solvents such as ethanol, propylene glycol, polyethylene
  • Compounds of the present invention may be administered or coadministered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, or intrathecally.
  • the compounds according to the invention may also be administered or coadministered in slow release dosage forms.
  • Compounds may be in gaseous, liquid, semi-liquid or solid form, formulated in a manner suitable for the route of administration to be used.
  • suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like.
  • suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • reconstitution of a lyophilized powder is typically used.
  • acyl means a carbonyl containing substituent represented by the formula -C(O)-R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein.
  • Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl.
  • “Aliphatic” means a moiety characterized by a straight or branched chain arrangement of constituent carbon atoms and may be saturated or partially unsaturated with one or more double or triple bonds.
  • alkyl refers to a straight or branched hydrocarbon containing 1-20 carbon atoms (e.g., Ci- Cio, Ci-Ce).
  • alkyl include, but are not limited to, methyl, methylene, ethyl, ethylene, n-propyl, i- propyl, n-butyl, i-butyl, and t-butyl.
  • the alkyl group has one to ten carbon atoms. More preferably, the alkyl group has one to four carbon atoms.
  • alkenyl refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C 2 - C10, C 2 -C 6 ) and one or more double bonds. Examples of alkenyl include, but are not limited to, ethenyl, propenyl, and allyl.
  • the alkylene group has two to ten carbon atoms. More preferably, the alkylene group has two to four carbon atoms.
  • alkynyl refers to a straight or branched hydrocarbon containing 2-20 carbon atoms (e.g., C2- C10, C 2 -C 6 ) and one or more triple bonds.
  • alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 1- and 2-butynyl, and 1-methyl-2-butynyl.
  • the alkynyl group has two to ten carbon atoms. More preferably, the alkynyl group has two to four carbon atoms.
  • alkylamino refers to an — N (R)-alkyl in which R can be H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
  • Alkoxy means an oxygen moiety having a further alkyl substituent.
  • Alkoxycarbonyl means an alkoxy group attached to a carbonyl group.
  • Oxoalkyl means an alkyl, further substituted with a carbonyl group.
  • the carbonyl group may be an aldehyde, ketone, ester, amide, acid or acid chloride.
  • cycloalkyl refers to a saturated hydrocarbon ring system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C8, Cs-Ce).
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkenyl refers to a non-aromatic hydrocarbon ring system having 3 to 30 carbons (e.g., C3-C12) and one or more double bonds. Examples include cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Spirocycloalkyl refers to a compound comprising two saturated cyclic alkyl rings sharing only one common atom (also known as a spiro atom), with no heteroatom and no unsaturated bonds on any of the rings.
  • the spiroalkyl is bicyclic.
  • the spiroalikyl has more than two cycles.
  • the spiroalkyl compound is a polyspiro compound connected by two or more spiroatoms making up three or more rings.
  • one of the rings of the bicyclic spiroalkyl has 3, 4, 5, 6, 7, or 8 atoms, including the common spito atom.
  • the spiroalkyl is a 5 to 20 membered, 5 to 14 membered, or 5 to 10 membered polycyclic spiroalkyl group.
  • Representative examples of spiroalkyl include, but are not limited to the following groups:
  • fused-carbocyclic refers to a polycyclic cyclyl group, wherein each ring in the group shares an adjacent pair of carbon atoms with another ring in the group, wherein one or more rings can contain one or more double bonds.
  • the fused heterocydyl is bicyclic.
  • the fused-carbocyclic contains more than two rings, at least two of which share an adjacent pair of atoms.
  • the fused-carbocyclic is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic cyclyl group.
  • Representative examples of fused-carbocyclic include, but are not limited to the following groups:
  • bridged-carbocyclic refers to a group having at least two rings sharing three or more common ring atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • the bridgehead atoms are the atoms from which three bonds radiate and where the rings meet.
  • the rings of the bridged carbocyclyl can have one or more double bonds.
  • the bridged carbocyclyl is bicyclic.
  • the bridged carbocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic carbocyclyl group.
  • Representative examples of bridged carbocyclyl include, but are not limited to the following groups:
  • heterocycloalkyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, 11-14 membered tricyclic, or 14-20 membered tetracyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se).
  • heterocycloalkyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.
  • heterocycloalkenyl refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, 11-14 membered tricyclic, or 14-20 membered tetracyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se) and one or more double bonds.
  • Spiroheterocyclyl refers to a compound comprising two non-saturated rings sharing only one common atom (also known as a spiro atom), with at least one heteroatom on one of the two rings, such as a polycyclic heterocyclyl group with rings connected through one common carbon atom.
  • the common atom can be carbon (C), silicon, or nitrogen (such as a positively charged quaternary nitrogen atom).
  • the heteroatoms can comprise nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, silicon, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C.
  • one or more of the rings may contain one or more double bonds.
  • the spiro heterocyclyl is bicyclic, with heteroatom(s) on either one or both cycles.
  • one of the rings of the bicyclic spiro heterocyclyl has 3, 4, 5, 6, 7, or 8 atoms, including the common spito atom.
  • the spiro heterocyclic compound is a polyspiro compound connected by two or more spiroatoms making up three or more rings.
  • the spiro heterocyclyl is a 5 to 20 membered, 5 to 14 membered, or 5 to 10 membered polycyclic heterocyclyl group. Representative examples of spiro heterocyclyl include, but are not limited to the following groups:
  • Fused heterocyclyl refers to a polycyclic heterocyclyl group, wherein each ring in the group shares an adjacent pair of atoms (such as carbon atoms) with another ring in the group, wherein one or more rings can contain one or more double bonds, and wherein said rings have one or more heteroatoms, which can be nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone, and the remaining ring atoms are C.
  • the fused heterocyclyl is bicyclic.
  • the fused heterocyclyl contains more than two rings, at least two of which share an adjacent pair of atoms.
  • the fused heterocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic heterocyclyl group.
  • Representative examples of fused heterocyclyl include, but are not limited to the following groups:
  • Bridged heterocyclyl refers to a compound having at least two rings sharing three or more common ring atoms, separating the two bridgehead atoms by a bridge containing at least one atom, wherein at least one ring atom is a heteroatom.
  • the bridgehead atoms are the atoms from which three bonds radiate and where the rings meet.
  • the rings of the bridged heterocyclyl can have one or more double bonds, and the ring heteroatom(s) can be nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), oxygen, and sulfur, including sulfoxide and sulfone as ring atoms, while the remaining ring atoms are C.
  • the bridged heterocyclyl is bicyclic.
  • the bridged heterocyclyl is a 5 to 20 membered, 5 to 16 membered, or 5 to 10 membered polycyclic heterocyclyl group.
  • Representative examples of bridged heterocyclyl include, but are not limited to the following groups:
  • aryl refers to a 6-carbon monocyclic, 10-carbon bicyclic, 14-carbon tricyclic aromatic ring system.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having one or more heteroatoms (such as O, N, S, P, or Se).
  • heteroaryl groups include pyridyl, furyl, imidazolyl, benzimidazolyl, pyrimidinyl, thienyl, quinolinyl, indolyl, and thiazolyl.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkylamino, spiroheterocydyl, fused heterocyclyl, bridged heterocyclyl, aryl, and heteroaryl mentioned above include both substituted and unsubstituted moieties.
  • alkyl, alkenyl, or alkynyl include all of the above-recited substituents except C1-C10 alkyl.
  • Cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl can also be fused with each other.
  • amino means a nitrogen moiety having two further substituents where each substituent has a hydrogen or carbon atom alpha bonded to the nitrogen.
  • the compounds of the invention containing amino moieties may include protected derivatives thereof. Suitable protecting groups for amino moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • “Aromatic” means a moiety wherein the constituent atoms make up an unsaturated ring system, all atoms in the ring system are sp2 hybridized and the total number of pi electrons is equal to 4n+2.
  • An aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon and non-carbon atoms (see Heteroaryl).
  • Carbamoyl means the radical -OC(O)NR a Rb where R a and Rb are each independently two further substituents where a hydrogen or carbon atom is alpha to the nitrogen. It is noted that carbamoyl moieties may include protected derivatives thereof. Examples of suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like. It is noted that both the unprotected and protected derivatives fall within the scope of the invention.
  • Carbonyl means the radical -C(O)-. It is noted that the carbonyl radical may be further substituted with a variety of substituents to form different carbonyl groups including acids, acid halides, amides, esters, and ketones.
  • Carboxy means the radical -C(O)O- It is noted that compounds of the invention containing carboxy moieties may include protected derivatives thereof, i.e., where the oxygen is substituted with a protecting group. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the like.
  • “Cyano” means the radical -CN.
  • Halo means fluoro, chloro, bromo or iodo.
  • Halo-substituted alkyl as an isolated group or part of a larger group, means “alkyl” substituted by one or more “halo” atoms, as such terms are defined in this Application.
  • Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like.
  • Haldroxy means the radical -OH.
  • stereoisomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and stereoisomers that are nonsuperimposable mirror images are termed “enantiomers” or sometimes “optical isomers.”
  • enantiomers or sometimes “optical isomers.”
  • a carbon atom bonded to four nonidentical substituents is termed a “chiral center.”
  • a compound with one chiral center has two enantiomeric forms of opposite chirality.
  • a mixture of the two enantiomeric forms is termed a “racemic mixture.”
  • Niro means the radical -NO2.
  • Protected derivatives means derivatives of compounds in which a reactive site are blocked with protecting groups. Protected derivatives are useful in the preparation of pharmaceuticals or in themselves may be active as inhibitors. A comprehensive list of suitable protecting groups can be found in T.W.Greene, Protecting Groups in Organic Synthesis, 3rd edition, Wiley & Sons, 1999.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position.
  • unsubstituted means that a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted).
  • a functional group is described as being “optionally substituted,” the function group may be either (1) not substituted, or (2) substituted. If a carbon of a functional group is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogen atoms on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent.
  • “Sulfide” means -S-R wherein R is H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfide groups are mercapto, alkylsulfide, for example methylsulfide (-S-Me); arylsulfide, e.g., phenylsulfide; aralkylsulfide, e.g., benzylsulfide.
  • “Sulfinyl” means the radical -S(O)-. It is noted that the sulfinyl radical may be further substituted with a variety of substituents to form different sulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters, and sulfoxides.
  • “Sulfonyl” means the radical -S(O)(O)-. It is noted that the sulfonyl radical may be further substituted with a variety of substituents to form different sulfonyl groups including sulfonic acids, sulfonamides, sulfonate esters, and sulfones.
  • Thiocarbonyl means the radical -C(S)-. It is noted that the thiocarbonyl radical may be further substituted with a variety of substituents to form different thiocarbonyl groups including thioacids, thioamides, thioesters, and thioketones.
  • “Animal” includes humans, non-human mammals (e.g., non-human primates, rodents, mice, rats, hamsters, dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • Bioavailability as used herein is the fraction or percentage of an administered dose of a drug or pharmaceutical composition that reaches the systemic circulation intact. In general, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (e.g., orally), its bioavailability decreases (e.g., due to incomplete absorption and first-pass metabolism). Methods to improve the bioavailability include prodrug approach, salt synthesis, particle size reduction, complexation, change in physical form, solid dispersions, spray drying, and hot-melt extrusion.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means organic or inorganic salts of compounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids, or with organic acids. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate,” ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1 ,1 '-methylene-bis-(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, al
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
  • the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
  • Camptothecin is the pharmacophore of the well known drug topotecan and irinotecan.
  • Mechlorethamine is the pharmacophore of a list of widely used nitrogen mustard drugs like Melphalan, Cyclophosphamide, Bendamustine, and so on.
  • Prodrug means a compound that is convertible in vivo metabolically into an active pharmaceutical according to the present invention.
  • an inhibitor comprising a hydroxyl group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxyl compound.
  • “Stability” in general refers to the length of time a drug retains its properties without loss of potency. Sometimes this is referred to as shelf life. Factors affecting drug stability include, among other things, the chemical structure of the drug, impurity in the formulation, pH, moisture content, as well as environmental factors such as temperature, oxidization, light, and relative humidity. Stability can be improved by providing suitable chemical and/or crystal modifications (e.g., surface modifications that can change hydration kinetics; different crystals that can have different properties), excipients (e.g., anything other than the active substance in the dosage form), packaging conditions, storage conditions, etc.
  • suitable chemical and/or crystal modifications e.g., surface modifications that can change hydration kinetics; different crystals that can have different properties
  • excipients e.g., anything other than the active substance in the dosage form
  • “Therapeutically effective amount” of a composition described herein is meant an amount of the composition which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (7.e. , measurable by some test or marker) or subjective (/.e., subject gives an indication of or feels an effect).
  • An effective amount of the composition described above may range from about 0.1 mg/kg to about 500 mg/kg, preferably from about 0.2 to about 50 mg/kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • treating refers to administering a compound to a subject that has a neoplastic or immune disorder, or has a symptom of or a predisposition toward it, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptoms of or the predisposition toward the disorder.
  • an effective amount refers to the amount of the active agent that is required to confer the intended therapeutic effect in the subject. Effective amounts may vary, as recognized by those skilled in the art, depending on route of administration, excipient usage, and the possibility of co-usage with other agents.
  • a “subject” refers to a human and a non-human animal.
  • a non-human animal include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates), dog, rodent (e.g., mouse or rat), guinea pig, cat, and non-mammals, such as birds, amphibians, reptiles, etc.
  • the subject is a human.
  • the subject is an experimental animal or animal suitable as a disease model.
  • “Combination therapy” includes the administration of the subject compounds of the present invention in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation treatment).
  • the compounds of the invention can be used in combination with other pharmaceutically active compounds, or non-drug therapies, preferably compounds that are able to enhance the effect of the compounds of the invention.
  • the compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other therapies.
  • a combination therapy envisions administration of two or more drugs/treatments during a single cycle or course of therapy.
  • the compounds of the invention are administered in combination with one or more of traditional chemotherapeutic agents.
  • the traditional chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms relating to the cancer or its treatment.
  • alkylating agents such as Nitrogen Mustards (e.g., Bendamustine, Cyclophosphamide, Melphalan, Chlorambucil, Isofosfamide), Nitrosureas (e.g., Carmustine, Lomustine and Streptozocin), ethylenimines (e.g., thiotepa, hexamethylmelanine), Alkylsulfonates (e.g., Busulfan), Hydrazines and Triazines (e.g., Altretamine, Procarbazine, dacarbazine and Temozolomide), and platinum based agents (e.g., Carboplatin, Cisplatin, and Oxaliplatin); plant alkaloids such as Podophyllotoxins (e.g., Etoposide and Tenisopide), Taxanes (e.g., Paclitaxel and Docetaxel), Vinca alkaloids (
  • the compounds may be administered in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states.
  • kinases may include, but are not limited ABL1 , ABL2/ARG, ACK1, AKT1 , AKT2, AKT3, ALK, ALK1/ACVRL1, ALK2/ACVR1, ALK4/ACVR1 B, ALK5/TGFBR1, ALK6/BMPR1 B, AMPK(A1/B1/G1), AMPK(A1/B1/G2), AMPK(A1/B1/G3), AMPK(A1/B2/G1 ), AMPK(A2/B1/G1 ), AMPK(A2/B2/G1 ), AMPK(A2/B2/G1 ), AMPK(A2/B2/G2), ARAF, ARK5/NUAK1 , ASK1/MAP3K5, ATM, Aurora A, Aurora B , Aurora C , AXL, BLK, BMPR2, BMX/ETK, B
  • the subject compounds may be administered in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathway, or processes.
  • targets pathways, or processes include but not limited to heat shock proteins (e.g.HSP90), poly-ADP (adenosine diphosphate)-ribose polymerase (PARP), hypoxia-inducible factors(HIF), proteasome, Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrix metalloproteinase, farnesyl transferase, apoptosis pathway (e.g Bcl-xL, Bcl- 2, Bcl-w), histone deacetylases (HDAC), histone acetyltransferases (HAT), and methyltransferase (e.g histone lysine methyltransferases, histone arginine methyltransferase, DNA methyltransferase, etc), and other immunotherapies
  • HSP90
  • the compounds of the invention are administered in combination with one or more of other anti-cancer agents that include, but are not limited to, gene therapy, RNAi cancer therapy, chemoprotective agents (e.g., amfostine, mesna, and dexrazoxane), antibody conjugate ⁇ .
  • chemoprotective agents e.g., amfostine, mesna, and dexrazoxane
  • antibody conjugate ⁇ e.g., amfostine, mesna, and dexrazoxane
  • cancer immunotherapy such as lnterleukin-2
  • cancer vaccines(e.g., sipuleucel-T) or monoclonal antibodies e.g., Bevacizumab, Alemtuzumab, Rituximab, Trastuzumab, etc).
  • the subject compounds are administered in combination with radiation therapy or surgeries.
  • Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation.
  • the combination therapy further comprises radiation treatment
  • the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • the compounds of the invention are administered in combination with one or more of radiation therapy, surgery, or anti-cancer agents that include, but are not limited to, DNA damaging agents, anti-metabolites, topoisomerase inhibitors, anti-microtubule agents, kinase inhibitors, epigenetic agents, HSP90 inhibitors, PARP inhibitors, and antibodies targeting VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.
  • the compounds of the invention are administered in combination with one or more of abarelix, abiraterone acetate, aldesleukin, alemtuzumab, altretamine, anastrozole, asparaginase, bendamustine, bevacizumab, bexarotene, bicalutamide, bleomycin, bortezombi, brentuximab vedotin, busulfan, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, clomifene, crizotinib, cyclophosphamide, dasatinib, daunorubicin liposomal, decitabine, degarelix, denileukin diftitox, denileukin diftitox, denosumab, docetaxel, doxorubicin,
  • the invention further provides methods for the prevention or treatment of a neoplastic disease or autoimmune disease.
  • the invention relates to a method of treating a neoplastic disease or autoimmune disease, in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention.
  • the invention further provides for the use of a compound of the invention in the manufacture of a medicament for halting or decreasing a neoplastic disease or autoimmune disease.
  • the neoplastic disease is a lung cancer, head and neck cancer, central nervous system cancer, prostate cancer, testicular cancer, colorectal cancer, pancreatic cancer, liver cancer, stomach cancer, biliary tract cancer, esophageal cancer, gastrointestinal stromal tumor, breast cancer, cervical cancer, ovarian cancer, uterine cancer, leukemia, lymphomas, multiple myeloma, melanoma, basal cell carcinoma, squamous cell carcinoma, bladder cancer, renal cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome, or myeloproliferative disease.
  • autoimmune diseases that can be affected using compounds and compositions according to the invention include, but are not limited to allergy, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, coeliac disease, chagas disease, chronic obstructive pulmonary disease, chronic Idiopathic thrombocytopenic purpura (ITP), churg-strauss syndrome, Crohn’s disease, dermatomyositis, diabetes mellitus type 1 , endometriosis, Goodpasture's syndrome (and associated glomerulonephritis and pulmonary hemorrhage), graves’ disease, guillain-barre syndrome, hashimoto’s disease, hidradenitis s
  • the compounds according to the present invention may be synthesized according to a variety of schemes. Necessary starting materials may be obtained by standard procedures of organic chemistry.
  • the compounds and processes of the present invention will be better understood in connection using the following representative synthetic schemes and examples, which are intended as an illustration only and not limiting of the scope of the invention.
  • Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
  • the starting material 1-1-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-1-1 is converted to intermediate 1-1-2 through a Suzuki coupling reaction, which can be hydrogenated to afford 1-1-3 readily.
  • the enantiomer 1-1-4 can be separated from 1-1-3 (racemate) via chiral resolution.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-1-4 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-1-4 can react with 1-2-1 to afford 1-2-2 via reductive amination.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-3-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-3-1 can react with 1-1-4 to afford 1-3-2 readily.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-1-4 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-1-4 can react with 1-4-1 to give 1-4-2 under a suitable condition.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-1-4 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-1-4 can react with sulfonyl chloride 1-5-1 to give the target compound 1-5-2 under a suitable condition.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-6-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-6-1 can be alkylated to give 1-6-2 readily, which is coverted to intermediate 1-6-3 through a Friedel-Crafts acylation reaction.
  • the intermediate 1-6-3 is reduced to 1-6-4 by a suitable reagent, which can be transform to chlorides 1-6-5.
  • 1-6-5 can react with 1-1-4 to yield the target compound 1-6-6.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-7-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-7-1 can be alkylated to give 1-7-2 readily, which is coverted to intermediate 1-7-3 through Heck coupling reaction.
  • the intermediate 1-7-3 is converted to 1-7-4 by a suitable reagent, which can be reduced to 1-7-5.
  • 1-7-5 can be transform to chlorides 1-7-6, which can react with 1-1-4 to yield the target compound 1-7-7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-8-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-8-1 can be oxidized to give 1-8-2 readily, which is coverted to intermediate 1-8-3 through Wittig reaction.
  • the intermediate 1-8-3 is hydrogenated to 1-8-4 under a suitable condition, which can be reduced to 1-8-5.
  • the intermediate 1-8-5 can be converted to 1-8-
  • 1-8-6 can be transform to bromides 1-8-7, which is react with 1-1-4 to yield the target compound 1-8-8.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-9-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-9-1 can be coverted to intermediate 1-9-2 through Sonogashira couping reaction.
  • the intermediate 1-9-2 is hydrogenated to 1-9-3 under a suitable condition, which can be converted to 1-9-4 via a intramolecular cyclization.
  • 1-9-4 can be transform to bromides 1-9-5, which is react with 1-1-4 to yield the target compound 1-9-6.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-10-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-10-1 can be alkylated to give 1-10-2 readily, which is coverted to intermediate 1-10-3 through Heck reaction.
  • the intermediate 1-10-3 is oxidized to 1-10-4 under a suitable condition, which can be reduced to 1-10-5.
  • 1-10-5 can be transform to chlorides 1-10-6, which is react with 1-1-4 to yield the target compound 1-10-7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-11-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-11-1 can be alkylated to give 1-11-2 readily, which is coverted to intermediate 1-11-3 through Heck reaction.
  • the intermediate 1-11-3 is oxidized to 1-11-4 under a suitable condition, which can be reduced to 1-11-5.
  • 1-11-5 can be transform to chlorides 1-11-6, which is react with 1-1-4 to yield the target compound 1-11-7.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-11-A1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-11-A1 can react with 1-1-4 to yield the target compound 1-11-A2 via reductive amination reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-12-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-12-1 can react with 1-1-4 to yield the target compound 1-12-2 via SN2 substitution reaction.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-13-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-13-1 can react with 1-1-4 to yield the target compound 1-13-2 via Buchwald coupling reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-14-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-14-1 can be converted to 1-14-2 readily, which is alkylated to give intermediate 1-14-3.
  • the intermediate 1-14-3 can be protected to afford 1-14-4, which is transform to 1-14-5 through an intramolecular reaction.
  • the intermediate 1-14-5 is decarboxylated to yield the target compound 1-14-6.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-15-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-15-1 can be converted to phosphonium ylide salts 1-15-2 readily, which can react with 1-14-6 to give the target compound via Wittig reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-16-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-16-1 can be coverted to intermediate 1-16-2 through Suzuki coupling reaction.
  • the intermediate 1-16-2 is alkylated to give quaternary ammonium salt 1-16-3, which can be reduced to 1-16-4 readily.
  • 1-16-4 can be oxidated to 1-16-5, which is deprotected to yield the target compound 1-16-6.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 1-17-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 1-17-1 can be converted to phosphonium ylide salts 1-17-2 readily, which can react with 1-16-6 to give the target compound 1-17-3 via Wittig reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the intermediate o can be prepared by the method similar to the
  • the intermediate can be prepared by the method similar to the
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the intermediate can be prepared by the method similar to
  • the starting material 2-2A-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 2-2A-1 can be brominated to give intermediated 2- 2A-2.
  • 2-2A-3 is reduced to give Amino alcohol 2-2A-4, which can be converted to 2-2A-5.
  • 2-2A-6 can be obtained via an intermolecular cyclization reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-2A-3 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material 2-2A-3 is converted to intermediated 2-2B-1, which can be further converted to 2-2B-2.
  • 2-2B-2 is deprotected to give Amino alcohol 2-2B-3, which can be transform to 2-2B-4.
  • 2-2B-5 can be obtained via an intermolecular cyclization.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-3-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-3-1 can be converted to 2-3-2 via a SNAr reaction, and then the sulfonylation of 2-3-2 can afford the intermediate 2-3-3.
  • the intermediate 2-3-3 goes through a two-step sequence of conventional organic reaction to yield the target compounds 2-3-5.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-4-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-4-1 can be converted to 2-4-3 via a two-step sequence of conventional organic reaction.
  • the intermediate 2-4-3 can be converted to the corresponding sulfonyl chlorides, which can react with ammonia to yield the target compounds 2-4-5.
  • target compounds can be synthesized by alternative methods but not limited to the above
  • the starting material 2-5-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-5-1 can be converted to 2-5-3 via a two-step sequence conventional organic reaction.
  • the intermediate 2-5-3 can be converted to the corresponding sulfonyl chlorides 2-5-4, which can react with ammonia to yield the target compounds 2-5-5.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-6-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-6-1 can be oxidized to yield 2-6-2, which can be converted to the intermediate 2-6-3 readily.
  • the intermediate 2-6-3 undergoes a SNAr reaction to give 2-6-4, which is converted to 2-6-5 through an intramolecular cyclization reaction.
  • the intermediate 2-6-5 can be converted to the corresponding sulfonyl chlorides 2-6-6, which can react with ammonia to yield the target compounds 2-6-7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-6-3 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-6-3 undergoes a SNAr reaction to give 2-7-1, which is converted to 2-7-2 through an intramolecular cyclization reaction.
  • the intermediate 2-7-2 can be converted to the corresponding sulfonyl chlorides 2-7-3, which can further react with ammonia to yield the target compounds 2-7-4.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • a typical approach to synthesize the intermediate is described in
  • the starting material 2-8-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-8-1 can be converted to 2-8-3 through a two-step sequence of conventional organic reactions. After that, the intermediate 2-8-3 is protected to give 2-8-4, which can be further reduced to yield the intermediate 2-8-5.
  • the intermediate 2-8-5 is oxidized to generate the ketone 2-8-6, which can be converted to 2-8-7 readily.
  • the intermediate 2-8-7 is deprotected to afford 2-8-8, which can be further converted to the intermediate 2-8-9.
  • 2-8-9 undergoes an intramolecular cyclization to afford the target compounds 2-8-10.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-9-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-9-1 can be converted to 2-9-3 through a two-step sequence of conventional organic reactions. After that, the intermediate 2-9-3 is protected to give 2-9-4, which can be further reduced to yield the intermediate 2-9-5.
  • the intermediate 2-9-5 is oxidized to generate the ketone 2-9-6, which can be converted to 2-9-7 readily.
  • the intermediate 2-9-7 is deprotected to afford 2-9-8, which can be further converted to the intermediate 2-9-9.
  • 2-9-9 undergoes an intramolecular cyclization to afford the target compounds 2-9-10.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures. described in
  • the starting material 2-10-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-10-1 can be converted to 2-10-3 through a two- step sequence of literate reported reactions. After that, the intermediate 2-10-3 can be converted to 2-10-4, which can be further hydrolyzed to yield the intermediate 2-10-5.
  • the intermediate 2-10-5 can be converted to 2- 10-6 readily, which is reduced to give 2-10-7.
  • the intermediate 2-10-7 can be converted to the intermediate 2-10-8, which undergoes an intramolecular cyclization and through a further chiral separation to afford the target compounds 2-10-9.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 2-10-8 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 2-10-8 can goes through a chiral separation to afford the target compound 2-11 -1 .
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the intermediate of can be prepared by the method similar to the
  • the intermediate of can be prepared by the method similar to the
  • the starting material 3-0-A1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 3-0-A1 can be converted to 3-0-A2 readily, which further undergoes a SNAr reaction to give 3-0-A3.
  • 3-0-A3 can be converted to 3-0-A4 through an intramolecular cyclization reaction, which is deprotected to afford the target compounds 3-0-A5.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-0-B1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 3-0-B1 can be converted to 3-0-B3 via a literature known reactions, which further undergoes a ring closing reaction to give 3-0-B4.
  • 3-0-B4 can be oxidied to 3-0-B5 readily, which is further converted to the intermediate 3-0-B6.
  • the intermediate 3-0-B6 undergoes a SNAr reaction to yiled 3-0-B7, which can further gothrough an intramolecular coupling reaction to give 3-0-B8.
  • the intermediate 3-0-B8 can be deprotected to afford the target compounds 3-0-B9.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-0-C1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 3-0-C1 can be converted to 3-0-C2 via a literature known reactions, which undergoes a SNAr reaction to yiled 3-0-C3.
  • the intermediate 3-0-C3 is deprotected to give 3-0-C4, which can be converted to the intermediate 3-0-C5 via a reductive amination reaction.
  • the intermediate 3-0-C5 goes through an intramolecular coupling reaction to afford the transracemate compounds 3-0-C6, which futher gothrough a chiral separation to yiled the target compounds 3-0-C7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-1-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 3-1-1 can be converted to 3-1-2 readily, which further undergoes a ring opening reaction to give 3-1-3.
  • 3-1-3 can be converted to 3-1-4 via a general condition, and the reaction of 3-1-3 with 3-1-4a can generate intermediate 3-1-5.
  • the intermediate 3-1-5 undergoes an intramolecular coupling reaction to give 3-1-6, which is further deprotected to afford 3-1-7.
  • the target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-2-1 can be prepared by conventional procedures using appropriate compounds and reagents.
  • the starting material 3-2-1 can be converted to 3-2-2 readily, which further undergoes a SNAr reaction with 3-1-4a to give 3-2-3.
  • 3-2-3 undergoes an intramolecular coupling reaction to generate 3-2-4, which can be deprotected to afford 3-2-5.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-3-1 can be converted to 3-3-3 through a two-step sequence of conventional reactions. After that, 3-3-3 can be converted to 3-3-4 readily, which can be deprotected to give 3-3- 5.
  • the reaction of 3-3-5 with 3-1 -4a can generate 3-3-6, which can be converted to 3-3-7 via an intramolecular cyclization reaction. Finally, the deprotection of 3-3-7 can generate the target compounds 3-3-8.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-4-1 can be converted to 3-4-3 through a two-step sequence of conventional reactions. After that, 3-4-3 can be converted to 3-4-4 readily, which can be deprotected to give 3-4- 5.
  • the reaction of 3-4-5 with 3-1 -4a can generate 3-4-6, which can be converted to 3-4-7 via an intramolecular cyclization reaction. Finally, the deprotection of 3-4-7 can generated the target compounds 3-4-8.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-5-1 can be converted to 3-5-2 via reductive amination reaction, and then 3-5-2 can be converted to 3-5-3 readily. After that, 3-5-3 can be reduced to 3-5-4.
  • the reaction of 3-5-4 with 3-1-4a can generate 3-5-5, which can be converted to 3-5-6 via an intramolecular cyclization reaction.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-7-1 can be reduced to give 3-7-2, and then 3-7-2 can be converted to 3-7-3 readily.
  • 3-7-3 can be converted to 3-7-5 through a two-step sequence of conventional reactions.
  • the reaction of 3-7-5 with 3-1 -4a can generate 3-7-6, which can be converted to 3-7-7 via an intramolecular cyclization reaction.
  • the deprotection of 3-7-7 can generate the target compounds 3-7-8.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-9-1 can be oxidized to give 3-9-2, and then 3-9-2 can be converted to 3-9-3 readily.
  • the hydrogenation of 3-9-3 can give 3-9-4, which is further converted to 3- 9-6 through a two-step sequence of conventional reactions.
  • the reaction of 3-9-6 with 3-1-4a can generate 3-9- 7, which can be converted to 3-9-8 via an intramolecular cyclization reaction.
  • the deprotection of 3-9-8 can generate the target compounds 3-9-9.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material 3-10-1 can be reduced to give 3-10-2, and then 3-10-2 can be converted to 3-10-3 readily.
  • the hydrogenation of 3-10-3 can give 3-10-4, which can be converted to 3- 10-6 through a two-step sequence of conventional reactions.
  • the reaction of 3-10-6 with 3-1 -4a can generate 3- 10-7, which can be converted to 3-10-8 via an intramolecular cyclization reaction.
  • the deprotection of 3- 10-8 can generate the target compounds 3-10-9.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the intermediate of H with different Z2, f, k, Rd and Qs can be prepared by the method similar to the Scheme 3-1 to 3-10 by using appropriate staring materials, and intermediates.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material A-2 can react with B-1a to afford B-1 readily. After that, the hydrolysis of B-1 to afford B-2, which can be further converted to B-3. The coupling reaction of B-3 with A-5a can generate B-4, which is deprotected to give B-5. Finally, the intermediate B-5 can gothrough a reductive amination reaction with A-7a to provide the target compounds B-6.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material A-2 can react with C-1a to afford C-1 readily. After that, the hydrolysis of C-1 to afford C-2, which can be further converted to C-3. The coupling reaction of C-3 with A-5a can generate C-4, which is deprotected to give C-5. Finally, the intermediate C-5 can gothrough a reductive amination reaction with A-7a to provide the target compounds C-6.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material E-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material E-1 can be coverted to intermediate E-2 through SNAr substitution reaction.
  • the intermediate E-2 can gothrough a reductive amination reaction with A-7a to provide the intermediate E-3, which can be hydrolyzed to E-4 readily.
  • E-4 can be converted to E-5, which can couple with A-5a to yield the target compound E-6.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material F-1 can be prepared by conventional procedures using appropriate compounds and reagent.
  • the starting material F-1 can be coverted to intermediate F-2 through Wittig reaction.
  • the intermediate E-2 can gothrough a [2+2] cyclization to afford F-3, which is de-chlorination to give F- 4.
  • the intermediate F-4 is deprotected to provide F-5, whihc can converted to F-6 readily.
  • the hydrolysis of F-6 can afford F-7, which can be further converted to F-8.
  • the coupling reaction of F-8 with A-5a can generate F-9.
  • the intermediate F-9 can gothrough a reductive amination reaction with A-7a to provide F-10, which is deprotected to yield the target compounds F-11 .
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material A-4 can react with G-1a to afford G-1 readily.
  • the coupling reaction of G-1 with G-2a can generate G-2, which is deprotected to give G-3.
  • the intermediate G-3 can gothrough a reductive amination reaction with A-7a to provide the target compounds G-4.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material A-7a can be converted to H-1 via reductive amination reaction, which is deprotected to give H-2.
  • the intermediate H-2 can gothrough a SNAr substitution reaction to afford H-3.
  • the hydrolysis of H-3 can yield H-4, which is further converted to H-5.
  • the coupling reaction of H-5 with G-2a can generate H-6, which is deprotected to provide the target compounds H-7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material A-7a can be converted to l-7a via reductive amination reaction.
  • the intermediate 1-1 can gothrough a SNAr substitution reaction to afford I-2.
  • the hydrolysis of I-2 can yield I-3, which is further converted to I-4.
  • the coupling reaction of I-4 with G-2a can generate I-5, which is deprotected to provide the target compounds I-6.
  • the intermediate I-6 can gothrough a reductive amination reaction with l-7a to provide the target compounds I-7.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the starting material J-1 can be converted to J-4 via literature known conditions.
  • the intermediate J-4 can gothrough a SNAr substitution reaction to afford J-5.
  • the hydrolysis of J-5 can yield J-6, which is further converted to J-7.
  • the coupling reaction of J-7 with G-2a can generate J-8, which is deprotected to provide the target compounds J-9.
  • the intermediate J-9 can gothrough a reductive amination reaction with A-7a to provide the target compounds J-10.
  • target compounds can be synthesized by alternative methods but not limited to the above procedures.
  • the compounds can be prepared by schemes similar to the Scheme A-Scheme J by using appropriate staring materials and intermediates.
  • the compounds can be prepared by schemes similar to the Scheme A-Scheme J by using appropriate staring materials and intermediates.
  • the compounds can be prepared by schemes similar to the Scheme A-Scheme J by using appropriate staring materials and intermediates.
  • the compounds can be prepared by schemes similar to the Scheme A-Scheme J by using appropriate staring materials and intermediates.
  • the compounds can be prepared by schemes similar to the Scheme A-Scheme J by using appropriate staring materials and intermediates.
  • Example INT_12 Preparation of (11 R,15S)-4-[[2-(trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10- triazatetracyclo[7.7.0.0 A [3,7].0 A [11,15]]hexadeca-1 (9),2,5,7-tetraene and (11S,15R)-4-[[2- (trimethylsilyl)ethoxy]methyl]-13,16-dioxa-2,4,10-triazatetracyclo[7.7.0.0 A [3,7].0 A [11 ,15]]hexadeca- 1(9),2,5,7-tetraene Synthesis of N-[(trans)(3S,4R)-4-hydroxyoxolan-3-yl]-4-methylbenzenesulfonamide: Into a 250 mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 3,6- dioxabi
  • the resulting solution was stirred for 2 days at 120°C.
  • the reaction mixture was cooled to 25°C.
  • the resulting solution was diluted with water (500 mL).
  • the resulting solution was extracted with ethyl acetate (3x200 mL) and the organic layers combined.
  • the resulting mixture was washed with brine (1000 mL).
  • the mixture was dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting solution was stirred for 2 hours at 60°C.
  • the reaction mixture was cooled to 25°C.
  • the resulting solution was diluted with 300/300 mL of NaHCOa and CH2CI2.
  • the solids were filtered out and the organic was separated.
  • the mixture was dried over anhydrous Na2SO4 After filtration, the filtrate was concentrated under reduced pressure.
  • mobile phase A n-Hexane (0.1 %DEA); mobile phase B: Ethanol, Cone, of Phase B: 50.0%, Column Temp: 25°C.
  • the resulting mixture was stirred for 3 hours at 30°C.
  • the resulting mixture was diluted with water (20 mL).
  • the resulting mixture was extracted with CH2CI2 (3x20mL).
  • the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • the resulting mixture was stirred for 2 hours at 100°C under nitrogen atmosphere. The mixture was allowed to cool down to 25°C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with Ethyl acetate (4x20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NasSC After filtration, the filtrate was concentrated under reduced pressure.
  • (3R,8R)-16- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,5- dioxa-10, 16, 18-tri azatetracydo[9.7.0.0 A ⁇ 3, 8 ⁇ .O A ⁇ 13, 17 ⁇ ]octadeca-1 (11 ), 12, 14, 17-tetraene was obtained as a brown solid (53 mg, 32.5%) and (3S,8S)-16- ⁇ [2-(trimethylsilyl)ethoxy]methyl]-2,5-dioxa-10,16,18- triazatetracyclo[9.7.0.0 A ⁇ 3,8 ⁇ .0 A ⁇ 13, 17 ⁇ ]octadeca-1 (11), 12, 14,17-tetraene was obtained as a brown solid (72 mg, 44.2%).
  • (3S,8S)-16- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,6-dioxa- 10, 16, 18-triazatetracydo[9.7.0.0 A ⁇ 3,8 ⁇ .0 A ⁇ 13, 17 ⁇ ]octadeca-1 (11 ), 12, 14, 17-tetraene was obtained as a brown oil (100 mg, 25.7%) and (3R,8R)-16- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ -2,6-dioxa-10,16,18- triazatetracyclo[9.7.0.0 A ⁇ 3,8 ⁇ .0 A ⁇ 13, 17 ⁇ ]octadeca-1 (11), 12, 14,17-tetraene was obtained as a brown oil (80 mg, 20.6%).
  • the reaction mixture was stirred for 3 hours at 100°C under nitrogen atmosphere.
  • the resulting mixture was quenched by the addition of water (200 mL) and extracted with EtOAc (3x50 mL).
  • the combined organic layer was washed with brine (200 mL), dried over anhydrous NasSCU. After filtration, the filtrate was concentrated under vacuum.
  • RT1 3.4 min in CHIRAL ART Cellulose-SZ, 3*25 cm, 5 pm; Mobile Phase A: CO 2 , Mobile Phase B: MeOH (0.1% 2M NH 3 - MeOH); Flow rate: 80 mL/min; Gradient: isocratic 15% B; Column Temperature: 35°C; Back Pressure: 100 bar; Wave Length: 220 nm; Sample Solvent: MeOH-HPLC; Injection Volume: 0.8 mL; Number of Runs: 80.
  • tert-butyl (3R)-3-(2-methylphenyl)piperazine-1 -carboxylate (385 mg, 48.1%) was obtained as a light yellow oil (385 mg, 48.1 %) and tert-butyl (3S)-3-(2-methylphenyl)piperazine-1 -carboxylate was obtained as a light yellow oil (380 mg, 47.5%).
  • RT1 0.396 min in CHIRALPACK IG-3 50*3.0mm,3.0um; Mobile Phase A: CO2, Mobile Phase B: MeOH (20 m MNH3); Gradient: 10% to 50%_B1_2_2200; Column Temperature: 35°C; Back Pressure: 2200 bar; Wave Length: 220 nm; Injection Volume: 1 uL.
  • RT2 0.524 min in CHIRALPACK IG- 3 50*3.0mm,3.0um; Mobile Phase A: CO2, Mobile Phase B: MeOH (20m MNH3); Gradient: 10% to 50%_B1_2_2200; Column Temperature: 35°C; Back Pressure: 2200bar; Wave Length: 220 nm; Injection Volume: 1uL.
  • RT1 0.569 min in CHIRALPACK IH-3 50*3.0mm,3.0um; Mobile Phase A: CO 2 , Mobile Phase B: MeOH (20 m MNH3); Gradient: 10% to 50%_B1_2_2200; Column Temperature: 35°C; Back Pressure: 2200 bar; Wave Length: 220 nm; Injection Volume: 0.5uL.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La divulgation concerne des composés de formules (1), Q1, Q2, Q3, Q4, Q5, Q6, Q7, Q8, Qx, R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, Rx, a, b, c, g, j, k, m, n, u, v, L, Z1, Z2, Z4 et Z5 étant tels que définis dans la description. L'invention concerne également une méthode de traitement d'une maladie néoplasique et d'une maladie auto-immune avec ces composés.
PCT/US2022/053328 2021-12-20 2022-12-19 Inhibiteurs de bcl-2 Ceased WO2023122000A1 (fr)

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PCT/US2021/064278 WO2022140224A1 (fr) 2020-12-22 2021-12-20 Dérivés de 1h-pyrrolo[2,3-b]pyridine comme inhibiteurs de bcl-2 pour le traitement de maladies néoplasiques et auto-immunes
USPCT/US2021/064278 2021-12-20
US202263298726P 2022-01-12 2022-01-12
US63/298,726 2022-01-12
USPCT/US2022/034518 2022-06-22
PCT/US2022/034518 WO2023121713A1 (fr) 2021-12-20 2022-06-22 Inhibiteurs de bcl-2
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024032755A1 (fr) * 2022-08-11 2024-02-15 Fochon Biosciences, Ltd. Composés en tant qu'inhibiteurs de bcl-2
CN119930409A (zh) * 2024-12-17 2025-05-06 苏州敬业医药化工有限公司 一种联合催化制备2-氯乙氧基乙醇的方法

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US8084607B2 (en) * 2003-11-13 2011-12-27 Abbott Laboratories Apoptosis promoters
US8691184B2 (en) * 2011-01-25 2014-04-08 The Regents Of The University Of Michigan Bcl-2/Bcl-xL inhibitors and therapeutic methods using the same
US20200197406A1 (en) * 2017-08-23 2020-06-25 Newave Pharmaceutical Inc. Bcl-2 inhibitors
WO2021208963A1 (fr) * 2020-04-15 2021-10-21 Beigene, Ltd. Inhibiteur de bcl -2

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Publication number Priority date Publication date Assignee Title
US8084607B2 (en) * 2003-11-13 2011-12-27 Abbott Laboratories Apoptosis promoters
US8691184B2 (en) * 2011-01-25 2014-04-08 The Regents Of The University Of Michigan Bcl-2/Bcl-xL inhibitors and therapeutic methods using the same
US20200197406A1 (en) * 2017-08-23 2020-06-25 Newave Pharmaceutical Inc. Bcl-2 inhibitors
WO2021208963A1 (fr) * 2020-04-15 2021-10-21 Beigene, Ltd. Inhibiteur de bcl -2

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024032755A1 (fr) * 2022-08-11 2024-02-15 Fochon Biosciences, Ltd. Composés en tant qu'inhibiteurs de bcl-2
CN119930409A (zh) * 2024-12-17 2025-05-06 苏州敬业医药化工有限公司 一种联合催化制备2-氯乙氧基乙醇的方法
CN119930409B (zh) * 2024-12-17 2025-12-05 苏州敬业医药化工有限公司 一种联合催化制备2-氯乙氧基乙醇的方法

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