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WO2025064952A1 - Inhibiteurs de bcl-2 - Google Patents

Inhibiteurs de bcl-2 Download PDF

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Publication number
WO2025064952A1
WO2025064952A1 PCT/US2024/047874 US2024047874W WO2025064952A1 WO 2025064952 A1 WO2025064952 A1 WO 2025064952A1 US 2024047874 W US2024047874 W US 2024047874W WO 2025064952 A1 WO2025064952 A1 WO 2025064952A1
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Prior art keywords
formula
cancer
compound
asb
eil
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English (en)
Inventor
Ruben Abagyan
Volodymyr KYSIL
Vladislav Zenonovich PARCHINSKY
Alexei Pushechnikov
Alexandre Vasilievich IVACHTCHENKO
Nikolay Savchuk
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Eil Therapeutics Inc
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Eil Therapeutics Inc
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Publication of WO2025064952A1 publication Critical patent/WO2025064952A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is directed to inhibitors of B-cell lymphoma 2 (BCL-2) proteins.
  • BCL-2 B-cell lymphoma 2
  • the inhibitors described herein can be useful in the treatment of diseases or disorders associated with BCL-2.
  • the invention is concerned with compounds and pharmaceutical compositions inhibiting BCL-2, methods of treating diseases or disorders associated with BCL-2, and methods of synthesizing these compounds.
  • Apoptosis or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.
  • Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischaemia.
  • deficits in the implementation of apoptosis play a significant role in the development of cancers and their chemoresistance, in auto-immune diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan, D.
  • the anti-apoptotic BCL-2 proteins interact with pro-apoptotic members and inhibit their function to maintain cellular homeostasis. It is the shift in balance between anti-apoptotic and pro-apoptotic BCL-2 proteins that may decide the fate of cancer cells.
  • a first aspect of the invention relates to compounds of Formula (I): (I), tautomers thereof, wherein: A is selected from CH and N; ; ASB Attorney Docket No.: Eil.23.0001 R 3 is selected ; R 4 is selected C3-C7 cycloalkyl, C6-C10 aryl, wherein alkyl, cycloalkyl, or aryl is one or more substitutients selected from -OH, -CN, halogen, C 1 –C 6 alkyl; R 5 is selected from H, halogen, -OH, -NH2, -CN, C1–C6 alkyl, and C1–C6 alkoxy; or R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered cycloalkyl or a 5-8 membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with one or more substituents independently selected from
  • a third aspect of the invention relates to compounds of Formula (III): , tautomers thereof, wherein: A is selected from CH and N; 6 ASB Attorney Docket No.: Eil.23.0001 , , C 1 – C 6 alkyl, C 3 -C 8 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with one or more halogen; each R 7 is independently selected from H, and C1–C6 alkyl; k is an integer selected from 0, 1, and 2.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins, such as Isoform 1 and Isoform 2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • the method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof.
  • Another aspect of the present invention relates to compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • 10 ASB Attorney Docket No.: Eil.23.0001 Another aspect of the present invention relates to compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.
  • Another aspect of the present invention relates to the use of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease associated with inhibiting BCL- 2 proteins, such as Isoform 1 and Isoform 2.
  • Another aspect of the present invention relates to the use of compounds of Formula (A), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (I), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • Another aspect of the present invention relates to the use of compounds of Formula (II), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • 11 ASB Attorney Docket No.: Eil.23.0001 Another aspect of the present invention relates to the use of compounds of Formula (III), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.
  • the present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention provides inhibitors of BCL-2 proteins that are therapeutic agents in the treatment of diseases such as cancer and metastasis.
  • the present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known BCL-2 protein inhibitors.
  • the present disclosure also provides agents with novel mechanisms of action toward BCL-2 protein in the treatment of various types of diseases including cancer and metastasis. 12 ASB Attorney Docket No.: Eil.23.0001 [0050]
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedures A–D).
  • the present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2.
  • the disclosure features methods of treating, preventing or ameliorating a disease or disorder in which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.
  • the methods of the present invention can be used in the treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins.
  • Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis.
  • Decreasing BCL-2 activity can suppress cancer mutagenesis, dampen tumor evolution, and/or decrease the probability of adverse outcomes, such as drug resistance and/or metastases.
  • the present disclosure relates to compounds and compositions that are capable of inhibiting the activity BCL-2 proteins including, but not limited to Isoform 1 and Isoform 2.
  • the disclosure features methods of treating, preventing or ameliorating a disease or disorder in 14 ASB Attorney Docket No.: Eil.23.0001 which BCL-2 plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.
  • the methods of the present invention can be used in the treatment of a variety of BCL-2 mediated diseases and disorders by inhibiting the activity of BCL- 2 proteins. Inhibition of BCL-2 can be an effective approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis.
  • the present invention relates to the compounds of Formula (A): , and and tautomers thereof, wherein A, G, R 1 , R 2 , R 3 , and k are described herein.
  • A, G, R 1 , R 2 , R 3 , and k can each be, where applicable, selected from the groups described herein, and any group described herein for any A, G, R 1 , R 2 , R 3 , and k can be combined, where applicable, with any group described herein for one or more of the remainders of A, G, R 1 , R 2 , R 3 , and k.
  • the compounds of Formula (I) are described: , ASB Attorney Docket No.: Eil.23.0001 and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , k, m, n, o and p are described herein.
  • A, R 1 , R 2 , R 3 , R 4 , R 5 , k, m, n, o and p can each be, where applicable, selected from the groups described herein, and any group described herein for any A, R 1 , R 2 , R 3 , R 4 , R 5 , k, m, n, o and p can be combined, where applicable, with any group described herein for one or more of the remainders of A, R 1 , R 2 , R 3 , R 4 , R 5 , k, m, n, o and p.
  • A, R 1 , R 2 , R 3 , R 6 , R 7 , k, m, n, o, p and r can each be, where applicable, selected from the groups described herein, and any group described herein for any A, R 1 , R 2 , R 3 , R 6 , R 7 , k, m, n, o, p and r can be combined, where applicable, with any group described herein for one or more of the remainders of A, R 1 , R 2 , R 3 , R 6 , R 7 , k, m, n, o, p and r.
  • the compounds of Formula (III) are described: 16 ASB Attorney Docket No.: Eil.23.0001 , and tautomers thereof, wherein A, W, R 1 , R 2 , R 3 , R 6 , R 7 , and k are described herein.
  • A, W, R 1 , R 2 , R 3 , R 6 , R 7 , and k can each be, where applicable, selected from the groups described herein, and any group described herein for any A, W, R 1 , R 2 , R 3 , R 6 , R 7 , and k can be combined, where applicable, with any group described herein for one or more of the remainders of A, W, R 1 , R 2 , R 3 , R 6 , R 7 , and k.
  • an element means one element or more than one element.
  • the term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. 17 ASB Attorney Docket No.: Eil.23.0001
  • the term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms).
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen.
  • any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • optionally substituted means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH 2 CN, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 - C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 - C6)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1- C6)alkyl, -NH2, -
  • substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. [0010] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, - H, -halogen, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, -O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 )alkynyl, (C 2 - 18 ASB Attorney Docket No.: Eil.23.0001 C 6 )alkenyl, (C 2 -C 6 )alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 )alkyl, - OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -NH
  • the substituents can themselves be optionally substituted.
  • the aryl groups herein defined may have a saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, the remaining ring atoms being C.
  • Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, Se, or B.
  • Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B.
  • the aromatic radical is optionally substituted independently with one or more substituents described herein.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3- c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyr
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring, e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo.
  • a fully unsaturated aromatic ring e.g., a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogens, wherein the saturated or partially unsaturated ring includes 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4- dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2- b]pyrrolizinyl, 8H-pyrido[3,2-b]
  • Halogen refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1–12 carbon atoms. Examples of a (C1–C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
  • Alkoxy refers to a straight or branched chain saturated hydrocarbon containing 1–12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.
  • Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined, may be straight or branched.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2–12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • alkylene or “alkylenyl” refers to a divalent alkyl radical. Any of the above- mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C 1 –C 6 alkylene. An alkylene may further be a C 1 –C 4 alkylene.
  • the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art.
  • GENERAL PROCEDURE A O ASB Attorney Docket No.: Eil.23.0001 Cl Cl Cl OH O
  • GENERAL PROCEDURE C 81 ASB Attorney Docket No.: Eil.23.0001 82 ASB Attorney Docket No.: Eil.23.0001
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (A).
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of BCL-2 proteins.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of BCL-2 proteins an effective amount the compositions and compounds of Formula (III).
  • the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A).
  • the present invention is directed to a method of inhibiting BCL-2 proteins. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I).
  • the disease may be, but not limited to, cancer and metastasis.
  • Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of BCL-2 proteins, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (III).
  • the disease may be, but not limited to, cancer and metastasis.
  • the present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (A).
  • the present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (I).
  • the present invention also relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (II).
  • the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (I).
  • the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (II).
  • the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by BCL-2 proteins, wherein the medicament comprises a compound of Formula (III).
  • Another aspect of the present invention relates to a compound of Formula (A) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.
  • Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.
  • Another aspect of the present invention relates to a compound of Formula (II) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.
  • Another aspect of the present invention relates to a compound of Formula (III) for use in the manufacture of a medicament for treating a disease associated with inhibiting BCL-2 proteins.
  • Another aspect of the invention relates to a method of treating or preventing cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (A).
  • Another aspect of the invention relates to a method of treating or preventing cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).
  • Another aspect of the invention relates to a method of treating or preventing cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (II).
  • Another aspect of the invention relates to a method of treating or preventing cancer.
  • the method comprises administering to a patient in need thereof an effective amount of a compound of Formula (III).
  • the present invention relates to the use of an inhibitor of BCL-2 proteins for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer.
  • the present invention relates to a compound of Formula (A) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, 87 ASB Attorney Docket No.: Eil.23.0001 selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head, spine and neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lymphoma, melanoma, multiple myeloma, pancreatic cancer, penile cancer, testicular germ cell cancer, thymoma carcinoma, thymic carcinoma, lung cancer
  • the present invention relates to a compound of Formula (A) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the present invention relates to a compound of Formula (II) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • the present invention relates to a compound of Formula (III) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers including, but not limited to, 89 ASB Attorney Docket No.: Eil.23.0001 marginal zone lymphoma (MZL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • MZL marginal zone lymphoma
  • FL follicular lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • CLL/SLL chronic lymphocytic leukemia/small lymphocytic lymphoma
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (A).
  • methods of treating a disease or disorder associated with modulation of BCL-2 proteins including, cancer or cell proliferative disorder comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).
  • One therapeutic use of the compounds or compositions of the present invention which inhibit BCL-2 proteins is to provide treatment to patients or subjects suffering from a cancer or cell proliferative disorder.
  • the disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for example,
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.
  • Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds can also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • a polymer e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • the pharmaceutical composition can further comprise an additional pharmaceutically active agent.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • the pharmaceutical composition can further comprise an additional pharmaceutically active agent.
  • Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • the pharmaceutical composition can further comprise an additional pharmaceutically active agent.
  • compositions comprising a compound of Formula (III) and a pharmaceutically acceptable carrier.
  • the pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.
  • the pharmaceutical composition can further comprise an additional pharmaceutically active agent.
  • Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the disclosed compounds, when used for the indicated effects range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition.
  • compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • Example 2 113 ASB Attorney Docket No.: Eil.23.0001 [0343]
  • Example 2 Compounds 2, 3, 8, 11, 12, 13, 17, 19 were prepared according to procedures described in Preparations P1-P4, and in Example 1 using corresponding starting matherials. Descriptions of the H-NMR spectra of some of these compounds are presented in the table below.
  • Example 4 4- ⁇ 2-[1-(4-chlorophenyl)-2-methylpropyl]-2,7-diazaspiro[3.5]non-7-yl ⁇ -N- ( ⁇ 3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl ⁇ sulfonyl)-2-(1H-pyrrolo[2,3- b]pyridin-5-yloxy)benzamide (Compound 4). This compound was prepared according to procedures described in P5-P8 and in Example 3 using corresponding starting matherials. [0346] Example 5.
  • Example 6 Compounds 5, 9, 14 were prepared according to procedures described in Preparations P9-P12, and in Example 5 using corresponding starting matherials. Descriptions of the H-NMR spectra of some of these compounds are presented in the table below.
  • Compound 1 H NMR (400 MHz DMSO-d6) ⁇ ASB Attorney Docket No.: Eil.23.0001
  • Example 9 4-(2-((Z)-2-(4-Chlorophenyl)cyclohept-2-enyl)-2,6-diazaspiro[3.4]octan-6- yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3- (trifluoromethylsulfonyl)phenylsulfonyl)benzamide (Compound 21).
  • Compound 24 was prepared according to procedures described in Preparations P13-P21 and in Example 7 using corresponding starting matherials. [0351] Example 10.
  • BCL-2 TR-FRET Assay (BPS Bioscience, #50222) The following assay concentrations and times were used: 3 ng BCL-2, 5 ⁇ l of 1:100 anti-His Tb-labeled donor, 5 ⁇ l of 1:100 Dye- labeled acceptor, 5 ⁇ l of 1:40 BCL-2 Peptide Ligand, and 2ul of test compound, with 60 min incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex/620 and 665em; 60 ⁇ sec Delay; and 500 ⁇ sec integration.
  • BCL-XL TR-FRET Assay (BPS Bioscience, #50223) The following assay concentrations and times were used: 10.5 ng BCL-XL, 5 ⁇ l of 1:100 anti-His Tb-labeled donor, 5 ⁇ l of 1:100 Dye-labeled acceptor, 5 ⁇ l of 1:80 BCL-XL Peptide Ligand, and 2 ⁇ l of test compound, with 60 min incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex/620 and 665em; 60 ⁇ sec Delay; and 500 ⁇ sec integration.
  • MCL-1 TR-FRET Assay (BPS Bioscience, #79506) The following assay concentrations and times were used: 10 ng MCL-1, 5 ⁇ l of 1:200 anti-His Tb-labeled donor, 5 ⁇ l of 1:200 Dye- labeled acceptor, 5 ⁇ l of 1:10 MCL-1 Peptide Ligand, and 2 ⁇ l of test compound, with 60 min 120 ASB Attorney Docket No.: Eil.23.0001 incubation time. The results of the assay were read using a Clariostar (BMG Labtech) plate reader with the following parameters: TR FRET, 340ex/620 and 665em; 60 ⁇ sec Delay; and 500 ⁇ sec integration.
  • Table B assigns a code for potency for BCL-2 TR-FRET Assay: A, B, C, or D. According to the code, A represents an IC50 value ⁇ 50 nM; B represents IC50 > 50 nM and ⁇ 100 nM; C represents IC50 >100 nM and ⁇ 500 nM D represents IC50 > 500 nM. [0358] Table B assigns a code for potency for BCL-XL TR-FRET Assay: A, B, or C. According to the code, A represents IC50 value ⁇ 2,000 nM; B represents IC50 values >2,000 nM and ⁇ 4,000 nM; C represents IC50 values >4,000 nM.
  • Example 13 Primary PPI inhibition Cmpd. Cmpd. Cmpd. BCL2 BCLxL BCL2 BCLxL BCL2 BCLxL BCL2 BCLxL [0359]
  • Example 13 Cell Viability Assays (Cell lines HEK293, RS4-11, MOLT-4). [0360] Culture medium for HEK293 – DMEM (PanEco, Cat# ⁇ 420) was used. RPMI-1640 (PanEco, Cat# ⁇ 363) was used for the rest of the cell lines. [0361] Compounds were prepared as 200x stocks with serial dilution in 100% DMSO with a final concentration of 1x.
  • Compound solutions were dispersed in 40 ⁇ L aliquots in 384-well plates at a concentration of 2000 cells per well for HEK293 and at a concentration of 4000 cells per well for the rest of the cell lines using a robotic station Biomek (Beckman). Before adding compounds, the cells were incubated at 37 °C (HEK293 were incubated for a day before adding compounds). 121 ASB Attorney Docket No.: Eil.23.0001 [0363] A dilution plate was prepared by pouring 78 ⁇ L of the appropriate culture medium using a robotic station Biomek (Beckman).
  • Table C assigns a code for potency for MOLT-4 Assay: A, B, or C.
  • Table C assigns a code for potency for HEK293 Assay: A, B, or C.
  • A represents an CC 50 value ⁇ 10 ⁇ M
  • B represents CC 50 >10 ⁇ M and ⁇ 20 ⁇ M
  • C represents CC 50 >20 ⁇ M.
  • Table C Cellular models efficacy and cytotoxicity.
  • Cmpd. No. RS4-11 MOLT-4 HEK293 ASB Attorney Docket No.: Eil.23.0001 Cmpd. No. RS4-11 MOLT-4 HEK293 20 C A C [0367]
  • Example 14. [0368] Assay Principle: The Caspase-Glo 3/7 Assay is homogeneous, luminescent assay that measures caspase-3 and -7 activities.
  • the assay provides a luminogenic caspase-3/7 substrate, which contains the tetrapeptide sequence DEVD, in a reagent optimized for caspase activity.
  • Assay Procedure Incubate RS4-11 cells with varying concentrations of test compounds for 3.5 h in a humidified incubator at 37 °C and 5 % CO2 and 30 min at r.t. Add 15 ⁇ l Caspase- Glo reagent to each well and incubate the plate for 30 min at r.t. Read on ClarioStar Plus instrument.
  • Materials Promega Caspase-Glo (Promega , #8212); Frozen RS4-11 cells; 384-well white plate (Corning, #3570).

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Abstract

La présente invention concerne de manière générale des inhibiteurs de protéines BCL-2 utiles dans le traitement de maladies et de troubles modulés par ladite enzyme et ayant la formule (A) :
PCT/US2024/047874 2023-09-22 2024-09-20 Inhibiteurs de bcl-2 Pending WO2025064952A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100305122A1 (en) * 2009-05-26 2010-12-02 Abbott Laboratories Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US20150203477A1 (en) * 2012-06-20 2015-07-23 University Of Kansas Compounds and methods for activating the apoptotic arm of the unfolded protein response
US20220306625A1 (en) * 2021-03-19 2022-09-29 Eil Therapeutics, Inc. Compounds having ((3-nitrophenyl)sulfonyl)acetamide as bcl-2 inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100305122A1 (en) * 2009-05-26 2010-12-02 Abbott Laboratories Apoptosis inducing agents for the treatment of cancer and immune and autoimmune diseases
US20150203477A1 (en) * 2012-06-20 2015-07-23 University Of Kansas Compounds and methods for activating the apoptotic arm of the unfolded protein response
US20220306625A1 (en) * 2021-03-19 2022-09-29 Eil Therapeutics, Inc. Compounds having ((3-nitrophenyl)sulfonyl)acetamide as bcl-2 inhibitors

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