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WO2023038500A1 - Composé de dégradation de la protéine enl et utilisations médicales associées - Google Patents

Composé de dégradation de la protéine enl et utilisations médicales associées Download PDF

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Publication number
WO2023038500A1
WO2023038500A1 PCT/KR2022/013646 KR2022013646W WO2023038500A1 WO 2023038500 A1 WO2023038500 A1 WO 2023038500A1 KR 2022013646 W KR2022013646 W KR 2022013646W WO 2023038500 A1 WO2023038500 A1 WO 2023038500A1
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Prior art keywords
methyl
benzo
imidazol
dioxopiperidin
methylpyrrolidin
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English (en)
Korean (ko)
Inventor
류제호
안정민
장미영
윤휘상
배온누리
이송희
서범선
김현휘
김한울
박지윤
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Ubix Therapeutics Inc
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Ubix Therapeutics Inc
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Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present disclosure relates to a group of compounds that have activity to degrade ENL proteins.
  • the present disclosure also relates to pharmaceutical compositions comprising such compounds.
  • the present disclosure also relates to useful methods of treating ENL protein-associated disorders using such compounds. That is, the present disclosure relates to the pharmaceutical use of the compounds according to the present disclosure for treating or preventing ENL protein related diseases.
  • the YEATS domain is a class of histone acetylation readers present in ENL, YEATS2, AF9 and glioma amplified sequence 41 (GAS41 or YEATS4).
  • ENL encoded by MLLT1 is a chromatin leader protein that binds to acylated lysine side chains (including acetyl and crotyl modifications) at positions 9, 18 and 27 of histone H3 using the YEATS domain.
  • Dysfunction of the YEATS protein is associated with disease, particularly cancer.
  • fusions of AF9 or ENL with human mixed lineage leukemia (MLL) proteins are frequently found in acute myelogenous leukemia, and these fusions constitute oncogenes.
  • MML human mixed lineage leukemia
  • SRCAP Snf2-related CREBBP activating protein
  • GAS41 GAS41
  • ENL (MLLT1) YEATS domain As a potent target in leukemia, including AML ( Nature volume 543, pages 265-269 (2017), Nature volume 543, pages 270-274 (2017)). That is, the interaction between the ENL YEATS domain and the acyl-lysine substrate is known to be a verified target for the development of therapeutic agents for leukemias such as acute lymphocytic leukemia and acute myelogenous leukemia (ALL and AML).
  • ALL and AML acute lymphocytic leukemia
  • ENL YEATS domain a hotspot mutation (gain-of-function mutation) in the ENL YEATS domain is also found in Wilms tumor, a form of renal cancer, and the mechanism by which increased activity of the ENL protein has carcinogenicity has been elucidated ( Nature volume 577, pages 121-126 (2020)).
  • useful inhibitors of ENL YEATS have not been reported so far.
  • the problem to be solved by the present invention is to provide compounds having ENL proteolytic activity, pharmaceutical compositions containing them as active ingredients, and pharmaceutical uses for treating or preventing ENL protein-related diseases.
  • Another problem to be solved by the present invention is that the compound according to the present invention, characterized in that it degrades the ENL protein and consequently lowers the ENL protein activity, is administered to a patient in need of treatment, improvement or prevention of ENL protein-related diseases.
  • the compound according to the present invention characterized in that it degrades the ENL protein and consequently lowers the ENL protein activity, is administered to a patient in need of treatment, improvement or prevention of ENL protein-related diseases.
  • the present invention provides a compound of Formula 1 below or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, or —OH ego,
  • X is NH or O
  • A is C 3-12 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein C 3-12 cycloalkyl, heterocycle, aryl, or heteroaryl is C 3-12 cycloalkyl, heterocycle, aryl, or heteroaryl wherein one or more hydrogens in the ring are optionally C 1- 6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • n 0, 1, or 2;
  • a 1 , A 2 and A 3 are each independently a direct bond, -O-, -N(R 3 )-, -C(R 3 )(R 3 ')-, -C(O)-, -C( O)NH-, -NHC(O)-, -C(O)CH 2 NH-, -C(O)CH 2 O-, -NHC(O)CH 2 NH-, or -NHC(O)CH 2 is O-,
  • B 1 , B 2 and B 3 are, independently of each other, a direct bond, C 3-12 cycloalkyl, heterocycle, aryl, or heteroaryl, wherein C 3-12 cycloalkyl, heterocycle, aryl, or heteroaryl ring at least one hydrogen in is optionally substituted with C 1-6 alkyl, halogen, haloC 1-6 alkyl, or -OH;
  • R 3 and R 3 ' are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or -OH;
  • q1 to q5 are independently integers from 0 to 10;
  • E is Formula 3 or 4.
  • R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • X 1 , X 2 and X 3 are independently of each other CH or N,
  • Z is a direct key, -C(R 5 )(R 5 ')-, -N(R 5 )-, -O-, or -C(O)NH-, wherein R 5 and R 5 'are independently of each other are H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy.
  • the present inventors degrade ENL protein by combining a CRBN ligand (E in Formula 1) of a specific structure that binds to E3 ubiquitin ligase and a moiety that binds to the ENL YEATS domain (left moiety relative to the linker).
  • E in Formula 1 a CRBN ligand of a specific structure that binds to E3 ubiquitin ligase and a moiety that binds to the ENL YEATS domain (left moiety relative to the linker).
  • the compounds according to the present disclosure bind to the ENL protein through a moiety that binds to the YEATS domain of ENL and bind to CRBN through the other moiety to induce ubiquitination of the ENL protein, thereby inducing ENL through the proteasome. It is expected to have proteolytic activity, but the present invention is not limited to this mechanism or prediction.
  • substituent may be (1) unsubstituted or (2) substituted with one or more of the defined substituents. If the substitutable position is unsubstituted, the default substituent is a hydrido radical.
  • alkyl refers to a saturated straight-chain or branched non-cyclic hydrocarbon having 1 to 10 carbon atoms (unless the number of carbon atoms is specifically limited). "Lower alkyl” means a straight chain or branched alkyl having 1 to 4 carbon atoms.
  • saturated straight-chain alkyls are -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n- decyl, while saturated branched alkyl is -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, isopentyl, 2-methylhexyl, 3-methylbutyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-
  • alkoxy means -OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O-(alkyl), including -O(CH 2 ) 5 CH 3 , and the like, wherein alkyl is as defined above.
  • C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms.
  • haloalkyl As used herein, the terms "haloalkyl”, “haloalkoxy”, “haloalkenyl” or “haloalkynyl” refer to an alkyl, alkoxy, alkenyl or alkynyl group in which one or more hydrogen atoms are replaced by halogen atoms, respectively. .
  • haloalkyl is -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 CI, -CI 3 , -CHI 2 , -CH 2 I, -CH 2 -CF 3 , -CH 2 -CHF 2 , -CH 2 -CH 2 F, -CH 2 -CBr 3 , -CH 2 -CHBr 2 , -CH 2 -CH 2 Br, -CH 2 -CC1 3 , -CH 2 -CHC1 2 , -CH 2 -CH 2 CI, -CH 2 -CI 3 , -CH 2 -CHI 2 , -CH 2 -CH 2 I, and the like include that In one preferred aspect of the present invention, haloalkyl is CF 3 . wherein alkyl and halogen
  • cycloalkyl means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having carbon-carbon multiple bonds.
  • monocyclic rings include, but are not limited to, (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl).
  • polycyclic rings examples include fused bicyclic rings such as octahydropentalene, decahydronaphthalene, and the like; spiro rings such as spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane and the like; and bridged bicyclic rings such as bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and the like. Cycloalkyl groups may be optionally substituted. In one embodiment, a cycloalkyl group is a monocyclic ring (ring).
  • a “heterocycle” or “heterocycloalkyl” is a saturated 5- to 7-membered monocyclic ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. , or a 7- to 12-membered bicyclic ring (ring) in which nitrogen and sulfur heteroatoms can be selectively oxidized and nitrogen heteroatoms can be selectively quaternized.
  • heterocycles include oxiran, oxetan, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, piperazine, pyrrolidinone, hydantoine, valerolactam, thiirane ), thietane, tetrahydrothiophene, tetrahydrothiopyra, morpholine, tetrahydropyridine, tetrahydropyrimidine, and the like.
  • Heterocycles include bicyclic rings in which a portion of the heterocycle is fused to a benzene or cyclopenta-1,3-diene ring. Heterocycles may be attached by heteroatoms or carbon atoms. Heterocycles also include fused bicyclic rings, spiro rings and bridged bicyclic rings in which one or more carbon atoms of the aforementioned polycyclic rings are replaced with nitrogen, oxygen or sulfur atoms. rings are included.
  • heterobicyclics such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, etc.
  • aryl refers to a carbocyclic aromatic group containing 5 to 10 ring atoms. Representative examples include phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Including, but not limited to. Carbocyclic aromatic groups may be optionally substituted.
  • heteroaryl has at least one heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur, and contains from 5 to 10 carbon atoms containing at least one carbon atom, including mono- and bicyclic ring systems. It is an aromatic heterocycle ring of a member.
  • Typical heteroaryls include furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, These include benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, and 1H-azepine.
  • R 1 and R 2 are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, or —OH ego,
  • X is NH
  • A is a heterocycle, aryl, or heteroaryl, wherein the heterocycle, aryl, or heteroaryl is wherein one or more hydrogens in the ring are optionally C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1 -6 alkoxy or haloC 1-6 alkoxy;
  • n 0 or 1
  • a 1 , A 2 and A 3 are each independently a direct bond, -O-, -N(R 3 )-, -C(R 3 )(R3')-, -C(O)-, -C(O )NH-, -NHC(O)-, -C(O)CH 2 NH-, -C(O)CH 2 O-, -NHC(O)CH 2 NH-, or -NHC(O)CH 2 O -ego,
  • B 1 , B 2 and B 3 are, independently of each other, a direct bond, heterocycle, or heteroaryl, wherein one or more hydrogens in the heterocycle or heteroaryl ring are optionally C 1-6 alkyl, halogen, haloC 1- 6 alkyl, or substituted with -OH;
  • R 3 and R 3 ' are independently of each other H, C 1-6 alkyl, halogen, or -OH;
  • q1 to q5 are independently integers from 0 to 10;
  • R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • R 5 and R 5 ' are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • a compound or a pharmaceutically acceptable salt thereof is provided.
  • R 1 and R 2 are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, hydroxyC 1-6 alkyl, C 1-6 alkoxyalkyl, C 1-6 alkoxy, or —OH ego,
  • X is NH
  • A is any one of the following substituents wherein one or more hydrogens in the ring are optionally C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1- is substituted with 6 alkoxy;
  • n 0 or 1
  • a 1 , A 2 and A 3 are each independently a direct bond, -O-, -N(R 3 )-, -C(R 3 )(R3')-, -C(O)-, -C(O )NH-, -NHC(O)-, -C(O)CH 2 NH-, -C(O)CH 2 O-, -NHC(O)CH 2 NH-, or -NHC(O)CH 2 O -ego,
  • B 1 , B 2 and B 3 are independently of each other a direct bond or any one of the following substituents, wherein one or more hydrogens in the ring are optionally C 1-6 alkyl, halogen, haloC 1-6 alkyl , or is substituted with -OH,
  • R 3 and R 3 ' are independently of each other H, C 1-6 alkyl, halogen, or -OH;
  • q1 to q5 are independently integers from 0 to 10;
  • R 4 is H, C 1-6 alkyl, or halogen
  • a compound or a pharmaceutically acceptable salt thereof is provided.
  • R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
  • E is or Provided is a compound or a pharmaceutically acceptable salt thereof, which is directly linked to.
  • a substituent it is more preferable for the purpose of the present invention in various aspects such as ENL proteolytic activity.
  • Formula 1 excluding -L-E (linked to *-L-E) may be any one of the following structures.
  • E in Formula 1 may be any one of the following structures.
  • E in Formula 1 has the following structure.
  • L in Formula 1 may be any one of the following structures.
  • Non-limiting examples of compounds of Formula 1 according to the present disclosure are the compounds prepared in the Examples described below. Each example number corresponds to a compound number. For example, the number of the final compound prepared in Example 30 is compound 30.
  • the compounds in Table 1 below were particularly preferred in various aspects such as ENL proteolytic activity, cancer cell line cytotoxicity, (metabolism) stability, and physicochemical properties.
  • “pharmaceutically acceptable salts” include salts of active compounds prepared with relatively non-toxic acids and bases depending on the specific substituents found in the compounds mentioned herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acidic addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid ( fumaric), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and their analogues.
  • Hydrogen chloride hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrosulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and its analogues.
  • salts of amino acids such as alginate and analogs thereof and analogs of organic acids such as glucuronic or galactunoric acids and analogs thereof.
  • Some particular compounds of the present invention have both basic and acidic functionality which allows them to be converted into basic or acidic addition salts.
  • Other examples of salts are well known from the literature known in the art to which this invention pertains.
  • the term "compound of the present invention” is meant to include not only each compound of Formula 1, but also clathrates, hydrates, solvates, or polymorphs thereof.
  • the term “compound of the present invention” is meant to include pharmaceutically acceptable salts of the compounds of the present invention when pharmaceutically acceptable salts thereof are not mentioned.
  • the compounds of the present invention are stereomerically pure compounds (e.g., substantially free of other stereoisomers (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, 97% ee or more, or 99% ee or more))).
  • the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or a stereoisomer (eg, geometrical isomer and conformational isomers), the separated isomer thereof and mixtures each are also included within the scope of the compounds of the present invention.
  • the compounds of the present invention or their salts have an asymmetric carbon in their structure, their optically active compounds and racemic mixtures are also included in the scope of the compounds of the present invention.
  • polymorph refers to a solid crystal form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in terms of physical properties include, but are not limited to, stability (e.g. heat or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). It doesn't. Differences in stability may be due to chemical reactivity changes (e.g. differential oxidation such as faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g.
  • kinetically Tablet fragments stored as the preferred polymorph may be thermodynamically converted to a more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity).
  • Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates, or may be more difficult to filter or wash, than another polymorph, eg, due to its shape or particle size distribution.
  • solvent compound refers to a compound of the present invention or a pharmaceutically acceptable salt thereof comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces.
  • Preferred solvents are volatile, non-toxic, and can be administered in very small amounts to humans.
  • hydrate refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) in which guest molecules (eg, solvent or water) are confined. or a salt thereof.
  • the term "purified" means that when isolated, the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In other embodiments, at least 99.9% pure.
  • the invention further provides a method of treating a disease or condition in a subject having or susceptible to having one or more of the following diseases or conditions by administering to the subject a therapeutically effective amount of one or more such compounds.
  • the treatment is a preventative treatment.
  • the treatment is a palliative treatment.
  • the treatment is a restorative treatment.
  • the compounds for degrading ENL protein of the present invention are useful for various therapeutic or prophylactic applications (eg, cancer). These compounds can be used to lower ENL protein activity by degrading ENL protein, and can also be used to treat ENL protein related diseases or to prevent exacerbation of these diseases. Accordingly, the present invention provides a method for degrading ENL protein in cells. In this method, the cells are contacted with an effective amount of a compound of the present invention. In one embodiment, the cell is within a subject.
  • the method of the present invention comprises administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a compound according to the present invention.
  • the present invention provides a method of degrading ENL protein in a cell in an ENL protein-associated disorder.
  • the present invention can be used to degrade the ENL protein in the cells of a subject having an ENL protein-related disease described later, and consequently lower the ENL protein activity.
  • the invention may be used to degrade ENL proteins within cells of cancer, particularly leukemia.
  • the present invention provides a method of treating an ENL protein-related disorder comprising administering to a subject a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Such methods include administering to a subject in need of treatment an amount of a compound of the present invention sufficient to degrade the ENL protein, i.e., a therapeutically effective amount.
  • a compound of the present invention can be administered to the subject in the form of a pharmaceutical composition described herein.
  • the ENL protein-associated disease is, but is not limited to, cancer, particularly leukemia or renal cancer.
  • the ENL protein-associated disease is acute lymphocytic leukemia, acute myeloid leukemia, or Wilms tumour.
  • the present invention provides a pharmaceutical use for treating or preventing the above diseases of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Suitable subjects to be treated according to the present invention include mammalian subjects.
  • Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, and pigs. (porcine), rodents (rodents), lagomorphs (lagomorphs), primates (primates) and the like, including mammals in utero ( in utero ).
  • a suitable subject to be treated according to the present invention is a human.
  • a compound of the present invention is generally administered in a therapeutically effective amount.
  • Effective amount means slowing down or minimizing the progression of an ENL protein related disease, particularly cancer (preferably leukemia or kidney cancer), or an ENL protein related disease, particularly cancer (preferably leukemia or kidney cancer) refers to an amount of a compound of the present invention sufficient to provide a therapeutic benefit in the treatment or management of "Effective amount” also refers to an amount sufficient to inhibit or reduce ENL protein activity, either in vitro or in vivo .
  • the compounds of the present invention can be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment.
  • An effective dosage is generally from about 0.001 to about 100 mg/kg of body weight/day, preferably from about 0.01 to about 50 mg/kg/day, in single or divided administration. Dosage levels below the lower end of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without detrimental side effects. Larger doses may be divided into several smaller doses for administration throughout the day.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.
  • the use of the pharmaceutical composition is for the treatment or prevention of an ENL protein-related disease, preferably cancer, more preferably leukemia or renal cancer, which will be described later.
  • pharmaceutically acceptable means suitable for use as a pharmaceutical preparation, generally considered safe for such use, and officially approved for such use by a national regulatory agency or approved by the Korean Pharmacopoeia or the United States Means in the pharmacopeia list.
  • the compound described herein, or a pharmaceutically acceptable salt thereof can be administered as follows.
  • the compound of the present invention can be administered orally, and oral is a concept including swallowing.
  • Oral administration allows the compounds of the present invention to enter the gastrointestinal tract or be directly absorbed from the mouth into the bloodstream, eg, by buccal or sublingual administration.
  • compositions suitable for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, powders, and the like. .
  • compositions for oral administration may optionally be enteric coated and exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.
  • Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be contained in soft or hard capsules.
  • Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil.
  • the formulation may also contain one or more emulsifying and/or suspending agents.
  • the amount of active ingredient drug may be present from about 0.05% to about 95% by weight, more typically from about 2% to about 50% by weight of the total weight of the tablet.
  • Tablets may also contain a disintegrant comprising from about 0.5% to about 35% by weight, more usually from about 2% to about 25% by weight of the dosage form.
  • disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
  • Suitable glidants included for making into tablets may be present in amounts from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. It can be used as a lubricant, but the present invention is not limited to these types of additives.
  • Gelatin polyethylene glycol, sugar, gum, starch, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc. may be used as a binder for preparing tablets.
  • Mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc. may be used as suitable diluents for preparation into tablets, but the present invention is not limited to these types of additives. .
  • the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethylisosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM and the like may be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to specific types of these solubilizers.
  • Compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine.
  • Suitable methods for parenteral administration include intravenous, intramuscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like.
  • Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
  • compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • parenteral formulations are liquid compositions, and these liquid compositions are aqueous solutions containing the active ingredient, salt, buffer, tonicity agent and the like according to the present invention.
  • Parenteral formulations may also be prepared in dried form (eg lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.
  • the compounds of the present invention may be administered topically to the skin or transdermally.
  • Formulations for this topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like.
  • Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration can also be performed by electroporation, iontophoresis, phonophoresis, and the like.
  • compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.
  • the present disclosure provides compounds capable of exhibiting various pharmacological activities by degrading ENL protein, pharmaceutical compositions containing them as active ingredients, their medicinal uses (particularly, cancer, preferably leukemia or renal cancer), and their treatment or prevention needs.
  • a method of treatment comprising administering to a subject is provided.
  • the compounds according to the present invention or pharmaceutically acceptable salts thereof are excellent in various aspects, such as activity, (metabolic) stability, and physicochemical properties.
  • Step 2 Synthesis of tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate
  • tert-butyl piperazine-1-carboxylate (552mg, 2.96mmol), (1-(chloromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (680mg, 2.47mmol), and K 2 CO 3 (683mg, 4.94mmol) were mixed with Acetonitrile (8.3ml). ) and then stirred at 60 ° C for 19 hours. After adding distilled water (30ml) to the reaction solution, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous sodium sulfate. Thereafter, the mixture was filtered and concentrated under reduced pressure. The resulting residue was subjected to MPLC (7% EtOAc/Hexane) to give 529 mg (74%) of a clear oil.
  • Step 2 Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate
  • Step 3 Synthesis of tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)piperazine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(2,2-difluoro-3-hydroxypropyl)piperazine-1-carboxylate
  • Step 5 Synthesis of tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate
  • Step 1 Synthesis of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate
  • Step 2 Synthesis of benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate
  • Step 1 Synthesis of tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamate
  • Step 2 Synthesis of 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamate (110mg, 0.13mmol) was suspended in DCM (2ml) After adding TFA (0.3ml), the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain 80 mg (94%) of a yellow solid.
  • Step 1 tert-butyl 4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)propyl)piperidine-1- Synthesis of carboxylate
  • Step 2 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamide synthesis
  • Step 2 Synthesis of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)carbamate
  • Step 3 Synthesis of 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride
  • Step 1 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione
  • Step 2 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde
  • 1,10-diazidodecane (1.3g, 5.8mol) was suspended in Et 2 O/THF/1M HCl (5:1:4, 20 ml), and then triphenylphosphine (1.4 g, 5.32 g, 5.32 g) suspended in Et 2 O (10ml). mmol) was added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure to obtain 870mg (76%) of a yellow solid.
  • Step 3 Synthesis of 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 1 Synthesis of methyl (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate
  • Step 2 Synthesis of (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid
  • Step 3 N 1 -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N 3 -(2-(((S Synthesis of )-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide
  • Example 2 was synthesized in the same manner as in Example 1 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-8).
  • Example 4 was synthesized in the same manner as in Example 1 using )amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-4).
  • Step 1 Synthesis of methyl (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate
  • Step 2 Synthesis of (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid
  • Step 3 N 1 -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-N 4 -(2-(((S Synthesis of )-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
  • Example 5 was synthesized in the same manner as the synthesis method of step 3 of Example 1 using dione (intermediate 3-5).
  • Example 6 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-6).
  • Example 7 N 1 -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
  • Example 7 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-1).
  • Example 8 N 1 -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
  • Example 8 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-2).
  • Example 9 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-7).
  • Example 10 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-8).
  • Example 11 was synthesized in the same manner as in Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-9).
  • Example 12 was synthesized in the same manner as in Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-10).
  • Example 14 was synthesized in the same manner as Example 5 using 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-12).
  • Example 16 was synthesized in the same manner as Example 5 using 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-14).
  • Example 19 4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)piperidine-1-carbonyl)-N -(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 19 was synthesized in the same manner as in Example 5 using )-4-((3-(piperidin-4-yl)propyl)amino)isoindoline-1,3-dione (Intermediate 3-15) .
  • Example 20 4-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)piperidine-1-carbonyl)-N -(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 20 was synthesized in the same manner as in Example 5 using )-5-((3-(piperidin-4-yl)propyl)amino)isoindoline-1,3-dione (Intermediate 3-16) .
  • Example 21 4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)propyl)piperidine-1 -carbonyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 21 2-((2-(2,6-dioxopiperidin -3-yl) -1,3-dioxoisoindolin-4-yl) oxy) -N- (3- (piperidin-4-yl) propyl) acetamide (Intermediate 3-17) using the same synthesis method as in Example 5
  • Example 21 was synthesized by the method.
  • Example 22 4-(4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)propyl)piperidine-1 -carbonyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 22 2-((2-(2,6-dioxopiperidin -3-yl) -1,3-dioxoisoindolin-5-yl) oxy) -N- (3- (piperidin-4-yl) propyl) acetamide (intermediate 3-18) using the same synthesis method as in Example 5
  • Example 22 was synthesized by the method.
  • Example 24 was synthesized in the same manner as in Example 5 using ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-22).
  • Example 25 was synthesized in the same manner as in Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-23).
  • Example 26 was synthesized in the same manner as in Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-24).
  • Example 27 4-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-pyrazol-4-yl )-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 Synthesis of tert-butyl (6-(4-bromo-1H-pyrazol-1-yl)hexyl)carbamate
  • Step 3 Synthesis of methyl 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoate
  • Step 4 Synthesis of 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoic acid
  • Step 5 tert-butyl (S)-(6-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl) Synthesis of phenyl)-1H-pyrazol-1-yl)hexyl)carbamate
  • Step 7 4-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-pyrazol-4-yl) Synthesis of -N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 28 4-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-1H-pyrazol-4-yl )-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 29 4-(1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)hexyl)-1H- pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 30 4-(1-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamido)hexyl)-1H- pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 31 4-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin -4-yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • 1-(4-Boc-1-piperidinyl)-4-bromopyrazole (1g, 3mmol), 4-methoxycarbonylphenylboronic acid pinacol ester (1.2g, 4.5mmol), Tetrakis(triphenylphosphine)palladium(0) (70mg, 2 mol%) , and cesium carbonate (1.5g, 4.5mmol) were suspended in 1,4-dioxane (20ml) and stirred at 90°C for 12 hours. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (50% EtOAc/Hexane) to obtain 1.1 g (94%) of a white solid.
  • MPLC 50% EtOAc/Hexane
  • Step 2 Synthesis of 4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)benzoic acid
  • Step 3 tert-butyl (S)-4-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl Synthesis of )-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 5 4-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperidin- 4-yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide synthesis
  • Example 32 4-(1-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin -4-yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 32 was synthesized in the same manner as Example 31 using -3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate 3-26).
  • Example 33 4-(1-(1-(2-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl )piperidin-4-yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl )benzamide
  • Example 33 was synthesized in the same manner as in Example 31 using 6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-4-yl) piperidin-4-yl) acetaldehyde (intermediate 3-27).
  • Example 34 4-(1-(1-(2-(1-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl )piperidin-4-yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl )benzamide
  • Example 34 was synthesized in the same manner as in Example 31 using 6-dioxopiperidin-3-yl) -1,3-dioxoisoindolin-5-yl) piperidin-4-yl) acetaldehyde (intermediate 3-28). .
  • Example 35 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(2-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate
  • Step 3 Synthesis of 4-(1-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzoic acid
  • Step 4 tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate
  • Step 5 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4 Synthesis of -yl)ethyl)-1H-pyrazol-4-yl)benzamide hydrochloride
  • Step 6 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1H- Synthesis of pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 36 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 37 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 37 was synthesized in the same manner as in Example 35.
  • Example 38 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 39 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 39 was synthesized in the same manner as in Example 35 using [d]imidazol-5-amine (Intermediate 1-4).
  • Example 40 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 41 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 42 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)benzamide
  • Example 43 4-(1-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)butan-2- yl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-hydroxybutyl)piperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(3-((methylsulfonyl)oxy)butyl)piperidine-1-carboxylate
  • Step 5 Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate
  • Step 6 Synthesis of tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate
  • Step 7 Synthesis of 4-(1-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzoic acid
  • tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate (50mg, 0.12mmol), and lithium hydroxide monohydrate (48mg, 0.12mmol) mmol) was suspended in THF (0.6ml) and H 2 O (0.6ml) and stirred at 50°C for 4 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 6, followed by extraction with EtOAc (20ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 53 mg (quant.) of a light brown solid.
  • Step 8 tert-butyl 4-(3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate
  • Step 9 N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(4-(piperidin-4 Synthesis of -yl)butan-2-yl)-1H-pyrazol-4-yl)benzamide hydrochloride
  • Step 10 4-(1-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)butan-2-yl Synthesis of )-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 44 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate (334 mg, 1.27 mmol), 4-bromo-1H-pyrazole (169 mg, 1.15 mmol), and Cs 2 CO 3 (497 mg, 1.5 mmol) were mixed with acetonitrile ( 12.7ml) and THF (2ml) and stirred at 80°C for 15 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 423 mg (89%) of a yellow oil.
  • MPLC 50% EtOAc/Hexane
  • Step 2 Synthesis of tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 3 Synthesis of 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzoic acid
  • Step 4 tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 5 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1 Synthesis of -yl)propyl)-1H-pyrazol-4-yl)benzamide hydrochloride
  • Step 6 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H- Synthesis of pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 45 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 45 was synthesized in the same manner as in Example 44 using [d]imidazol-5-amine (Intermediate 1-4).
  • Example 46 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -pyrazol-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 47 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2,2 -difluoropropyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2,2-difluoropropyl)piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(2,2-difluoro-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 3 Synthesis of 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2-difluoropropyl)-1H-pyrazol-4-yl)benzoic acid
  • tert-butyl 4-(2,2-difluoro-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (117mg, 0.25mmol), and lithium Hydroxide monohydrate (63mg, 1.5mmol) was suspended in THF (1.2ml) and H 2 O (1.2ml) and stirred at 50°C for 17 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 5, followed by extraction with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 107 mg (95%) of a clear oil.
  • Step 4 tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d] Synthesis of imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 5 (S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin Synthesis of -1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 6 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2,2- Synthesis of difluoropropyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 48 4-(1-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl) cyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 48 was synthesized in the same manner as in Example 47 using -carboxylate (intermediate 2-1).
  • Example 49 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2-hydroxypropyl )-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2-hydroxypropyl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(2-hydroxy-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 4 Synthesis of 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-hydroxypropyl)-1H-pyrazol-4-yl)benzoic acid
  • Step 5 tert-butyl 4-(2-hydroxy-3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- Synthesis of 5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 6 4-(1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1 Synthesis of -yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 7 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2-hydroxypropyl) Synthesis of -1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 50 4-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-1H-1,2,3 -triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 4-(1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-1H-1,2,3- Synthesis of triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 51 4-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3 -triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 51 was synthesized in the same manner as in Example 50 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-36).
  • Example 52 4-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-1H-1,2,3 -triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 52 was synthesized in the same manner as in Example 50 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-37).
  • Example 53 4-(1-(10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)decyl)-1H-1,2,3 -triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 53 was synthesized in the same manner as in Example 50 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-35).
  • Example 54 4-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12 -trioxa-3-azatetradecan-14-yl)-1H-1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H -benzo[d]imidazol-5-yl)benzamide
  • Example 54 was synthesized in the same manner as in Example 50.
  • Example 55 4-(1-(10-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)decyl)-1H- 1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 56 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1H -1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 tert-butyl 4-(2-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1, Synthesis of 2,3-triazol-1-yl)ethyl)piperidine-1-carboxylate
  • Step 3 4-(1-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H Synthesis of -benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 4 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1H- Synthesis of 1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 57 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 58 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 58 was synthesized in the same manner as in Example 56 using [d]imidazol-5-amine (Intermediate 1-1).
  • Example 59 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 59 was synthesized in the same manner as in Example 56 using -(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845).
  • Example 60 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 61 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide
  • Example 62 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 63 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide
  • Example 63 was synthesized in the same manner as in Example 56 using 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of WO2010/081036). did
  • Example 64 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)benzamide
  • Example 65 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 tert-butyl 4-(3-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1, Synthesis of 2,3-triazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 2 4-(1-(3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H Synthesis of -benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 3 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H- Synthesis of 1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 66 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 67 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1H -1,2,3-triazol-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide
  • Example 68 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2,2 -difluoropropyl)-1H-1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5 -yl)benzamide
  • Step 1 Synthesis of (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d] Synthesis of imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate
  • Step 3 (S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2 Synthesis of -((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 4 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-2,2- difluoropropyl)-1H-1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5- Synthesis of yl)benzamide
  • Example 69 4-(1-((1-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl) cyclopropyl)methyl)-1H-1,2,3-triazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide
  • Example 69 was synthesized in the same manner as in Example 68 using Intermediate 2-2).
  • Example 70 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H -1,2,4-triazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-(3-bromo-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
  • Step 3 Synthesis of 4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzoic acid
  • Step 4 tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
  • Step 5 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperidin-4 Synthesis of -yl)propyl)-1H-1,2,4-triazol-3-yl)benzamide hydrochloride
  • Step 6 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1H- Synthesis of 1,2,4-triazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 71 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-5 -methyl-1H-1,2,4-triazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5- yl)benzamide
  • Step 2 Synthesis of methyl 4-(2-(1-iminoethyl)hydrazine-1-carbonyl)benzoate
  • Step 3 Synthesis of methyl 4-(5-methyl-1H-1,2,4-triazol-3-yl)benzoate
  • Methyl 4-(2-(1-iminoethyl)hydrazine-1-carbonyl)benzoate (660mg, 3.04mmol) was stirred at 180°C for 40 minutes.
  • the residue obtained by concentrating the reaction solution under reduced pressure was subjected to MPLC (70% EtOAc/Hexane) to obtain 283 mg (43%) of a white solid.
  • Step 4 Synthesis of tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
  • Step 5 Synthesis of 4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-5-methyl-1H-1,2,4-triazol-3-yl)benzoic acid
  • tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (374mg, 0.85mmol ), and lithium hydroxide monohydrate (178mg, 4.23mmol) were suspended in THF (4.3ml) and H 2 O (4.3ml) and stirred at room temperature for 17 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 4, followed by extraction with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 348mg (96%) of a white solid.
  • Step 6 tert-butyl (S)-4-(3-(5-methyl-3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- Synthesis of 5-yl)carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
  • Step 7 (S)-4-(5-methyl-1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)-N-(2-( Synthesis of (2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride
  • Step 8 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-5- methyl-1H-1,2,4-triazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl ) Synthesis of benzamide
  • Example 72 6-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)nicotinamide
  • Step 1 Synthesis of methyl 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinate
  • Step 2 Synthesis of 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinic acid
  • Step 3 tert-butyl (S)-4-(2-(4-(5-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate
  • Step 4 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-6-(4-(2-(piperidin-4 Synthesis of -yl)ethyl)piperazin-1-yl)nicotinamide hydrochloride
  • Step 5 6-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)piperazin-1 Synthesis of -yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)nicotinamide
  • Example 73 6-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)nicotinamide
  • Example 74 6-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)nicotinamide
  • Example 74 was synthesized in the same manner as in Example 72 using carboxylate (intermediate 2-6).
  • Example 75 6-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)nicotinamide
  • Example 76 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of methyl (E)-4-(N'-hydroxycarbamimidoyl)benzoate
  • Methyl 4-cyano benzoate 500mg, 3.1mmol
  • hydroxylamine hydrochloride 216mg, 3.1mmol
  • NaHCO 3 260mg, 3.1mmol
  • Step 2 Synthesis of tert-butyl 4-(4-((4-(methoxycarbonyl)benzimidamido)oxy)-4-oxobutyl)piperidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate
  • Step 4 Synthesis of 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzoic acid
  • Step 5 tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate
  • Step 6 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4 Synthesis of -yl)propyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride
  • Step 7 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1, Synthesis of 2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 77 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 77 was synthesized in the same manner as in Example 76 using -dione (WO2010/081036).
  • Example 78 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5- yl)benzamide
  • Example 79 4-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 79 3-(1-(tert-butoxycarbonyl)piperidin- Example 79 was synthesized in the same manner as in Example 76 using 4-yl)propanoic acid (WO1994/027965).
  • Example 80 4-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 80 was synthesized in the same manner as in Example 76 using -dioxopiperidin-3-yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
  • Example 81 4-(5-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1 ,2,4-oxadiazol-3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 82 4-(3-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-cyanopropyl)piperidine-1-carboxylate
  • tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458, 600mg, 1.5mmol) and sodium cyanide (148mg, 3mmol) were suspended in EtOH (3ml) and then incubated at 80°C for 2 Stir for an hour. After concentrating the reaction solution under reduced pressure, distilled water (20ml) was added and extracted with EtOAc (30ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (30% EtOAc/Hexane) to give 333 mg (88%) of a clear oil.
  • Step 2 Synthesis of tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperidine-1-carboxylate
  • tert-butyl 4-(3-cyanopropyl)piperidine-1-carboxylate 100mg, 0.4mmol
  • hydroxylamine hydrochloride 56mg, 0.8mmol
  • K 2 CO 3 122mg, 0.88mmol
  • Step 3 Synthesis of tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate
  • Step 4 Synthesis of 4-(3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid
  • Step 5 tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate
  • Step 6 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperidin-4 Synthesis of -yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride
  • Step 7 4-(3-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1, Synthesis of 2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 83 4-(3-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 83 was synthesized in the same manner as in Example 82 using -dione (WO2010/081036).
  • Example 84 4-(3-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5- yl)benzamide
  • Example 85 4-(3-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 86 4-(3-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 86 was synthesized in the same manner as in Example 82 using -dioxopiperidin-3-yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
  • Example 87 4-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1 ,2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(3-cyanopropyl)piperazine-1-carboxylate
  • tert-butyl piperazine-1-carboxylate 500mg, 2.7mmol
  • 4-bromobutanenitrile (0.54ml, 5.4mmol
  • Na 2 CO 3 0.569mg, 5.4mmol
  • acetonitrile 2.68ml
  • EtOAc 20ml
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 665 mg (98%) of a clear oil.
  • Step 2 Synthesis of tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperazine-1-carboxylate
  • tert-butyl 4-(3-cyanopropyl)piperazine-1-carboxylate (660mg, 2.61mmol), hydroxylamine hydrochloride (363mg, 5.22mmol), and K 2 CO 3 (792mg, 5.73mmol) were mixed with EtOH (3.2ml) and H After suspension in 2 O (0.8ml), the mixture was stirred at 90°C for 14 hours. The reaction solution was concentrated under reduced pressure to obtain 696 mg of pale yellow oil.
  • Step 3 Synthesis of tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate
  • tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperazine-1-carboxylate (692mg, 3.48mmol), methyl 4-(chlorocarbonyl)benzoate (460mg, 2.32mmol), and DIPEA ( 0.5ml, 2.78mmol) was suspended in THF (10ml) and stirred at room temperature for 1 hour. After adding Cs 2 CO 3 (1.49g, 4.6mmol), the mixture was stirred at 60°C for 4 hours. After concentrating the reaction solution under reduced pressure, distilled water (20ml) was added and extracted with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 231 mg of a brown oil.
  • MPLC 50% EtOAc/Hexane
  • Step 4 Synthesis of 4-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid
  • Step 5 tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate
  • Step 6 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperazin-1 Synthesis of -yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride
  • Step 7 4-(3-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propyl)-1, Synthesis of 2,4-oxadiazol-5-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 88 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1 ,3,4-oxadiazol-2-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 2 Synthesis of tert-butyl 4-(4-(2-(4-(methoxycarbonyl)benzoyl)hydrazineyl)-4-oxobutyl)piperidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate
  • Step 4 Synthesis of 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzoic acid
  • Step 5 tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate
  • Step 6 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4 Synthesis of -yl)propyl)-1,3,4-oxadiazol-2-yl)benzamide hydrochloride
  • Step 7 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-1, Synthesis of 3,4-oxadiazol-2-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 89 4-(5-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-1 ,3,4-oxadiazol-2-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 90 4-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-1 ,3,4-oxadiazol-2-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 91 4-(5-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-1 ,3,4-oxadiazol-2-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 92 4-(6-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)pyridin- 3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(2-(5-bromopyridin-2-yl)ethyl)piperidine-1-carboxylate
  • Step 2 Synthesis of tert-butyl 4-(2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate
  • Step 3 Synthesis of 4-(6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)pyridin-3-yl)benzoic acid
  • Step 4 tert-butyl (S)-4-(2-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate
  • Step 5 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(6-(2-(piperidin-4 Synthesis of -yl)ethyl)pyridin-3-yl)benzamide hydrochloride
  • Step 6 4-(6-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)pyridin-3 Synthesis of -yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 93 4-(6-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)pyridin- 3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 94 4-(6-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)pyridin- 3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380) was used instead of tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192) in the same manner as in the synthesis method of Example 92.
  • Example 94 was synthesized.
  • Example 95 4-(6-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)pyridin- 3-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 95 was synthesized in the same manner as in Example 92 using
  • Example 96 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperidine-1-carboxylate
  • Step 5 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N-(2- Synthesis of (((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 97 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 97 was synthesized in the same manner as in Example 96 using 3-dione (WO2010/081036).
  • Example 98 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N-(2 -(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 99 4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N-(2 -(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 99 was synthesized in the same manner as in Example 96 using [d]imidazol-5-amine (Intermediate 1-4).
  • Example 100 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 100 was synthesized.
  • Example 101 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 101 was synthesized in the same manner as in Example 96 using the same method.
  • Example 102 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Step 1 Synthesis of tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperazine-1-carboxylate
  • tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperazine-1-carboxylate (306mg, 0.88mmol), and lithium hydroxide monohydrate (221mg, 5.3mmol) were suspended in THF (2ml) and H 2 O (2ml) After stirring at 50 °C for 6 hours. 1N HCl aqueous solution was added to the reaction solution to adjust the pH to 5, followed by extraction with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 304 mg (quant.) of a white solid.
  • Step 5 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)-N-(2- Synthesis of (((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
  • Example 103 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)-N-(2 -(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide

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Abstract

La présente invention concerne un composé ayant une structure chimique spécifique et ayant une activité de dégradation d'ENL, ou des sels pharmaceutiquement acceptables de celui-ci. La présente divulgation concerne également une composition comprenant le composé ou des sels pharmaceutiquement acceptable de celui-ci. La présente divulgation concerne également des utilisations médicales du composé selon la présente divulgation, de ses sels, et d'une composition les comprenant pour le traitement ou la prévention de maladies liées à la protéine ENL. La présente divulgation concerne également un procédé de traitement ou de prévention de maladies associées à la protéine ENL, comprenant l'administration d'une quantité efficace du composé selon la présente divulgation, de sels de celui-ci, ou d'une composition les comprenant à un sujet ayant besoin d'un traitement.
PCT/KR2022/013646 2021-09-13 2022-09-13 Composé de dégradation de la protéine enl et utilisations médicales associées Ceased WO2023038500A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015160845A2 (fr) * 2014-04-14 2015-10-22 Arvinas, Inc. Modulateurs de la protéolyse, à base d'imide, et procédés d'utilisation associés
WO2022086937A1 (fr) * 2020-10-21 2022-04-28 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels en tant qu'agents de dégradation de enl

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2015160845A2 (fr) * 2014-04-14 2015-10-22 Arvinas, Inc. Modulateurs de la protéolyse, à base d'imide, et procédés d'utilisation associés
WO2022086937A1 (fr) * 2020-10-21 2022-04-28 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels en tant qu'agents de dégradation de enl

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HAI-TSANG HUANG, DENNIS DOBROVOLSKY, JOSHIAWA PAULK, GUANG YANG, ELLEN L. WEISBERG, ZAINAB M. DOCTOR, DENNIS L. BUCKLEY, JOONG-HEU: "A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader", CELL CHEMICAL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 25, no. 1, 1 January 2018 (2018-01-01), AMSTERDAM, NL , pages 88 - 99.e6, XP055745243, ISSN: 2451-9456, DOI: 10.1016/j.chembiol.2017.10.005 *
ITO TAKUMI, YAMAGUCHI YUKI, HANDA HIROSHI: "Exploiting ubiquitin ligase cereblon as a target for small-molecule compounds in medicine and chemical biology", CELL CHEMICAL BIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 28, no. 7, 1 July 2021 (2021-07-01), AMSTERDAM, NL , pages 987 - 999, XP055906932, ISSN: 2451-9456, DOI: 10.1016/j.chembiol.2021.04.012 *
MOSES MOUSTAKIM; THOMAS CHRISTOTT; OCTOVIA P. MONTEIRO; JAMES BENNETT; CHARLINE GIROUD; JENNIFER WARD; CATHERINE M. ROGERS; PAUL S: "Discovery of an MLLT1/3 YEATS Domain Chemical Probe", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, VERLAG CHEMIE, HOBOKEN, USA, vol. 57, no. 50, 16 November 2018 (2018-11-16), Hoboken, USA, pages 16302 - 16307, XP072103717, ISSN: 1433-7851, DOI: 10.1002/anie.201810617 *

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