WO2023038500A1 - Compound for degrading enl protein and medical uses thereof - Google Patents

Compound for degrading enl protein and medical uses thereof 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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PCT/KR2022/013646
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French (fr)
Korean (ko)
Inventor
류제호
안정민
장미영
윤휘상
배온누리
이송희
서범선
김현휘
김한울
박지윤
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주식회사 유빅스테라퓨틱스
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Publication of WO2023038500A1 publication Critical patent/WO2023038500A1/en

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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
    • A61K31/44—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

The present invention provides a compound having a specific chemical structure and having an activity of degrading ENL, or pharmaceutically acceptable salts thereof. The present disclosure also provides a composition comprising the compound or pharmaceutically acceptable salts thereof. The present disclosure also provides medicinal uses of the compound according to the present disclosure, salts thereof, and a composition comprising same for the treatment or prevention of ENL protein-related diseases. The present disclosure also provides a method for treating or preventing ENL protein-related diseases, comprising administering an effective amount of the compound according to the present disclosure, salts thereof, or a composition comprising same to a subject in need of treatment.

Description

ENL 단백질 분해용 화합물 및 이들의 의약 용도Compounds for degrading ENL proteins and their medicinal uses
본 출원은 2021년 9월 13일에 출원된 한국특허출원 제10-2021-0122049호에 기초한 우선권을 주장하며, 해당 출원의 명세서 및 도면에 개시된 모든 내용은 본 출원에 원용된다.This application claims priority based on Korean Patent Application No. 10-2021-0122049 filed on September 13, 2021, and all contents disclosed in the specification and drawings of the application are incorporated into this application.
본 개시는 ENL 단백질을 분해하는 활성을 가지는 일 군의 화합물에 관한 것이다. 본 개시는 또한 이러한 화합물을 포함하는 약학 조성물에 관한 것이다. 본 개시는 또한 이러한 화합물을 이용하여, ENL 단백질 관련 질환을 치료하는 유용한 방법에 관한 것이다. 즉, 본 개시는 본 개시에 따른 화합물들의 ENL 단백질 관련 질환을 치료 또는 예방하기 위한 의약 용도에 관한 것이다.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.
YEATS 도메인은 ENL, YEATS2, AF9 및 신경교종 증폭 서열 41(GAS41 또는 YEATS4)에 존재하는 히스톤 아세틸화 리더(histone acetylation reader)의 한 부류이다. The YEATS domain is a class of histone acetylation readers present in ENL, YEATS2, AF9 and glioma amplified sequence 41 (GAS41 or YEATS4).
이 중 ENL(MLLT1에 의해 인코딩됨)은 YEATS 도메인을 사용하여 히스톤 H3의 위치 9, 18 및 27에서 아실화된 라이신 측쇄(아세틸 및 크로토닐 변형 포함)에 결합하는 염색질 리더 단백질이다. Among these, 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.
YEATS 단백질의 기능장애는 질병, 특히 암과 관련이 있다. 예를 들어 AF9 또는 ENL과 인간 혼합 계통 백혈병(mixed lineage leukemia, MLL) 단백질의 융합은 급성 골수성 백혈병에서 자주 발견되며, 이러한 융합은 종양 유전자(oncogene)를 구성한다. 또한, SRCAP(Snf2 관련 CREBBP 활성화 단백질) 및 Tip60 HAT 복합체의 공통 서브유닛인 GAS41은 성장 촉진 단백질이다. 이러한 역할은 YEATS 단백질이 약물 개발의 잠재적 표적임을 시사한다. Dysfunction of the YEATS protein is associated with disease, particularly cancer. For example, fusions of AF9 or ENL with human mixed lineage leukemia (MLL) proteins are frequently found in acute myelogenous leukemia, and these fusions constitute oncogenes. In addition, SRCAP (Snf2-related CREBBP activating protein) and GAS41, a common subunit of the Tip60 HAT complex, are growth promoting proteins. These roles suggest that the YEATS protein is a potential target for drug development.
실제로, 최근 연구에서는 ENL(MLLT1) YEATS 도메인이 AML 등을 포함하는 백혈병에서 강력한 표적으로 확인되었다(Nature volume 543, pages 265-269 (2017), Nature volume 543, pages 270-274 (2017)). 즉, ENL YEATS 도메인과 아실-리신 기질의 상호작용이 급성 림프구성 백혈병, 급성 골수성 백혈병(ALL 및 AML) 등의 백혈병에 대한 치료제 개발을 위한 검증된 표적이라고 알려져 있다. 또, ENL YEATS domain의 hotspot mutation (gain-of-function mutation)은 신장암의 한 형태인 Wilms tumor에서도 발견되며, ENL 단백질의 활성 증가가 발암성을 가지는 기전에 대해 밝혀지고 있다 (Nature volume 577, pages 121-126 (2020)). 그러나, 유용한 ENL YEATS의 억제제는 지금까지 보고되지 않았다.Indeed, recent studies have identified the 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). In addition, 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)). However, useful inhibitors of ENL YEATS have not been reported so far.
따라서 본 발명이 해결하고자 하는 과제는 ENL 단백질 분해 활성을 가지는 화합물, 이들을 유효성분으로 포함하는 약학 조성물, 및 이들의 ENL 단백질 관련 질환 치료 또는 예방용 의약 용도를 제공하는 것이다. Therefore, 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.
본 발명이 해결하고자 하는 다른 과제는 ENL 단백질을 분해하여 결과적으로 ENL 단백질 활성을 낮추는 것을 특징으로 하는, 본 발명에 따른 화합물을 ENL 단백질 관련 질환의 치료, 개선 또는 예방이 필요한 환자에게 투여하는 것을 특징으로 하는 ENL 단백질 관련 질환의 치료 또는 개선 방법을 제공하는 것이다.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. To provide a method for treating or improving ENL protein-related diseases.
본 발명 화합물Compound of the present invention
상기 해결하고자 하는 과제를 달성하기 위하여, 일 태양에서, 본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. In order to achieve the above object to be solved, in one aspect, the present invention provides a compound of Formula 1 below or a pharmaceutically acceptable salt thereof.
Figure PCTKR2022013646-appb-img-000001
Figure PCTKR2022013646-appb-img-000001
상기 화학식 1에서, In Formula 1,
R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고,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,
X는 NH 또는 O이고,X is NH or O;
A는 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며, 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;
n은 0, 1, 또는 2이고, n is 0, 1, or 2;
L은 하기 화학식 2이고,L is Formula 2 below,
[화학식 2][Formula 2]
Figure PCTKR2022013646-appb-img-000002
Figure PCTKR2022013646-appb-img-000002
상기 화학식 2에 있어서, In Formula 2,
A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고,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-,
B1, B2 및 B3은 서로 독립적으로 직접 결합, C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며, 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;
R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH이며,R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or -OH;
q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
E는 하기 화학식 3 또는 4임.E is Formula 3 or 4.
[화학식 3][Formula 3]
Figure PCTKR2022013646-appb-img-000003
Figure PCTKR2022013646-appb-img-000003
상기 화학식 3에 있어서, In Formula 3,
R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-, wherein R 5 and R 5 'are mutually independently H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
[화학식 4][Formula 4]
Figure PCTKR2022013646-appb-img-000004
Figure PCTKR2022013646-appb-img-000004
화학식 4에서, In Formula 4,
R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고,R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
X1, X2 및 X3는 서로 독립적으로 CH 또는 N이며, X 1 , X 2 and X 3 are independently of each other CH or N,
Z는 직접 결합, -C(R5)(R5')-, -N(R5)-, -O-, 또는 -C(O)NH-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시임.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.
본 발명자들은, E3 유비퀴틴 리가아제에 결합하는 특정 구조의 세레브론(CRBN) 리간드(화학식 1의 E)와 ENL YEATS 도메인에 결합하는 모이어티(링커를 기준으로 왼쪽 모이어티)를 결합하여 ENL 단백질 분해 활성, (대사)안정성 등이 우수하고, 약효 성분으로서의 물리화학적 성질(cLogP value, 수용해성, 세포막 투과성) 등이 우수한 새로운 화합물을 개발하고자 하였다.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). An attempt was made to develop a new compound with excellent activity, (metabolism) stability, etc., and excellent physicochemical properties (cLogP value, water solubility, cell membrane permeability) as a medicinal ingredient.
즉, 본 개시에 따른 화합물들은 ENL의 YEATS domain에 binding하는 모이어티를 통해 ENL 단백질에 결합하고 다른 한쪽의 모이어티를 통해 세레브론에 결합하여 ENL 단백질의 유비퀴틴화를 유도함으로써 프로테아좀을 통한 ENL 단백질 분해 활성을 가질 것으로 예상되나, 본 발명은 이러한 기전 또는 예측에 한정되는 것은 아니다.That is, 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.
본 개시에 따른 화합물(들)은 특정 조합에서 보다 충분하게 본 발명의 여러 목적에 부합하였다. 예를 들어, 링커(화학식 1의 L)의 경우 긴 carbon chain 또는 PEG (polyethylene glycol)를 사용하는 것보다 짧은 carbon chain을 거쳐 heterocycle을 통해 CRBN binder(화학식 1의 E)에 연결하는 것이 ENL 단백질 분해 활성, 대사안정성 등의 측면에서 더욱 바람직하다. CRBN binder로 thalidomide를 사용할 경우 heterocycle이 5번 위치보다 4번 위치로 연결될 때 ENL 단백질 분해 활성이 상대적으로 우수한 사례가 많다. 또한, ENL YEATS binder 끝부분의 치환기(화학식 1의 R1, 및 R2)를 적절하게 조합하여 대사안정성을 개선할 수 있다. The compound(s) according to the present disclosure more fully met the various objects of the present invention in certain combinations. For example, in the case of the linker (L in Formula 1), linking to the CRBN binder (E in Formula 1) through a short carbon chain through a heterocycle rather than using a long carbon chain or PEG (polyethylene glycol) reduces ENL protein degradation. It is more preferable in terms of activity, metabolic stability, and the like. When thalidomide is used as a CRBN binder, there are many cases in which the ENL proteolytic activity is relatively excellent when the heterocycle is connected to the 4-position rather than the 5-position. In addition, metabolic stability can be improved by properly combining the substituents at the end of the ENL YEATS binder (R 1 and R 2 in Formula 1).
본 명세서에서 용어 "치환기(substituent)", "라디칼(radical)", "기(group)", "모이어티(moiety)", 및 "절편(fragment)"은 서로 바꾸어 사용할 수 있다.In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.
만약 치환기가 "임의로 치환된" 또는 “선택적으로 치환된”으로 설명된다면, 상기 치환기는 (1) 치환되지 않거나 (2) 또는 정의된 치환기들 중 하나 이상으로 치환될 수 있다. 만약 치환 가능한 위치가 치환되지 않은 경우 기본(default) 치환기는 하이드리도 라디칼이다.If a substituent is described as "optionally substituted" or "optionally substituted", the 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.
본 명세서에서 사용된 용어 "알킬"은 (탄소수가 특별히 한정되지 않은 경우) 탄소수 1 내지 10을 가진 포화된 직쇄상 또는 분지상의 비-고리(cyclic) 탄화수소를 의미한다. "저급 알킬"은 탄소수가 1 내지 4인 직쇄상 또는 분지상 알킬을 의미한다. 대표적인 포화 직쇄상 알킬은 -메틸, -에틸, -n-프로필, -n-부틸, -n-펜틸, -n-헥실, -n-헵틸, -n-옥틸, -n-노닐 과 -n-데실을 포함하고, 반면에 포화 분지상 알킬은 -이소프로필, -sec-부틸, -이소부틸, -tert-부틸, 이소펜틸, 2-메틸헥실, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 4-메틸헥실, 5- 메틸헥실, 2,3-디메틸부틸, 2,3-디메틸펜틸, 2,4-디메틸펜틸, 2,3-디메틸헥실, 2,4-디메틸헥실, 2,5-디메틸헥실, 2,2-디메틸펜틸, 2,2-디메틸헥실, 3,3-디메틸펜틸, 3,3-디메틸헥실, 4,4-디메틸헥실, 2-에틸펜틸, 3-에틸펜틸, 2-데틸헥실, 3-에틸헥실, 4-에틸헥실, 2-메틸-2-에틸펜틸, 2-메틸-3-에틸펜틸, 2-메틸-4-에틸펜틸, 2-메틸-2-에틸헥실, 2-메틸-3-에틸헥실, 2-메틸-4-에틸헥실, 2,2-디에틸펜틸, 3,3-디에틸헥실, 2,2-디에틸헥실, 및 3,3-디에틸헥실을 포함한다. As used herein, the term "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. Representative 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-methylhexyl, 5- Methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethyl Pentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-decylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl.
본 명세서에서 사용된 용어 "알콕시"는 -OCH3, -OCH2CH3, -O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, -O(CH2)5CH3, 및 이와 유사한 것을 포함하는 -O-(알킬)을 의미하며, 여기에서 알킬은 위에서 정의된 것과 같다. As used herein, the term "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.
본 명세서에서 “C1-6”, "C1-6", 또는 "C1-C6"와 같이 기재될 경우 이는 탄소수가 1 내지 6개임을 의미한다. 예를 들어, C1-6알킬은 탄소수가 1 내지 6인 알킬을 의미한다.In the present specification, when described as “C 1-6 ”, “C1-6”, or “C1-C6”, it means that the number of carbon atoms is 1 to 6. For example, C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms.
본 명세서에서 사용된 용어 "할로겐" 및 "할로"는 플루오린, 클로린, 브로민 또는 아이오딘을 의미한다. 본 발명의 바람직한 일 태양에 있어, 할로겐은 클로린 또는 플루오린이다.As used herein, the terms "halogen" and "halo" mean fluorine, chlorine, bromine or iodine. In a preferred aspect of the present invention, halogen is chlorine or fluorine.
본 명세서에서 사용된 용어 "할로알킬", “할로알콕시”, “할로알케닐” 또는 “할로알키닐”은 각각 하나 이상의 수소 원자가 할로겐 원자로 치환된 알킬, 알콕시, 알케닐 또는 알키닐 그룹을 의미한다. 예를 들어, 할로알킬은 -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CC13, -CHC12, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CC13, -CH2-CHC12, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, 및 이와 유사한 것을 포함한다. 본 발명의 바람직한 일 태양에서, 할로알킬은 CF3이다. 여기에서 알킬 및 할로겐은 위에서 정의된 것과 같다.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. . For example, 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 are as defined above.
본 명세서에서 사용된 용어 "사이클로알킬(cycloalkyl)"은 탄소 및 수소 원자를 가지며 탄소-탄소 다중 결합을 가지지 않는 모노사이클릭 또는 폴리사이클릭 포화 고리(ring)를 의미한다. 모노사이클릭 고리의 예는 (C3-C7)사이클로알킬 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 및 사이클로헵틸)을 포함하나 이에 한정되는 것은 아니다. 폴리사이클릭 고리의 예는 octahydropentalene, decahydronaphthalene 등과 같은 융합된(fused) 바이사이클릭(bicyclic) 고리; spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane 등과 같은 스피로 고리; 및 bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane 등과 같은 가교된(bridged) 바이사이클릭 고리를 포함하나 이에 한정되는 것은 아니다. 사이클로알킬 그룹은 선택적으로 치환될 수 있다. 일 실시예에서, 사이클로알킬 그룹은 모노사이클릭 링(고리)이다. As used herein, the term "cycloalkyl" means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and not having carbon-carbon multiple bonds. Examples of monocyclic rings include, but are not limited to, (C 3 -C 7 )cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl). Examples of polycyclic rings 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).
본 명세서에서 사용된 "헤테로사이클(헤테로고리)" 또는 “헤테로사이클로알킬”은 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4의 헤테로원자를 함유하는 포화된 5- 내지 7-멤버의 모노사이클릭, 또는 7- 내지 12-멤버의 바이사이클릭 링(고리)를 의미하며, 여기에서 질소 및 황 헤테로원자는 선택적으로 산화될 수 있고, 질소 헤테로원자는 선택적으로 사가화(quaternized)될 수 있다. 대표적인 헤테로고리는 옥시란(oxiran), 옥세탄(oxetan), 테트라하이드로퓨란(tetrahydrofuran), 테트라하이드로피란(tetrahydropyran), 1,4-디옥산(1,4-dioxane), 아지리딘(aziridine), 아제티딘(azetidine), 피롤리딘(pyrrolidine), 피페리딘(piperidine), 피페라진(piperazine), 피롤리디논(pyrrolidinone), 히단토인(hydantoine), 발레롤락탐(valerolactam), 티이란(thiirane), 티에탄(thietane), 테트라하이드로티오펜(tetrahydrothiophene), 테트라하이드로티오피란(tetrahydrothiopyra), 모포린(morpholine), 테트라하이드로피리딘(tetrahydropyridine), 테트라하이드로피리미딘(tetrahydropyrimidine) 등을 포함한다. 헤테로사이클에는 헤테로고리 중 일부가 벤젠 또는 cyclopenta-1,3-diene 고리에 융합한 바이사이클릭 링이 포함된다. 헤테로고리는 헤테로원자 또는 탄소 원자에 의하여 부착될 수 있다. 또한, 헤테로사이클에는 앞서 언급된 폴리사이클릭 고리의 1개 이상의 탄소 원자가 질소, 산소 또는 황 원자로 치한된 융합된(fused) 바이사이클릭(bicyclic) 고리, 스피로 고리 및 가교된(bridged) 바이사이클릭 고리가 포함된다. 이러한 예로는, 예를 들어, 헤테로원자가 질소일 경우 octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine 등과 같은 융합된(fused) 헤테로바이사이클릭(bicyclic) 고리; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane 등과 같은 스피로 고리; 및 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane 등과 같은 가교된(bridged) 헤테로바이사이클릭 고리를 포함하나 이에 한정되는 것은 아니다.As used herein, 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. Representative 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. For example, when the heteroatom is nitrogen, fused heterobicyclics such as octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine, etc. bicyclic) rings; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[ 3.5]nonane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3, spiro rings such as 9-diazaspiro[5.5]undecane; and 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2 .2]octane and the like, but is not limited to bridged heterobicyclic rings.
본 명세서에서 사용된 용어 "아릴"은 5 내지 10의 고리 원자를 함유하는 탄소고리 방향족 그룹을 의미한다. 대표적인 예는 페닐, 톨일(tolyl), 자이릴(xylyl), 나프틸, 테트라하이드로나프틸, 안트라세닐(anthracenyl), 플루오레닐(fluorenyl), 인데닐(indenyl), 아주레닐(azulenyl) 등을 포함하나 이에 한정되는 것은 아니다. 탄소고리 방향족 그룹은 선택적으로 치환될 수 있다.As used herein, the term “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.
본 명세서에서 사용된 "헤테로아릴"은 질소, 산소 및 황으로 구성된 군으로부터 선택된 적어도 하나의 헤테로원자를 가지고, 모노- 및 바이사이클릭 링 시스템을 포함하는 적어도 하나의 탄소 원자를 포함하는 5 내지 10 멤버의 방향족 헤테로고리(heterocycle) 링이다. 대표적인 헤테로아릴은 furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine 등이다. As used herein, "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.
ENL 단백질 분해 활성, (대사)안정성, 물리화학적 특성 등 여러 측면에서, 본 발명의 바람직한 일 태양은 상기 화학식 1에서, In various aspects such as ENL proteolytic activity, (metabolism) stability, and physicochemical properties, a preferred embodiment of the present invention is in Formula 1 above,
R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고, 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,
X는 NH이고,X is NH;
A는 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 헤테로사이클, 아릴, 또는 헤테로아릴은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며, 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;
n은 0 또는 1이고, n is 0 or 1;
L은 하기 화학식 2이고,L is Formula 2 below,
[화학식 2][Formula 2]
Figure PCTKR2022013646-appb-img-000005
Figure PCTKR2022013646-appb-img-000005
상기 화학식 2에 있어서, In Formula 2,
A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고, 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,
B1, B2 및 B3은 서로 독립적으로 직접 결합, 헤테로사이클, 또는 헤테로아릴이며, 여기에서 헤테로사이클, 또는 헤테로아릴 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며, 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;
R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 또는 -OH이며, R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, or -OH;
q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
E는 하기 화학식 3임.E is Formula 3 below.
[화학식 3][Formula 3]
Figure PCTKR2022013646-appb-img-000006
Figure PCTKR2022013646-appb-img-000006
상기 화학식 3에 있어서, In Formula 3,
R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-;
R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시인,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;
화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. A compound or a pharmaceutically acceptable salt thereof is provided.
본 발명의 보다 바람직한 일 태양은 또한 상기 화학식 1에서A more preferred aspect of the present invention is also in the above formula (1)
R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고,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,
X는 NH이고,X is NH;
A는 하기 치환기들 중 어느 하나이며, 여기에서 하기 치환기들은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며,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;
Figure PCTKR2022013646-appb-img-000007
Figure PCTKR2022013646-appb-img-000007
n은 0, 또는 1이고, n is 0 or 1;
L은 하기 화학식 2이고,L is Formula 2 below,
[화학식 2][Formula 2]
Figure PCTKR2022013646-appb-img-000008
Figure PCTKR2022013646-appb-img-000008
상기 화학식 2에 있어서, In Formula 2,
A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고, 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,
B1, B2 및 B3은 서로 독립적으로 직접 결합, 또는 하기 치환기들 중 어느 하나이며, 여기에서 하기 치환기들은 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며,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,
Figure PCTKR2022013646-appb-img-000009
Figure PCTKR2022013646-appb-img-000009
R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 또는 -OH이며, R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, or -OH;
q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
E는 하기 화학식 3임.E is Formula 3 below.
[화학식 3][Formula 3]
Figure PCTKR2022013646-appb-img-000010
Figure PCTKR2022013646-appb-img-000010
상기 화학식 3에 있어서, In Formula 3,
R4는 H, C1-6알킬, 또는 할로겐이고, R 4 is H, C 1-6 alkyl, or halogen;
Y는 -CH2-, -C(O)-, 또는 -N=N-인,Y is -CH 2 -, -C(O)-, or -N=N-;
화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. A compound or a pharmaceutically acceptable salt thereof is provided.
본 발명의 보다 바람직한 다른 태양은 또한 상기 화학식 1에서Another more preferred aspect of the present invention is also in the above formula (1)
상기 E는 하기 화학식 3'이며, E is Formula 3' below,
[화학식 3'][Formula 3']
Figure PCTKR2022013646-appb-img-000011
Figure PCTKR2022013646-appb-img-000011
상기 화학식 3'에서, In Formula 3',
R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-, wherein R 5 and R 5 'are mutually independently H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
E는
Figure PCTKR2022013646-appb-img-000012
또는
Figure PCTKR2022013646-appb-img-000013
에 직접 연결되어 있는, 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. 이와 같은 치환기를 가질 경우 ENL 단백질 분해 활성 등 다양한 측면에서 본 발명의 목적상 더욱 바람직하다. E is
Figure PCTKR2022013646-appb-img-000012
or
Figure PCTKR2022013646-appb-img-000013
Provided is a compound or a pharmaceutically acceptable salt thereof, which is directly linked to. When having such a substituent, it is more preferable for the purpose of the present invention in various aspects such as ENL proteolytic activity.
본 발명의 일 태양에 있어, -L-E를 제외한 (*-L-E에 연결되는) 화학식 1은 하기 구조들 중 어느 하나일 수 있다.In one aspect of the present invention, Formula 1 excluding -L-E (linked to *-L-E) may be any one of the following structures.
Figure PCTKR2022013646-appb-img-000014
Figure PCTKR2022013646-appb-img-000014
본 발명의 일 태양에 있어, 화학식 1의 E는 하기 구조들 중 어느 하나일 수 있다.In one aspect of the present invention, E in Formula 1 may be any one of the following structures.
Figure PCTKR2022013646-appb-img-000015
Figure PCTKR2022013646-appb-img-000015
본 발명의 바람직한 일 태양에 있어, 화학식 1의 E는 하기 구조를 가진다.In a preferred aspect of the present invention, E in Formula 1 has the following structure.
Figure PCTKR2022013646-appb-img-000016
Figure PCTKR2022013646-appb-img-000016
본 발명의 일 태양에 있어, 화학식 1의 L은 하기 구조들 중 어느 하나일 수 있다.In one aspect of the present invention, L in Formula 1 may be any one of the following structures.
Figure PCTKR2022013646-appb-img-000017
Figure PCTKR2022013646-appb-img-000017
Figure PCTKR2022013646-appb-img-000018
Figure PCTKR2022013646-appb-img-000018
본 명세서에 있어, * 또는
Figure PCTKR2022013646-appb-img-000019
은 다른 moiety와 연결되어 있는 것을 의미한다.In this specification, * or
Figure PCTKR2022013646-appb-img-000019
means that it is connected to another moiety.
비-한정적인, 본 개시에 따른 화학식 1의 화합물의 예는 후술하는 실시예들에서 제조된 화합물들이다. 각 실시예 번호는 화합물 번호에 대응한다. 예를 들어, 실시예 30에서 제조된 최종 화합물의 번호는 화합물 30이다. 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.
상기 화합물들 중에서도, 특히 하기 표 1의 화합물들이 ENL 단백질 분해 활성, 암 세포주 세포독성, (대사)안정성, 물리화학적 성질 등 다양한 측면에서 더욱 바람직하였다.Among the above compounds, 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.
Figure PCTKR2022013646-appb-img-000020
Figure PCTKR2022013646-appb-img-000020
Figure PCTKR2022013646-appb-img-000021
Figure PCTKR2022013646-appb-img-000021
Figure PCTKR2022013646-appb-img-000022
Figure PCTKR2022013646-appb-img-000022
본 발명에 있어 "약학적으로 허용 가능한 염"은 여기서 언급한 화합물들에서 발견되는 특정 치환체에 의존하는 비교적 비독성 산 및 염기로 제조된 활성 화합물의 염들을 포함한다. 본 발명의 화합물들은 상대적으로 산성 기능성을 포함할 때, 염기(base) 부가 염들은 충분한 양의 원하는 염기, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 염기 부가 염의 예들은 나트륨, 칼륨, 칼슘, 암모늄, 유기 아미노 또는 마그네슘 염 또는 유사한 염을 포함한다. 본 발명의 화합물들은 상대적으로 염기성 기능성을 포함할 때, 산성 부가 염들은 충분한 양의 원하는 산, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 산성 부가 염의 예들은 초산, 프로피온산, 이소부틸산, 옥살릭산(oxalic), 마레익(maleic), 말로닉(malonic), 안식향성, 숙신산, 수버릭(suberic), 푸마릭(fumaric), 만데릭(mandelic), 프탈릭(phthalic), 벤젠설포닉(benzenesulfonic), p-토릴설포닉(tolylsulfonic), 구연산, 주석산, 메탄솔포닉(methanesulfonic), 및 그 유사체를 포함하는 상대적으로 비독성 유기산에서 유래한 염들 뿐만 아니라, 염화수소, 브롬화 수소, 질산, 탄산, 일수소탄산(monohydrogencarbonic), 인산(phosphoric), 일수소인산, 이수소인산, 황산, 일수소황산, 요오드화수소 또는 아인산(phosphorous acid) 및 그 유사체를 포함한다. 또한 알긴네이트(arginate)와 그 유사체와 같은 아미노산의 염 및 글루쿠로닉(glucuronic) 또는 갈락투노릭(galactunoric) 산들과 그 유사체와 같은 유기산의 유사체를 포함한다. 본 발명의 일부 특정한 화합물들은 화합물들을 염기성 또는 산성 부가(addition) 염들로 전환하게 하는 염기성 및 산성 기능성 모두를 갖는다. 염들의 다른 예들은 본 발명이 속한 분야에서 공지된 문헌들을 통해 잘 알려져 있다. In the present invention, "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. When compounds of the present invention contain relatively acidic functionality, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functionality, 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. Also included are 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.
본 명세서에서 사용된 용어인 "본 발명의 화합물"은 화학식 1 각각의 화합물들뿐만 아니라, 이들의 클라드레이트(clathrates), 수화물, 용매화물, 또는 다형체를 포함하는 의미이다. 또한 용어 “본 발명의 화합물”은 이의 약학적으로 허용 가능한 염이 언급되지 않을 경우 본 발명 화합물의 약학적으로 허용 가능한 염도 포함하는 의미이다. 일 실시예에 본 발명의 화합물은 입체이성질체적으로 순수한 화합물들(예를 들어, 다른 입체이성질체가 실질적으로 없는(예를 들어, 85% ee 이상, 90% ee 이상, 95% ee 이상, 97% ee 이상, 또는 99% ee 이상))로 존재할 수 있다. 즉, 본 발명에 따른 화학식 1의 화합물 또는 그의 염이 호변이성적(tautomeric) 이성질체 및/또는 입체이성질체(예를 들어, 기하이성질체(geometrical isomer) 및 배좌 이성질체(conformational isomers))일 경우 그들의 분리된 이성질체 및 혼합물 각각 또한 본 발명의 화합물의 범주에 포함된다. 본 발명의 화합물 또는 그의 염이 구조 내에 비대칭 탄소(asymmetric carbon)를 가지고 있는 경우에, 그들의 광학 활성 화합물 및 라세믹 혼합물들 또한 본 발명의 화합물의 범위에 포함된다. As used herein, 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. In addition, 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. In one embodiment, 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))). That is, when 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. In case 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.
본 명세서에서 사용될 경우, 용어 "결정다형(polymorph)"은 본 발명의 화합물의 고체 결정 형태 또는 그것의 복합체를 의미한다. 같은 화합물의 다른 결정다형은 다른 물리적, 화학적 그리고/또는 스펙트럼적 특성을 보인다. 물리적 특성 측면의 차이점으로는 안정성(예를 들어, 열 또는 빛 안정성), 압축성과 밀도(제제화 및 생산물 제조에 중요함), 그리고 용해율(생물학적 이용률에 영향을 줄 수 있음)을 포함하나, 이에 한정되지 아니한다. 안정성에서 차이는 화학반응성 변화들(예를 들어, 또 다른 다형으로 구성되었을 때보다 하나의 다형으로 구성되었을 때 더 빠르게 변색이 되는 것 같은 차별적 산화) 또는 기계적인 특징들(예를 들어 동역학적으로 선호된 다형체로서 저장된 정제 파편들이 열역학 적으로 더 안정된 다형으로 변환) 또는 둘 다(하나의 다형의 정제는 높은 습도에서 더 분해에 예민)를 야기한다. 결정다형의 다른 물리적 성질들은 그들의 가공에 영향을 줄 수 있다. 예를 들어, 한 결정다형은 또 다른 결정다형에 비하여, 예를 들어, 그것의 형태 또는 입자의 크기 분포에 기인하여 용매화합물을 형성할 가능성이 많을 수 있거나, 여과 또는 세척이 더 어려울 수 있다.As used herein, the term "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.
본 명세서에서 사용된 용어 "용매 화합물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.As used herein, the term “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.
본 명세서에서 사용된 용어 "수화물(hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. As used herein, the term "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. .
본 명세서에서 사용된 용어 "클라드레이트(clathrate)"은 게스트 분자(예를 들어, 용매 또는 물)를 가두어 놓은 공간(예를 들어, 채널(channel))을 포함한 결정 격자의 형태의 본 발명의 화합물 또는 그것의 염을 의미한다. As used herein, the term "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.
본 명세서에서 사용된 용어 "정제된(purified)"은 분리될 때, 분리체는 90% 이상 순수한 것을 의미하며, 일 실시예에서는 95% 이상 순수하고, 다른 실시 예에서는 99% 이상 순수하고, 또 다른 실시예에서는 99.9% 이상 순수한 것을 의미한다.As used herein, 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.
본 발명 화합물의 의약 용도 및 치료 방법Medical Uses and Treatment Methods of the Compounds of the Invention
본 발명은 하나 이상의 상기와 같은 화합물의 치료적으로 유효한 양을 개체에게 투여함으로써 하기 질병 또는 상태(condition)를 갖거나 갖기 쉬운 개체에서 하기 질병 또는 상태(condition)를 치료하는 방법을 더 제공한다. 일 태양에서, 상기 치료는 예방 치료(preventative treatment)이다. 또 다른 태양에서, 상기 치료는 완화 치료(palliative treatment)이다. 또 다른 태양에서, 상기 치료는 회복 치료(restorative treatment)이다.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. In one aspect, the treatment is a preventative treatment. In another aspect, the treatment is a palliative treatment. In another aspect, the treatment is a restorative treatment.
1. 질병 또는 상태(Condition)1. Disease or Condition
본 발명의 ENL 단백질 분해용 화합물들은 다양한 치료학적 또는 예방학적 용도(예를 들어, 암)에 유용하다. 이러한 화합물들은 ENL 단백질을 분해하여 ENL 단백질 활성을 낮추기 위해 사용될 수 있으며, 또 ENL 단백질 관련 질환의 치료를 위해서 또는 이러한 질병의 악화를 방지하기 위하여 사용될 수 있다. 따라서 본 발명은 세포 내 ENL 단백질을 분해하는 방법을 제공한다. 이러한 방법에서 상기 세포는 본 발명의 화합물의 유효한 양과 접촉하게 된다. 일 실시예에서, 상기 세포는 개체 내에 존재한다. 본 발명의 방법은 치료 또는 예방이 필요한 개체에게 치료적으로 또는 예방학적으로 유효한 양의 본 발명에 따른 화합물을 포함하는 약학 조성물을 투여하는 것을 포함한다. 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.
일 태양에서, 본 발명은 ENL 단백질 관련 질환의 세포 내에서 ENL 단백질을 분해하는 방법을 제공한다. 예를 들어, 본 발명은 후술하는 ENL 단백질 관련 질환을 가진 개체의 세포 내에서 ENL 단백질을 분해하여 결과적으로 ENL 단백질 활성을 낮추기 위하여 이용될 수 있다. 본 발명의 다른 태양에서, 본 발명은 암, 특히 백혈병의 세포 내에서 ENL 단백질을 분해하기 위하여 이용될 수 있다. In one aspect, the present invention provides a method of degrading ENL protein in a cell in an ENL protein-associated disorder. For example, 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. In another aspect of the invention, the invention may be used to degrade ENL proteins within cells of cancer, particularly leukemia.
다른 태양에서, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 개체에게 투여하는 단계를 포함하는 ENL 단백질 관련 질환을 치료하는 방법을 제공한다. 이러한 방법은 ENL 단백질을 분해하기 위해 충분한 양, 즉, 치료학적으로 유효한 양의 본 발명 화합물을 치료가 필요한 개체에게 투여하는 단계를 포함한다. 이러한 방법에 있어, 본 발명의 화합물은 본 명세서에서 설명되는 약학 조성물의 형태로 상기 개체에 투여될 수 있다. In another aspect, 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. In this method, a compound of the present invention can be administered to the subject in the form of a pharmaceutical composition described herein.
본 발명에 있어, ENL 단백질 관련 질환은, 이에 한정되는 것은 아니지만, 암, 특히 백혈병 또는 신장암이다. 본 발명의 바람직한 일 태양에서, ENL 단백질 관련 질환은 급성 림프구성 백혈병, 급성 골수성 백혈병, 또는 Wilms tumour이다. In the present invention, the ENL protein-associated disease is, but is not limited to, cancer, particularly leukemia or renal cancer. In a preferred aspect of the invention, the ENL protein-associated disease is acute lymphocytic leukemia, acute myeloid leukemia, or Wilms tumour.
즉, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 상기 질병을 치료 또는 예방하기 위한 의약 용도를 제공한다. That is, 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.
2. 개체 (Subjects)2. Subjects
본 발명에 따라 치료될 적합한 개체는 포유동물 개체를 포함한다. 본 발명에 따른 포유동물은, 이에 한정되는 것은 아니지만, 인간, 개(canine), 고양잇과동물(feline), 소(bovine), 염소(caprine), 말(equine), 양(ovine), 돼지(porcine), 설치류(rodents), 토끼목(lagomorphs), 영장류(primates) 등을 포함하고, 자궁 내의(in utero) 포유동물을 포함한다. 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 ).
일 태양에서, 본 발명에 따른 치료될 적합한 개체는 인간이다.In one aspect, a suitable subject to be treated according to the present invention is a human.
3. 투여 및 투여량 (Administration and Dosing)3. Administration and Dosing
본 발명의 화합물은 일반적으로 치료적으로 유효한 양이 투여된다. A compound of the present invention is generally administered in a therapeutically effective amount.
본 명세서에서 사용된 "유효량"은 ENL 단백질 관련 질환, 특히 암 (바람직하게는 백혈병 또는 신장암)의 진행을 늦추거나 또는 최소화하거나, ENL 단백질 관련 질환, 특히 암 (바람직하게는 백혈병 또는 신장암)의 치료 또는 관리에서 치료상 이점을 제공하기에 충분한 본 발명의 화합물의 양을 말한다. "유효량"은 또한 생체외(in vitro) 또는 생체내(in vivo) 어떤 쪽이든 ENL 단백질 활성을 억제 또는 줄이기에 충분한 양을 말한다. "Effective amount" as used herein 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 .
본 발명의 화합물은 임의의 적합한 경로에 의하여 이러한 경로에 적당한 약학 조성물의 형태, 그리고 의도된 치료를 위하여 효과적인 투여량으로 투여될 수 있다. 효과적인 투여량은 단일 또는 분할 투여로 일반적으로 약 0.001 내지 약 100 mg/체중kg/일이고, 바람직하게는 약 0.01 내지 약 50 mg/kg/일이다. 나이, 종, 및 치료될 질병 또는 상태(condition)에 따라 이 범위의 하한 미만의 투여량 수준이 적합할 수 있다. 다른 경우에는, 여전히 더 큰 투여량이 해로운 부작용없이 사용될 수 있다. 더 큰 투여량은 하루 동안 투여를 위하여, 여러 작은 투여량으로 분할될 수 있다. 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.
본 발명 화합물의 약학 조성물Pharmaceutical composition of the compound of the present invention
다른 태양에서, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체 또는 첨가제를 포함하는 약학 조성물이 제공한다. 본 발명의 일 태양에 있어, 상기 약학 조성물의 용도는 후술하는 ENL 단백질 관련 질환, 바람직하게는 암, 더욱 바람직하게는 백혈병 또는 신장암의 치료 또는 예방 용도이다.In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive. In one aspect of the present invention, 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.
용어 "약학적으로 허용 가능한"은 약학적 제제로 사용하기에 적합한 것을 의미하며, 일반적으로 이러한 사용을 위하여 안전한 것으로 간주되며, 이러한 사용을 위하여 국가의 관리 기관에 의하여 공식적으로 승인되거나 한국 약전 또는 미국 약전의 명단에 있는 것을 의미한다. The term "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.
약학 조성물, 제형 및 투여 경로Pharmaceutical Compositions, Formulations and Routes of Administration
상기 설명된 질병 또는 상태(condition)의 치료를 위하여, 본 명세서에서 설명된 상기 화합물 또는 이의 약학적으로 허용 가능한 염은 다음과 같이 투여될 수 있다.For the treatment of a disease or condition described above, the compound described herein, or a pharmaceutically acceptable salt thereof, can be administered as follows.
구강 투여(Oral administration)Oral administration
본 발명의 화합물은 구강으로 투여될 수 있으며, 구강은 연하(swallowing)를 포함하는 개념이다. 구강 투여에 의하여 본 발명의 화합물이 위장관(gastrointestinal tract)에 들어가거나, 예를 들어, 구강(buccal) 또는 설하(sublingual) 투여와 같이, 입으로부터 혈류로 직접적으로 흡수될 수 있다. 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.
구강 투여를 위한 적합한 조성물은 고형상, 액상, 겔(gel), 또는 파우더 형상일 수 있으며, 정제(tablet), 로젠지(lozenge), 캡슐(capsule), 과립제, 산제 등의 제형을 가질 수 있다. 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. .
구강 투여를 위한 조성물은 선택적으로 장용 코팅(enteric coating)될 수 있으며, 장용 코팅을 통하여 지연된(delayed) 또는 지속된(sustained) 방출을 나타낼 수 있다. 즉, 본 발명에 따른 구강 투여를 위한 조성물은 즉시 또는 변형된(modified) 방출 패턴을 가진 제형일 수 있다. 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.
액체 제형은 용액, 시럽 및 현탁액을 포함할 수 있으며, 이러한 액상 조성물은 연질 또는 경질 캡슐 내에 함유된 형태일 수 있다. 이러한 제형은 약학적으로 허용 가능한 담체, 예를 들어, 물, 에탄올, 폴리에틸렌글리콜, 셀룰로오스, 또는 오일(oil)을 포함할 수 있다. 상기 제형은 또한 하나 이상의 유화제 및/또는 현탁제를 포함할 수 있다.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.
정제(tablet) 제형에서, 활성 성분인 약물의 양은 정제 총 중량 대비 약 0.05 중량% 내지 약 95 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 50 중량%로 존재할 수 있다. 또한, 정제는 약 0.5 중량% 내지 약 35 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 25 중량%를 포함하는 붕해제를 함유할 수 있다. 붕해제의 예로는 유당, 전분, 소디움스타치글리콜레이트, 크로스포비돈, 크로스카멜로스소디움(croscarmellose sodium), 말토덱스트린 또는 이들의 혼합물이 사용될 수 있으나 이에 한정되는 것은 아니다.In tablet formulations, 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. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.
정제로 제조하기 위해 포함되는 적합한 활택제는 약 0.1 중량% 내지 약 5 중량% 양으로 존재할 수 있고, 탈크(talc), 이산화규소, 스테아린산, 칼슘, 아연 또는 마그네슘 스테아레이트, 소듐 스테아릴 푸마레이트 등이 활택제로 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. 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.
정제로 제조하기 위한 결합제(binder)로는 젤라틴, 폴리에틸렌글리콜, 당(sugar), 검(gum), 녹말(starch), 폴리비닐피롤리돈, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등이 사용될 수 있으며, 정제로 제조하기 위한 적합한 희석제로는 만니톨, 자일리톨, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 녹말(starch), 미결정셀룰로오스 등이 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. 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. .
선택적으로 정제에 포함될 수 있는 가용화제는 정제 총 중량 대비 약 0.1 중량% 내지 약 3 중량% 양이 사용될 수 있고, 예를 들어, 폴리소르베이트, 소디움 라우릴설페이트, 소디움 도데실설페이트, 프로필렌 카보네이트, 디에틸렌글리콜모노에틸에테르, 디메틸이소소르비드, 폴리옥시에틸렌글리콜화된 천연 또는 수소화 피마자유, HCORTM(Nikkol), 올레일에스테르, 젤루시어(GelucireTM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HSTM 등이 본 발명에 따른 약학 조성물에 사용될 수 있으나, 본 발명은 이러한 가용화제의 구체적 종류에 한정되는 것은 아니다.Optionally, 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 ™ (Nikkol), oleyl ester, Gelucire ™ , 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.
비경구 투여(Parenteral Administration)Parenteral Administration
본 발명의 화합물은 혈류, 근육, 또는 내장 내로 직접 투여될 수 있다. 비경구 투여를 위한 적합한 방법은 정맥내(intravenous), 근육내(intra-muscular), 피하 동맥내(subcutaneous intraarterial), 복강내(intraperitoneal), 척추강내(intrathecal), 두개내(intracranial) 주사 등을 포함한다. 비경구 투여를 위한 적합한 장치는 (바늘 및 바늘 없는 주사기를 포함하는) 주사기(injector) 및 주입 방법(infusion method)을 포함한다.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. include Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.
비경구 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. 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.
대부분의 비경구 제형은 액상 조성물이며, 이러한 액상 조성물은 본 발명에 따른 약효 성분, 염, 완충제, 등장화제 등을 포함하는 수용액이다.Most 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.
비경구 제형은 또한 건조된 형태(예를 들어, 동결 건조) 또는 멸균 비-수용액으로서 제조될 수 있다. 이들 제형은 멸균수(sterile water)와 같은 적합한 비히클(vehicle)과 함께 사용될 수 있다. 용해도 증강제(solubility-enhancing agents) 또한 비경구 용액의 제조에 사용될 수 있다.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.
국소 투여(Topical Administration)Topical Administration
본 발명의 화합물은 피부 또는 경피로 국소적으로 투여될 수 있다. 이 국소 투여를 위한 제형은 로션, 용액, 크림, 젤, 하이드로젤, 연고, 폼(foam), 임플란트(implant), 패치 등을 포함한다. 국소 투여 제형을 위한 약학적으로 허용 가능한 담체는 물, 알코올, 미네랄 오일, 글리세린, 폴리에틸렌글리콜 등을 포함할 수 있다. 국소 투여는 또한 전기천공법(electroporation), 이온도입법(iontophoresis), 음파영동(phonophoresis) 등에 의하여 수행될 수 있다.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.
국소 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. 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.
본 개시는 ENL 단백질을 분해하여 다양한 약리 활성을 나타낼 수 있는 화합물, 이들을 유효 성분으로 포함하는 약학 조성물, 이들의 의약 용도(특히, 암, 바람직하게는 백혈병 또는 신장암) 및 이들을 치료 또는 예방이 필요한 개체에게 투여하는 것을 포함하는 치료 방법을 제공한다. 본 발명에 따른 화합물 또는 이들의 약학적으로 허용 가능한 염은 활성, (대사)안정성, 물리화학적 성질 등이 다양한 측면에서 우수하다.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.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to aid understanding of the present invention. However, the embodiments according to the present invention can be modified in many different forms, and the scope of the present invention should not be construed as being limited to the following examples. Embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.
본 발명 화합물들의 제조Preparation of compounds of the present invention
이하, 본 발명 일부 화합물들의 합성 과정을 기재하며, 하기 언급되지 않은 화합물들의 경우 출발 물질, 중간체 및/또는 반응 물질을 대체하여 유사한 방법으로 제조될 수 있다.Hereinafter, synthetic processes of some compounds of the present invention will be described, and compounds not mentioned below may be prepared by similar methods by substituting starting materials, intermediates, and/or reactants.
중간체 1-1: (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amineIntermediate 1-1: (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine
Figure PCTKR2022013646-appb-img-000023
Figure PCTKR2022013646-appb-img-000023
단계 1: 2-(chloromethyl)-5-nitro-1H-benzo[d]imidazole의 합성Step 1: Synthesis of 2-(chloromethyl)-5-nitro-1H-benzo[d]imidazole
4-nitrobenzene-1,2-diamine (5g, 32.6mmol)를 MeCN (22ml)에 현탁 시킨 후 2-chloro-1,1-triethoxyethane (6.8ml, 35.8mmol)를 천천히 가하고 80℃에서 6시간 동안 교반 하였다. 반응물을 감압 농축하여 얻은 잔사를 MPLC (2% MeOH/DCM)하여 암적색 고체 3.5g (51%)을 수득하였다. After 4-nitrobenzene-1,2-diamine (5g, 32.6mmol) was suspended in MeCN (22ml), 2-chloro-1,1-triethoxyethane (6.8ml, 35.8mmol) was slowly added and stirred at 80℃ for 6 hours. did The residue obtained by concentrating the reaction product under reduced pressure was subjected to MPLC (2% MeOH/DCM) to obtain 3.5 g (51%) of a dark red solid.
단계 2: (S)-2-((2-methylpyrrolidin-1-yl)methyl)-5-nitro-1H-benzo[d]imidazole의 합성Step 2: Synthesis of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-5-nitro-1H-benzo[d]imidazole
2-(chloromethyl)-5-nitro-1H-benzo[d]imidazole (2.5g, 11.8mmol), 및 Na2CO3 (3.1g, 29.6mmol)를 MeCN (35ml)에 현탁 시킨 후 (S)-2-methylpyrrolidine HCl (1.7g, 14.2mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 반응물을 Celite를 통해 여과한 후 여과액을 농축하였다. 얻어진 잔사를 MPLC (2% MeOH/DCM)하여 황색 고체 1.8g (58%)을 수득하였다. After suspending 2-(chloromethyl)-5-nitro-1H-benzo[d]imidazole (2.5g, 11.8mmol) and Na 2 CO 3 (3.1g, 29.6mmol) in MeCN (35ml), (S)- After adding 2-methylpyrrolidine HCl (1.7g, 14.2mmol), the mixture was stirred at room temperature for 16 hours. After the reaction was filtered through Celite, the filtrate was concentrated. The resulting residue was subjected to MPLC (2% MeOH/DCM) to give 1.8 g (58%) of a yellow solid.
단계 3: (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine의 합성Step 3: Synthesis of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-5-nitro-1H-benzo[d]imidazole (1.5g, 5.7mmol)을 MeOH (35ml)에 녹인 후 palladium (10 wt. % on activated carbon, 150mg)을 가하고 수소 기류 하 상온에서 15시간 동안 교반 하였다. 반응물을 Celite를 통해 여과한 후 여과액을 감압 농축하였다. 얻은 잔사를 고체화 (DCM/Et2O)하여 갈색 고체 1g (77%)을 수득하였다. After dissolving (S)-2-((2-methylpyrrolidin-1-yl)methyl)-5-nitro-1H-benzo[d]imidazole (1.5g, 5.7mmol) in MeOH (35ml), palladium (10 wt. % on activated carbon, 150 mg) was added and stirred for 15 hours at room temperature under a hydrogen stream. After filtering the reaction product through Celite, the filtrate was concentrated under reduced pressure. The obtained residue was solidified (DCM/Et 2 O) to give 1 g (77%) of a brown solid.
중간체 1-2 내지 중간체 1-5Intermediate 1-2 to Intermediate 1-5
중간체 1-1의 합성법과 유사한 방법으로 중간체 1-2 내지 중간체 1-5를 합성하였다.Intermediates 1-2 to 1-5 were synthesized in a similar manner to the synthesis method of Intermediate 1-1.
Figure PCTKR2022013646-appb-img-000024
Figure PCTKR2022013646-appb-img-000024
중간체 1-6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochlorideIntermediate 1-6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride
Figure PCTKR2022013646-appb-img-000025
Figure PCTKR2022013646-appb-img-000025
단계 1: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidine-1-carboxylate의 합성Step 1: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidine- Synthesis of 1-carboxylate
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (597mg, 1.95mmol), EDCI (749mg, 3.91mmol), 및 HOBt (317mg, 2.34mol)를 DMF (20ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 450mg, 1.95mmol), 및 DIPEA (1ml, 5.86mmol)를 가한 후 상온에서 19시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 연한 갈색 고체 799mg (79%)을 수득 하였다.After suspending 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzoic acid (597mg, 1.95mmol), EDCI (749mg, 3.91mmol), and HOBt (317mg, 2.34mol) in DMF (20ml) It was stirred for 10 minutes at room temperature. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 450 mg, 1.95 mmol), and DIPEA (1 ml, 5.86 mmol) was added, and the mixture was stirred at room temperature for 19 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 799 mg (79%) of a pale brown solid.
단계 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride의 합성Step 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride synthesis
tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidine-1-carboxylate (799mg, 1.54mmol)를 DCM (15ml)에 현탁 시킨 후 4M HCl in dioxane (3.9ml, 15.4mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 900mg (quant.)를 수득하였다.tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidine-1-carboxylate (799mg, 1.54mmol) was suspended in DCM (15ml), 4M HCl in dioxane (3.9ml, 15.4mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 900 mg (quant.) of a white solid.
중간체 1-7 내지 중간체 1-10Intermediate 1-7 to Intermediate 1-10
중간체 1-6의 합성법과 유사한 방법으로 중간체 1-7 내지 중간체 1-10을 합성하였다.Intermediates 1-7 to 1-10 were synthesized in a similar manner to the synthesis method of Intermediate 1-6.
Figure PCTKR2022013646-appb-img-000026
Figure PCTKR2022013646-appb-img-000026
중간체 2-1: tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylateIntermediate 2-1: tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate
Figure PCTKR2022013646-appb-img-000027
Figure PCTKR2022013646-appb-img-000027
단계 1: (1-(chloromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate의 합성Step 1: Synthesis of (1-(chloromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate
cyclopropane-1,1-diyldimethanol (1g, 9.8mmol), 및 p-Toluenesulfonyl chloride (4.9g, 14.7mmol)를 DCM (33ml)에 현탁 시켰다. 이후 0 ℃에서 DMAP (60mg, 0.49mmol), 및 TEA (2.7ml, 19mmol)를 천천히 첨가하고 상온에서 24시간 동안 교반 하였다. 반응액에 증류수 (30ml)를 가한 후 DCM (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (7% EtOAc/Hexane)하여 투명한 오일 686mg (26%)를 수득하였다.Cyclopropane-1,1-diyldimethanol (1g, 9.8mmol) and p-Toluenesulfonyl chloride (4.9g, 14.7mmol) were suspended in DCM (33ml). Afterwards, DMAP (60mg, 0.49mmol) and TEA (2.7ml, 19mmol) were slowly added at 0 °C and stirred at room temperature for 24 hours. After adding distilled water (30ml) to the reaction solution, extraction was performed with DCM (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (7% EtOAc/Hexane) to give 686 mg (26%) of a clear oil.
단계 2: tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate의 합성Step 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), 및 K2CO3 (683mg, 4.94mmol)를 Acetonitrile (8.3ml)에 현탁 시킨 후 60℃에서 19시간 동안 교반 하였다. 반응액에 증류수 (30ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조하였다. 이후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (7% EtOAc/Hexane)하여 투명한 오일 529mg (74%)를 수득 하였다. 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.
중간체 2-2: tert-butyl 4-((1-(azidomethyl)cyclopropyl)methyl)piperazine-1-carboxylateIntermediate 2-2: tert-butyl 4-((1-(azidomethyl)cyclopropyl)methyl)piperazine-1-carboxylate
Figure PCTKR2022013646-appb-img-000028
Figure PCTKR2022013646-appb-img-000028
tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate (중간체 2-1, 164mg, 0.57 mmol)를 DMF (5.7ml)에 녹인 후 sodium azide (48mg, 0.74mmol)를 가하고 90℃에서 20시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 3), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 투명한 액체 110 mg (65%)을 수득하였다.After dissolving tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate (intermediate 2-1, 164mg, 0.57mmol) in DMF (5.7ml), sodium azide (48mg, 0.74mmol) was added. It was added and stirred at 90°C for 20 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 3) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to give 110 mg (65%) of a clear liquid.
중간체 2-3: tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylateIntermediate 2-3: tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate
Figure PCTKR2022013646-appb-img-000029
Figure PCTKR2022013646-appb-img-000029
단계 1: 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol의 합성Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol
2,2-difluoropropane-1,3-diol (575mg, 5.13mmol)을 THF (11ml)에 녹인 후 sodium hydride (60% dispersion in mineral oil, 205mg, 5.13mmol)를 0℃에서 천천히 가하고 30분 동안 교반하였다. 반응액에 THF (15ml), 및 TBDPSCl (1.33ml, 5.13mmol)을 가하고 3시간 동안 교반하였다. 반응액에 EtOAc (70ml)를 가한 뒤 물 (30ml x 2), 및 brine (30ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (3% EtOAc/Hexane)하여 투명한 액체 1.13g (63%)을 수득하였다.After dissolving 2,2-difluoropropane-1,3-diol (575mg, 5.13mmol) in THF (11ml), sodium hydride (60% dispersion in mineral oil, 205mg, 5.13mmol) was slowly added at 0℃ and stirred for 30 minutes. did THF (15ml) and TBDPSCl (1.33ml, 5.13mmol) were added to the reaction mixture and stirred for 3 hours. After adding EtOAc (70ml) to the reaction mixture, the mixture was washed with water (30ml x 2) and brine (30ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (3% EtOAc/Hexane) to give 1.13 g (63%) of a clear liquid.
단계 2: 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate의 합성Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate
3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol (1.13g, 3.24mmol), 및 2,6-lutidine (1.1ml, 9.71mmol)을 DCM (22ml)에 녹인 후 trifluoromethanesulfonic anhydride (1.1ml, 6.48mmol)를 0℃에서 천천히 가하고 4시간 동안 교반하였다. 반응액에 DCM (70ml)을 가한 뒤 1N HCl 수용액 (20ml x 1), NaHCO3 포화수용액 (30ml x 1), 및 brine (30ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (2% EtOAc/Hexane)하여 투명한 액체 1.46g (94%)을 수득하였다.After dissolving 3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropan-1-ol (1.13g, 3.24mmol) and 2,6-lutidine (1.1ml, 9.71mmol) in DCM (22ml), trifluoromethanesulfonic Anhydride (1.1ml, 6.48mmol) was slowly added at 0°C and stirred for 4 hours. After adding DCM (70ml) to the reaction mixture, the mixture was washed with 1N HCl aqueous solution (20ml x 1), NaHCO 3 saturated aqueous solution (30ml x 1), and brine (30ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (2% EtOAc/Hexane) to give 1.46 g (94%) of a clear liquid.
단계 3: tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)piperazine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)piperazine-1-carboxylate
3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate (593mg, 1.23mmol), 및 tert-butyl piperazine-1-carboxylate (2.52mg, 1.35mmol)를 1,4-dioxane (12ml)에 녹인 후 DIPEA (0.64ml, 3.69mmol)를 가하고 80℃에서 17시간 동안 교반하였다. 반응액에 EtOAc (50ml)을 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (6% EtOAc/Hexane)하여 노란색 액체 591mg (93%)을 수득하였다.3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl trifluoromethanesulfonate (593mg, 1.23mmol), and tert-butyl piperazine-1-carboxylate (2.52mg, 1.35mmol) were dissolved in 1,4-dioxane (12ml). After dissolving, DIPEA (0.64ml, 3.69mmol) was added and the mixture was stirred at 80°C for 17 hours. After adding EtOAc (50ml) to the reaction solution, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (6% EtOAc/Hexane) to give 591 mg (93%) of a yellow liquid.
단계 4: tert-butyl 4-(2,2-difluoro-3-hydroxypropyl)piperazine-1-carboxylate의 합성Step 4: Synthesis of tert-butyl 4-(2,2-difluoro-3-hydroxypropyl)piperazine-1-carboxylate
tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)piperazine-1-carboxylate (337mg, 0.65mmol)를 THF (6.5ml)에 녹인 후 TBAF (1.0M in THF, 0.65ml, 0.65mmol)를 가하고 상온에서 30분 동안 교반하였다. 반응액에 EtOAc (50ml)을 가한 뒤 물 (20ml x 2), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (25% EtOAc/Hexane)하여 하얀색 고체 162mg (89%)을 수득하였다.After dissolving tert-butyl 4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)piperazine-1-carboxylate (337mg, 0.65mmol) in THF (6.5ml), TBAF (1.0M in THF, 0.65ml, 0.65mmol) was added and stirred at room temperature for 30 minutes. After adding EtOAc (50ml) to the reaction mixture, the mixture was washed with water (20ml x 2) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (25% EtOAc/Hexane) to give 162mg (89%) of a white solid.
단계 5: tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate의 합성Step 5: Synthesis of tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate
tert-butyl 4-(2,2-difluoro-3-hydroxypropyl)piperazine-1-carboxylate (125mg, 0.45mmol), 및 p-toluenesulfonyl chloride (102mg, 0.54mmol)를 DCM (4.5ml)에 녹인 후 TEA (0.31ml, 2.23mmol)를 가하고 상온에서 14시간 동안 교반 하였다. 반응액에 DCM (40ml)을 가한 뒤 물 (20ml x 2), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (15% EtOAc/Hexane)하여 하얀색 고체 172mg (89%)을 수득하였다.After dissolving tert-butyl 4-(2,2-difluoro-3-hydroxypropyl)piperazine-1-carboxylate (125mg, 0.45mmol) and p-toluenesulfonyl chloride (102mg, 0.54mmol) in DCM (4.5ml), TEA ( 0.31ml, 2.23mmol) was added and stirred at room temperature for 14 hours. After adding DCM (40ml) to the reaction solution, it was washed with water (20ml x 2) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (15% EtOAc/Hexane) to obtain 172mg (89%) of a white solid.
중간체 2-4: tert-butyl 4-(3-azido-2,2-difluoropropyl)piperazine-1-carboxylateIntermediate 2-4: tert-butyl 4-(3-azido-2,2-difluoropropyl)piperazine-1-carboxylate
Figure PCTKR2022013646-appb-img-000030
Figure PCTKR2022013646-appb-img-000030
tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (중간체 2-3, 97mg, 0.22mmol)를 DMF (2.2ml)에 녹인 후 sodium azide (17mg, 0.27mmol)를 가하고 90℃에서 14시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% EtOAc/Hexane)하여 노란색 액체 51mg (75%)을 수득하였다.After dissolving tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (intermediate 2-3, 97mg, 0.22mmol) in DMF (2.2ml), sodium azide (17mg, 0.27mg) mmol) was added and stirred at 90 °C for 14 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% EtOAc/Hexane) to give 51 mg (75%) of a yellow liquid.
중간체 2-5: tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylateIntermediate 2-5: tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate
Figure PCTKR2022013646-appb-img-000031
Figure PCTKR2022013646-appb-img-000031
단계 1: tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate
tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1g, 4.36mmol)를 DCM (30ml)에 현탁 시킨 후 DMP (2.8g, 6.54mmol)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액에 Na2S2O3 수용액 (20ml)를 가한 뒤 DCM (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 투명한 오일 743mg (75%)를 수득 하였다. After tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1g, 4.36mmol) was suspended in DCM (30ml), DMP (2.8g, 6.54mmol) was added and stirred at room temperature for 1 hour. After adding Na 2 S 2 O 3 aqueous solution (20ml) to the reaction solution, extraction was performed with DCM (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 743 mg (75%) of a clear oil.
단계 2: benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate의 합성Step 2: Synthesis of benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate
tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (740mg, 3.26mmol), benzyl piperazine-1-carboxylate (640mg, 2.94mmol)를 MeOH (32.6ml)에 현탁 시킨 후 sodium triacetoxyborohydride (1.38g, 6.52mmol)를 가하고 상온에서 12시간 동안 교반 하였다. 반응액에 NaHCO3 수용액 (10ml)를 가한 뒤 DCM (20ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (3% MeOH/DCM)하여 투명한 오일 1.2g (86%)를 수득하였다. After suspending tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (740mg, 3.26mmol) and benzyl piperazine-1-carboxylate (640mg, 2.94mmol) in MeOH (32.6ml), sodium triacetoxyborohydride (1.38g, 6.52 mmol) was added and stirred at room temperature for 12 hours. After adding NaHCO 3 aqueous solution (10ml) to the reaction solution, extraction was performed with DCM (20ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (3% MeOH/DCM) to give 1.2 g (86%) of a clear oil.
단계 3: tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate
benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate (1.2g, 2.78mmol)을 MeOH (24ml)에 녹인 후 palladium (10 wt. % on activated carbon, 590mg)을 가하고 수소 기류 하 상온에서 14시간 동안 교반 하였다. 반응물을 Celite를 통해 여과한 후 여과액을 감압 농축하여 흰색 고체 823mg (99%)을 수득하였다. After dissolving benzyl 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazine-1-carboxylate (1.2g, 2.78mmol) in MeOH (24ml), palladium (10 wt.% on activated carbon, 590mg) was added and stirred for 14 hours at room temperature under a hydrogen stream. After filtering the reaction product through Celite, the filtrate was concentrated under reduced pressure to obtain 823 mg (99%) of a white solid.
중간체 2-6 내지 중간체 2-8Intermediate 2-6 to Intermediate 2-8
중간체 2-5의 합성법과 유사한 방법으로 중간체 2-6 내지 중간체 2-8을 합성하였다.Intermediates 2-6 to 2-8 were synthesized in a similar manner to the synthesis method of Intermediate 2-5.
Figure PCTKR2022013646-appb-img-000032
Figure PCTKR2022013646-appb-img-000032
중간체 3-1: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneIntermediate 3-1: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure PCTKR2022013646-appb-img-000033
Figure PCTKR2022013646-appb-img-000033
단계 1: tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamate의 합성Step 1: Synthesis of tert-butyl (5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamate
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 138mg, 0.49mmol), 및 tert-butyl (5-aminopentyl)carbamate (100mg, 0.49mmol), DIPEA (0.17ml, 0.98mmol)를 DMSO (2ml)에 현탁 시킨 후 100℃에서 1시간 동안 교반 하였다. 반응액에 증류수 (30ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 노란색 고체 110 mg (51%)을 수득하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 138mg, 0.49mmol), and tert-butyl (5-aminopentyl)carbamate (100mg, 0.49mmol) , DIPEA (0.17ml, 0.98mmol) was suspended in DMSO (2ml) and then stirred at 100°C for 1 hour. 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, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 110 mg (51%) of a yellow solid.
단계 2: 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione의 합성Step 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)를 DCM (2ml)에 현탁 시킨 후 TFA (0.3ml)를 가하고 상온에서 30분 동안 교반 하였다. 반응액을 농축하여 노란색 고체 80mg (94%)를 수득하였다.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.
중간체 3-2 내지 중간체 3-16Intermediate 3-2 to Intermediate 3-16
중간체 3-1의 합성법과 유사한 방법으로 중간체 3-2 내지 중간체 3-16을 합성하였다.Intermediates 3-2 to 3-16 were synthesized in a similar manner to the synthesis method of Intermediate 3-1.
Figure PCTKR2022013646-appb-img-000034
Figure PCTKR2022013646-appb-img-000034
Figure PCTKR2022013646-appb-img-000035
Figure PCTKR2022013646-appb-img-000035
중간체 3-17: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamideIntermediate 3-17: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl) acetamide
Figure PCTKR2022013646-appb-img-000036
Figure PCTKR2022013646-appb-img-000036
단계 1: tert-butyl 4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)propyl)piperidine-1-carboxylate의 합성Step 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
2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231, 120mg, 0.36mmol), tert-butyl 4-(3-aminopropyl) piperidine-1-carboxylate (96mg, 0.4mmol), EDCI (138mg, 0.72mmol), HOBt (111mg, 0.72mmol), 및 DIPEA (0.19ml, 1.1mmol)를 DMF (1.5ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (15ml)를 가한 뒤 EtOAc (2.0ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 흰색 고체 120mg (60%)을 수득하였다.2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231, 120mg, 0.36mmol), tert-butyl 4-(3 -aminopropyl) piperidine-1-carboxylate (96mg, 0.4mmol), EDCI (138mg, 0.72mmol), HOBt (111mg, 0.72mmol), and DIPEA (0.19ml, 1.1mmol) were suspended in DMF (1.5ml). It was stirred for 16 hours at room temperature. After adding distilled water (15ml) to the reaction solution, extraction was performed with EtOAc (2.0ml x 2), and 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 obtain 120 mg (60%) of a white solid.
단계 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamide의 합성Step 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamide synthesis
tert-butyl 4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)propyl)piperidine-1-carboxylate (110mg, 0.16mmol)를 DCM (2ml)에 현탁 시킨 후 TFA (0.5ml)를 가하고 상온에서 30분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 90mg (86%)를 수득하였다.tert-butyl 4-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)propyl)piperidine-1-carboxylate (110mg , 0.16 mmol) was suspended in DCM (2ml), and then TFA (0.5ml) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain 90 mg (86%) of a white solid.
중간체 3-18 내지 중간체 3-20Intermediate 3-18 to Intermediate 3-20
중간체 3-17의 합성법과 유사한 방법으로 중간체 3-18 내지 중간체 3-20을 합성하였다.Intermediates 3-18 to 3-20 were synthesized in a similar manner to the synthesis method of Intermediate 3-17.
Figure PCTKR2022013646-appb-img-000037
Figure PCTKR2022013646-appb-img-000037
중간체 3-21: 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochlorideIntermediate 3-21: 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride
Figure PCTKR2022013646-appb-img-000038
Figure PCTKR2022013646-appb-img-000038
단계 1: 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate의 합성Step 1: Synthesis of 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate
tert-butyl (4-hydroxybutyl)carbamate (1g, 5.28mmol), 및 p-toluenesulfonyl chloride (1.2g, 6.34mmol)를 DCM (20ml)에 현탁 시킨 후 0℃에서 DMAP (128mg, 1.05mmol), 및 TEA (1.47ml, 10.57mmol)를 천천히 첨가하였다. 그 후 상온에서 2시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 DCM (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (15% EtOAc/Hexane)하여 투명한 오일 1.76g (97%)를 수득하였다. After tert-butyl (4-hydroxybutyl)carbamate (1g, 5.28mmol) and p-toluenesulfonyl chloride (1.2g, 6.34mmol) were suspended in DCM (20ml), DMAP (128mg, 1.05mmol) and TEA at 0°C. (1.47ml, 10.57mmol) was added slowly. After that, the mixture was stirred at room temperature for 2 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with DCM (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (15% EtOAc/Hexane) to give 1.76 g (97%) of a clear oil.
단계 2: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)carbamate의 합성Step 2: Synthesis of tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)carbamate
2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (WO2019/170150, 423mg, 1.54mmol), 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate (530mg, 1.54mmol), 및 K2CO3 (319mg, 2.31mmol)를 DMF (3.85ml)에 현탁 시킨 후 70℃에서 4시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 흰색 고체 150mg (22%)를 수득하였다. 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (WO2019/170150, 423mg, 1.54mmol), 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzenesulfonate (530mg , 1.54 mmol), and K 2 CO 3 (319 mg, 2.31mmol) was suspended in DMF (3.85ml) and stirred at 70°C for 4 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 150 mg (22%) of a white solid.
단계 3: 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride의 합성Step 3: Synthesis of 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride
tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)carbamate (150mg, 0.34mmol)를 DCM (3.4ml)에 현탁 시킨 후 4M HCl in dioxane (0.5ml)를 가하고 상온에서 4시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 108mg (84%)를 수득하였다.tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)carbamate (150 mg, 0.34 mmol) in DCM (3.4 ml) After suspension, 4M HCl in dioxane (0.5ml) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain 108 mg (84%) of a white solid.
중간체 3-22 내지 중간체 3-24Intermediate 3-22 to Intermediate 3-24
중간체 3-21의 합성법과 유사한 방법으로 중간체 3-22 내지 중간체 3-24를 합성하였다.Intermediates 3-22 to 3-24 were synthesized in a similar manner to the synthesis method of Intermediate 3-21.
Figure PCTKR2022013646-appb-img-000039
Figure PCTKR2022013646-appb-img-000039
중간체 3-25: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehydeIntermediate 3-25: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde
Figure PCTKR2022013646-appb-img-000040
Figure PCTKR2022013646-appb-img-000040
단계 1: 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione의 합성Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 1g, 3.6mmol), piperidin-4-ylmethanol (414mg, 3.6mmol), 및 DIPEA (1.3ml, 7.2mmol)를 DMSO (12ml)에 현탁 시킨 후 microwave 120℃에서 1시간 30분 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 3)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (2% MeOH/DCM)하여 노란색 고체 1.05g (78%)를 수득하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 1 g, 3.6 mmol), piperidin-4-ylmethanol (414 mg, 3.6 mmol), and DIPEA (1.3 ml, 7.2mmol) was suspended in DMSO (12ml) and stirred at 120℃ in a microwave for 1 hour and 30 minutes. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml x 3), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (2% MeOH/DCM) to give 1.05 g (78%) of a yellow solid.
단계 2: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde의 합성Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde
2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (500mg, 1.35mmol)를 DCM (13.5ml)에 현탁 시킨 후 DMP (687mg, 1.62mmol)를 가하고 상온에서 30분 동안 교반 하였다. 반응액에 Na2S2O3 수용액 (20ml)를 가한 뒤 DCM (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (3% MeOH/DCM)하여 노란색 고체 238mg (48%)를 수득하였다.2-(2,6-dioxopiperidin-3-yl)-4-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (500mg, 1.35mmol) suspended in DCM (13.5ml) After adding DMP (687mg, 1.62mmol), the mixture was stirred at room temperature for 30 minutes. After adding Na 2 S 2 O 3 aqueous solution (20ml) to the reaction solution, extraction was performed with DCM (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (3% MeOH/DCM) to give 238 mg (48%) of a yellow solid.
중간체 3-26 내지 중간체 3-30Intermediate 3-26 to Intermediate 3-30
중간체 3-25의 합성법과 유사한 방법으로 중간체 3-26 내지 중간체 3-30을 합성하였다.Intermediates 3-26 to 3-30 were synthesized in a similar manner to the synthesis method of Intermediate 3-25.
Figure PCTKR2022013646-appb-img-000041
Figure PCTKR2022013646-appb-img-000041
Figure PCTKR2022013646-appb-img-000042
Figure PCTKR2022013646-appb-img-000042
중간체 3-31: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acidIntermediate 3-31: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid
Figure PCTKR2022013646-appb-img-000043
Figure PCTKR2022013646-appb-img-000043
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 800mg, 2.89mmol), 3-(piperidin-4-yl)propanoic acid (681mg, 4.34mmol), 및 DIPEA (1.5ml, 8.67mmol)를 DMSO (9.7ml)에 현탁 시킨 후 100℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 3)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 고체화 (DCM)하여 노란색 고체 1.29g (quant.)를 수득하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 800mg, 2.89mmol), 3-(piperidin-4-yl)propanoic acid (681mg, 4.34mmol) ), and DIPEA (1.5ml, 8.67mmol) were suspended in DMSO (9.7ml) and then stirred at 100°C for 16 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml x 3), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was solidified (DCM) to obtain 1.29 g (quant.) of a yellow solid.
중간체 3-32 내지 중간체 3-34Intermediate 3-32 to Intermediate 3-34
중간체 3-31의 합성법과 유사한 방법으로 중간체 3-32 내지 중간체 3-34를 합성하였다.Intermediates 3-32 to 3-34 were synthesized in a similar manner to the synthesis method of Intermediate 3-31.
Figure PCTKR2022013646-appb-img-000044
Figure PCTKR2022013646-appb-img-000044
중간체 3-35: 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneIntermediate 3-35: 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
Figure PCTKR2022013646-appb-img-000045
Figure PCTKR2022013646-appb-img-000045
단계 1: 1,10-diazidodecane의 합성Step 1: Synthesis of 1,10-diazidodecane
1,10-dibromodecane (2g, 6.7mmol), 및 NaN3 (1.7g, 26.8mmol)을 DMF (15ml)에 현탁 시킨 후 80℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 3)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 노란색 액체 1.3g (87%)를 수득하였다.After suspending 1,10-dibromodecane (2g, 6.7mmol) and NaN 3 (1.7g, 26.8mmol) in DMF (15ml), the mixture was stirred at 80℃ for 16 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (30ml x 3), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 1.3g (87%) of a yellow liquid.
단계 2: 10-azidodecan-1-amine의 합성Step 2: Synthesis of 10-azidodecan-1-amine
1,10-diazidodecane (1.3g, 5.8mol)를 Et2O/THF/1M HCl (5:1:4, 20 ml)에 현탁 시킨 후 Et2O (10ml)에 현탁 시킨 triphenylphosphine (1.4 g, 5.32 mmol)를 첨가하였다. 상온에서 16시간 동안 교반 한 후 반응액을 감압 농축하여 노란색 고체 870mg (76%)를 수득하였다. 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.
단계 3: 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione의 합성Step 3: Synthesis of 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 100mg, 0.5mmol), 10-azidodecan-1-amine (139mg, 0.7mmol), 및 DIPEA (0.17ml, 1mmol)를 DMSO (2ml)에 현탁 시킨 후 100℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 3)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 노란색 고체 71mg (22%)를 수득하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 100 mg, 0.5 mmol), 10-azidodecan-1-amine (139 mg, 0.7 mmol), and DIPEA (0.17ml, 1mmol) was suspended in DMSO (2ml) and stirred at 100℃ for 16 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml x 3), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 71 mg (22%) of a yellow solid.
중간체 3-36 내지 중간체 3-40Intermediate 3-36 to Intermediate 3-40
중간체 3-35의 합성법과 유사한 방법 또는 중간체 3-17 및 중간체 3-35의 합성법을 이용한 방법으로 중간체 3-36 내지 중간체 3-40을 합성하였다.Intermediates 3-36 to 3-40 were synthesized by a method similar to the synthesis method of Intermediate 3-35 or a method using the synthesis method of Intermediates 3-17 and 3-35.
Figure PCTKR2022013646-appb-img-000046
Figure PCTKR2022013646-appb-img-000046
실시예 1: N1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N3-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamideExample 1 N 1 -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N 3 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide
Figure PCTKR2022013646-appb-img-000047
Figure PCTKR2022013646-appb-img-000047
단계 1: methyl (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate의 합성 Step 1: Synthesis of methyl (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 150mg, 0.65mmol), 3-(methoxycarbonyl)benzoic acid (140mg, 0.78mmol), HATU (296mg, 0.78mmol), 및 DIPEA (0.22ml, 1.3mmol)를 DCM (7ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (15ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 170mg (67%)을 수득하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 150mg, 0.65mmol), 3-(methoxycarbonyl)benzoic acid ( 140mg, 0.78mmol), HATU (296mg, 0.78mmol), and DIPEA (0.22ml, 1.3mmol) were suspended in DCM (7ml) and stirred at room temperature for 16 hours. After adding distilled water (15ml) to the reaction solution, extraction was performed with EtOAc (20ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 170 mg (67%) of a white solid.
단계 2: (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid의 합성Step 2: Synthesis of (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid
methyl (S)-3-((2-((2-methylpyrrolidin-1-yl) methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate (130mg, 0.33mmol)를 THF : H2O = 3 : 1 (4ml)에 현탁 시킨 후 LiOH monohydrate (28mg, 0.66mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 용매를 증발시키고 증류수를 가한 후 1N HCl을 첨가하고 EtOAc (30ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 133mg (96%)을 수득하였다.methyl (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate (130mg, 0.33mmol) was added to THF:H 2 After suspension in O = 3: 1 (4ml), LiOH monohydrate (28mg, 0.66mmol) was added and stirred at room temperature for 16 hours. After evaporating the solvent and adding distilled water, 1N HCl was added and extracted with EtOAc (30ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 133 mg (96%) of a white solid.
단계 3: N1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N3-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide의 합성Step 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
(S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid (48mg, 0.13mmol), 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7, 53mg, 0.14mmol), HATU (98mg, 0.26mmol), 및 DIPEA (0.07ml, 0.39mmol)를 DMF (1ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (1.5ml)를 가한 뒤 EtOAc (2.0ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 9 mg (9%)을 수득하였다.(S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid (48mg, 0.13mmol), 4-(( 6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-7, 53 mg, 0.14 mmol), HATU (98 mg, 0.26 mmol), and DIPEA ( 0.07ml, 0.39mmol) was suspended in DMF (1ml) and stirred at room temperature for 16 hours. After adding distilled water (1.5ml) to the reaction mixture, extraction was performed with EtOAc (2.0ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 9 mg (9%) of a white solid.
실시예 2: N1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-N3-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamideExample 2 N 1 -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-N 3 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide
Figure PCTKR2022013646-appb-img-000048
Figure PCTKR2022013646-appb-img-000048
4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7) 대신 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-8)을 사용하여 실시예 1의 합성법과 동일한 방법으로 실시예 2를 합성하였다. 5-((6-aminohexyl)amino)-2 instead of 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-7) 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).
실시예 3: N1-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl)-N3-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamideExample 3 N 1 -(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)ethyl) -N 3 -(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide
Figure PCTKR2022013646-appb-img-000049
Figure PCTKR2022013646-appb-img-000049
4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7) 대신 5-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-3)을 사용하여 실시예 1의 합성법과 동일한 방법으로 실시예 3을 합성하였다.5-((2-(2-(2- Example 3 in the same manner as in Example 1 using aminoethoxy) ethoxy) ethyl) amino) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Intermediate 3-3) was synthesized.
실시예 4: N1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-N3-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamideExample 4 N 1 -(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethyl)-N 3 -( 2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)isophthalamide
Figure PCTKR2022013646-appb-img-000050
Figure PCTKR2022013646-appb-img-000050
4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7) 대신 5-((2-(2-aminoethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-4)을 사용하여 실시예 1의 합성법과 동일한 방법으로 실시예 4를 합성하였다. 5-((2-(2-aminoethoxy)ethyl instead of 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-7) 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).
실시예 5: N1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 5 N 1 -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000051
Figure PCTKR2022013646-appb-img-000051
단계 1: methyl (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate의 합성Step 1: Synthesis of methyl (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 300mg, 1.3mmol), 및 DIPEA (0.68ml, 3.9mmol)를 DCM (13ml)에 현탁 시킨 후 methyl 4-(chloroformyl)benzoate (388mg, 1.95mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 반응액을 감압 농축하여 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 410 mg (78%)을 수득하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 300mg, 1.3mmol), and DIPEA (0.68ml, 3.9mmol ) was suspended in DCM (13ml), methyl 4-(chloroformyl)benzoate (388mg, 1.95mmol) was added and stirred at room temperature for 16 hours. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to MPLC (5% MeOH/DCM) to obtain 410 mg (78%) of a white solid.
단계 2: (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid의 합성Step 2: Synthesis of (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid
methyl (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate (170mg, 0.4mmol)를 THF : H2O = 4 : 1 (5 ml)에 현탁 시킨 후 LiOH monohydrate (35mg, 0.86mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 용매를 증발시키고 증류수를 가한 후 1N HCl을 첨가하고 EtOAc (30ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 170mg (95%)을 수득하였다.methyl (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoate (170mg, 0.4mmol) was added to THF:H 2 After suspension in O = 4: 1 (5 ml), LiOH monohydrate (35mg, 0.86mmol) was added and stirred at room temperature for 16 hours. After evaporating the solvent and adding distilled water, 1N HCl was added and extracted with EtOAc (30ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 170 mg (95%) of a white solid.
단계 3: N1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide의 합성 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
(S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid 대신 (S)-4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid를 사용하고 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7) 대신 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5)을 사용하여 실시예 1의 단계 3의 합성법과 동일한 방법으로 실시예 5를 합성하였다. Instead of (S)-3-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid (S)-4-((2- ((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)benzoic acid was used and 4-((6-aminohexyl)amino)-2-(2,6- 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- instead of dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-7) Example 5 was synthesized in the same manner as the synthesis method of step 3 of Example 1 using dione (intermediate 3-5).
실시예 6: N1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 6 N 1 -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000052
Figure PCTKR2022013646-appb-img-000052
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-6)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 6을 합성하였다. 5-((4-aminobutyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-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).
실시예 7: N1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 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
Figure PCTKR2022013646-appb-img-000053
Figure PCTKR2022013646-appb-img-000053
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-1)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 7을 합성하였다. 4-((5-aminopentyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) Example 7 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-1).
실시예 8: N1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)pentyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 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
Figure PCTKR2022013646-appb-img-000054
Figure PCTKR2022013646-appb-img-000054
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-2)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 8을 합성하였다. 5-((5-aminopentyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) Example 8 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-2).
실시예 9: N1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 9 N 1 -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000055
Figure PCTKR2022013646-appb-img-000055
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-7)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 9를 합성하였다. 4-((6-aminohexyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) Example 9 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-7).
실시예 10: N1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 10 N 1 -(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000056
Figure PCTKR2022013646-appb-img-000056
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-8)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 10을 합성하였다. 5-((6-aminohexyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) Example 10 was synthesized in the same manner as Example 5 using -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-8).
실시예 11: N1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 11 N 1 -(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000057
Figure PCTKR2022013646-appb-img-000057
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-9)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 11을 합성하였다. 4-((8-aminooctyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 12: N1-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 12 N 1 -(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000058
Figure PCTKR2022013646-appb-img-000058
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-10)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 12를 합성하였다. 5-((8-aminooctyl)amino)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 13: N1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 13 N 1 -(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)-N 4 - (2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000059
Figure PCTKR2022013646-appb-img-000059
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-(4-(2-aminoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-11)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 13을 합성하였다. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) instead of 4-(4-(2-aminoethyl)piperidin- Example 13 was synthesized in the same manner as Example 5 using 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-11).
실시예 14: N1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 14 N 1 -(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)-N 4 - (2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000060
Figure PCTKR2022013646-appb-img-000060
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-(4-(2-aminoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-12)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 14를 합성하였다. 5-(4-(2-aminoethyl)piperidin- instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 15: N1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 15 N 1 -(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)-N 4 - (2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000061
Figure PCTKR2022013646-appb-img-000061
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-(4-(3-aminopropyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-13)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 15를 합성하였다. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) instead of 4-(4-(3-aminopropyl)piperidin- Example 15 was synthesized in the same manner as Example 5 using 1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-13).
실시예 16: N1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 16 N 1 -(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)-N 4 - (2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000062
Figure PCTKR2022013646-appb-img-000062
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-(4-(3-aminopropyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-14)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 16을 합성하였다. 5-(4-(3-aminopropyl)piperidin- instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 17: N1-(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4-yl)propyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 17 N 1 -(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetyl)piperidin-4- yl)propyl)-N 4 -(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000063
Figure PCTKR2022013646-appb-img-000063
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-(2-(4-(3-aminopropyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-19)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 17을 합성하였다. 4-(2-(4-(3-aminopropyl) instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) )piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-19) using the same synthesis method as in Example 5 Example 17 was synthesized with
실시예 18: N1-(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)propyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 18 N 1 -(3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4- yl)propyl)-N 4 -(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000064
Figure PCTKR2022013646-appb-img-000064
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-(2-(4-(3-aminopropyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-20)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 18을 합성하였다. 5-(2-(4-(3-aminopropyl) instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) )piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-20) using the same method as the synthesis method of Example 5 Example 18 was synthesized with
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000065
Figure PCTKR2022013646-appb-img-000065
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 2-(2,6-dioxopiperidin-3-yl)-4-((3-(piperidin-4-yl)propyl)amino)isoindoline-1,3-dione (중간체 3-15)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 19를 합성하였다. 2-(2,6-dioxopiperidin-3-yl instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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) .
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000066
Figure PCTKR2022013646-appb-img-000066
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 2-(2,6-dioxopiperidin-3-yl)-5-((3-(piperidin-4-yl)propyl)amino)isoindoline-1,3-dione (중간체 3-16)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 20을 합성하였다. 2-(2,6-dioxopiperidin-3-yl instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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) .
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000067
Figure PCTKR2022013646-appb-img-000067
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamide (중간체 3-17)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 21을 합성하였다. 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.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000068
Figure PCTKR2022013646-appb-img-000068
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-N-(3-(piperidin-4-yl)propyl)acetamide (중간체 3-18)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 22를 합성하였다. 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.
실시예 23: N1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 23 N 1 -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000069
Figure PCTKR2022013646-appb-img-000069
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-21)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 23을 합성하였다. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) instead of 4-(4-aminobutoxy)-2-(2 Example 23 was synthesized in the same manner as in Example 5 using ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-21).
실시예 24: N1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 24 N 1 -(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)butyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000070
Figure PCTKR2022013646-appb-img-000070
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-(4-aminobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-22)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 24를 합성하였다. 5-(4-aminobutoxy)-2-(2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) Example 24 was synthesized in the same manner as in Example 5 using ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate 3-22).
실시예 25: N1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 25 N 1 -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)pentyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000071
Figure PCTKR2022013646-appb-img-000071
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 4-((5-aminopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-23)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 25를 합성하였다. 4-((5-aminopentyl)oxy)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 26: N1-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-N4-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamideExample 26 N 1 -(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)pentyl)-N 4 -(2-((( S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)terephthalamide
Figure PCTKR2022013646-appb-img-000072
Figure PCTKR2022013646-appb-img-000072
4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-5) 대신 5-((5-aminopentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-24)을 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 26을 합성하였다. 5-((5-aminopentyl)oxy)-2 instead of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-5) 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).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000073
Figure PCTKR2022013646-appb-img-000073
단계 1: 6-((tert-butoxycarbonyl)amino)hexyl methanesulfonate의 합성Step 1: Synthesis of 6-((tert-butoxycarbonyl)amino)hexyl methanesulfonate
tert-butyl (6-hydroxyhexyl)carbamate (1g, 4.6mmol)를 DCM (15ml)에 현탁 시킨 후 0℃에서 methanesulfonyl chloride (0.42ml, 5.5mmol), 및 TEA (0.76ml, 5.5mmol)를 천천히 첨가하고 상온에서 12시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 DCM (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 투명한 오일 1.1g (81%)를 수득하였다.After tert-butyl (6-hydroxyhexyl)carbamate (1g, 4.6mmol) was suspended in DCM (15ml), methanesulfonyl chloride (0.42ml, 5.5mmol) and TEA (0.76ml, 5.5mmol) were slowly added at 0℃. It was stirred for 12 hours at room temperature. After adding distilled water (20ml) to the reaction solution, extraction was performed with DCM (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 1.1 g (81%) of a clear oil.
단계 2: tert-butyl (6-(4-bromo-1H-pyrazol-1-yl)hexyl)carbamate의 합성Step 2: Synthesis of tert-butyl (6-(4-bromo-1H-pyrazol-1-yl)hexyl)carbamate
6-((tert-butoxycarbonyl)amino)hexyl methanesulfonate (900mg, 3mmol), 4-bromo-1H-pyrazole (895mg, 6mmol), 및 K2CO3 (1g, 7.6mmol)를 DMF (15ml)에 현탁 시킨 후 70℃에서 14시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (33% EtOAc/Hexane)하여 투명한 액체 890mg (85%)를 수득하였다.6-((tert-butoxycarbonyl)amino)hexyl methanesulfonate (900mg, 3mmol), 4-bromo-1H-pyrazole (895mg, 6mmol), and K 2 CO 3 (1g, 7.6mmol) were suspended in DMF (15ml) After stirring at 70 ℃ for 14 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (33% EtOAc/Hexane) to give 890 mg (85%) of a clear liquid.
단계 3: methyl 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoate의 합성Step 3: Synthesis of methyl 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoate
tert-butyl (6-(4-bromo-1H-pyrazol-1-yl)hexyl)carbamate (230mg, 0.66mmol), (4-(methoxycarbonyl)phenyl)boronic acid (120mg, 0.66mmol), tricyclohexylphosphine (51mg, 0.18mmol), PdCl2(dppf)CH2Cl2 (179mg, 0.219mmol), 및 Cs2CO3 (328mg, 1mmol)를 1,4-dioxane : water = 5 : 1 (12 ml)에 현탁 시킨 후 95℃에서 12시간 동안 교반 하였다. 반응물을 Celite로 여과한 후 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 흰색 고체 160mg (61%)를 수득하였다.tert-butyl (6-(4-bromo-1H-pyrazol-1-yl)hexyl)carbamate (230mg, 0.66mmol), (4-(methoxycarbonyl)phenyl)boronic acid (120mg, 0.66mmol), tricyclohexylphosphine (51mg, 0.18mmol), PdCl 2 (dppf)CH 2 Cl 2 (179mg, 0.219mmol), and Cs 2 CO 3 (328mg, 1mmol) were suspended in 1,4-dioxane : water = 5 : 1 (12 ml) Stirred at 95 °C for 12 hours. The reaction product was filtered through Celite and then concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 160 mg (61%) of a white solid.
단계 4: 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 4: Synthesis of 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoic acid
methyl 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoate (150mg, 0.37mmol), lithium hydroxide monohydrate (43mg, 1.1mmol)를 THF : H2O = 4 : 1 (5ml)에 현탁 시킨 후 50℃에서 20시간 동안 교반 하였다. 반응액에 1N HCl 수용액 (10ml)을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 93 mg (64%)를 수득하였다.methyl 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoate (150mg, 0.37mmol), lithium hydroxide monohydrate (43mg, 1.1mmol) was mixed with THF:H 2 After suspension in O = 4: 1 (5ml), the mixture was stirred at 50°C for 20 hours. 1N HCl aqueous solution (10ml) was added to the reaction solution to adjust pH = 6, followed by extraction with EtOAc (20ml x 2), drying the organic layer over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain 93 mg (64%) of a white solid. did
단계 5: tert-butyl (S)-(6-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)hexyl)carbamate의 합성Step 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
4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoic acid (151mg, 0.39mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 90mg, 0.39mmol), HATU (297mg, 0.78mmol), 및 DIPEA (0.2ml, 1.17mmol)를 DMF (3ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 110mg (48%)을 수득하였다. 4-(1-(6-((tert-butoxycarbonyl)amino)hexyl)-1H-pyrazol-4-yl)benzoic acid (151mg, 0.39mmol), (S)-2-((2-methylpyrrolidin-1- yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 90mg, 0.39mmol), HATU (297mg, 0.78mmol), and DIPEA (0.2ml, 1.17mmol) were mixed with DMF (3ml). and then stirred at room temperature for 16 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 110 mg (48%) of a white solid.
단계 6: (S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성 Step 6: (S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d Synthesis of ]imidazol-5-yl)benzamide hydrochloride
tert-butyl (S)-(6-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)hexyl)carbamate (110mg, 0.18mmol)에 4M HCl in dioxane (2 ml)를 가한 후 상온에서 12시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 90mg (88%)을 수득하였다.tert-butyl (S)-(6-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)- After adding 4M HCl in dioxane (2 ml) to 1H-pyrazol-1-yl)hexyl)carbamate (110mg, 0.18mmol), the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated to obtain 90 mg (88%) of a white solid.
단계 7: 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)benzamide의 합성Step 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
(S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (30mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 10mg, 0.05mmol), DIPEA (0.04ml, 0.25 mmol)를 DMSO (0.08ml)에 현탁 시킨 후 90 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (1.5ml)를 가한 뒤 EtOAc (2.5ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 황색 고체 9mg (25%)을 수득하였다. (S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide hydrochloride (30mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 10mg, 0.05mmol), DIPEA (0.04 ml, 0.25 mmol) was suspended in DMSO (0.08ml) and stirred at 90 °C for 16 hours. After adding distilled water (1.5ml) to the reaction solution, extraction was performed with EtOAc (2.5ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 9 mg (25%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000074
Figure PCTKR2022013646-appb-img-000074
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 27의 합성법과 동일한 방법으로 실시예 28을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 28 was synthesized in the same manner as in Example 27 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000075
Figure PCTKR2022013646-appb-img-000075
(S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (12mg, 0.02mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231, 15mg, 0.04mmol), HATU (25mg, 0.06mmol), 및 DIPEA (0.02ml, 0.11mmol)를 DMF (0.2ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (1ml)를 가한 뒤 EtOAc (1.0ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 4mg (23%)을 수득하였다. (S)-4-(1-(6-aminohexyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol- 5-yl)benzamide hydrochloride (12mg, 0.02mmol), 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231, 15mg, 0.04mmol), HATU (25mg, 0.06mmol), and DIPEA (0.02ml, 0.11mmol) were suspended in DMF (0.2ml) and stirred at room temperature for 16 hours. After adding distilled water (1ml) to the reaction solution, extraction was performed with EtOAc (1.0ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (5% MeOH/DCM) to give 4mg (23%) of a white solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000076
Figure PCTKR2022013646-appb-img-000076
2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231) 대신 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid (WO2019/241231)를 사용하여 실시예 29의 합성법과 동일한 방법으로 실시예 30을 합성하였다. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid (WO2019/241231) instead of 2-((2-(2,6-dioxopiperidin) Example 30 was synthesized in the same manner as in Example 29 using -3-yl) -1,3-dioxoisoindolin-5-yl) oxy) acetic acid (WO2019/241231).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000077
Figure PCTKR2022013646-appb-img-000077
단계 1: tert-butyl 4-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate의 합성Step 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%), 및 cesium carbonate (1.5g, 4.5mmol)를 1,4-dioxane (20ml)에 현탁 시킨 후 90℃에서 12시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 흰색 고체 1.1g (94%)를 수득하였다.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℃ 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.
단계 2: 4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 2: Synthesis of 4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)benzoic acid
tert-butyl 4-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1g, 2.6mmol), lithium hydroxide monohydrate (218mg, 5.2mmol)를 THF : H2O = 5 : 1 (18ml)에 현탁 시킨 후 상온에서 12시간 동안 교반 하였다. 반응액에 1N HCl 수용액 (10ml)을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 910mg (94%)를 수득하였다. tert-butyl 4-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (1g, 2.6mmol), lithium hydroxide monohydrate (218mg, 5.2mmol) was mixed with THF:H After suspension in 2 O = 5: 1 (18ml), the mixture was stirred at room temperature for 12 hours. 1N HCl aqueous solution (10ml) was added to the reaction solution to adjust the pH to 6, followed by extraction with EtOAc (20ml x 2), drying the organic layer over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain 910mg (94%) of a white solid. .
단계 3: tert-butyl (S)-4-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate의 합성Step 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
4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)benzoic acid (800mg, 2.15mmol), EDCI (825mg, 4.3mmol), HOBt (660mg, 4.3mmol)를 DMF (6ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 490mg, 2.15mmol), DIPEA (1.13ml, 6.45mmol)를 가한 후 상온에서 48시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 흰색 고체 560mg (45%)을 수득하였다.4-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)benzoic acid (800mg, 2.15mmol), EDCI (825mg, 4.3mmol), HOBt (660mg, 4.3mmol) mmol) was suspended in DMF (6ml) and stirred at room temperature for 10 minutes. (S) -2-((2-methylpyrrolidin-1-yl)methyl) -1H-benzo[d]imidazol-5-amine (intermediate 1-1, 490 mg, 2.15 mmol), DIPEA (1.13 ml, 6.45 mmol) was added, and the mixture was stirred at room temperature for 48 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 560 mg (45%) of a white solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzamide hydrochloride의 합성Step 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(piperidin-4-yl) Synthesis of -1H-pyrazol-4-yl)benzamide hydrochloride
tert-butyl (S)-4-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (100mg, 0.17mmol)를 DCM (1.7ml)에 현탁 시킨 후 4M HCl in dioxane (0.26ml)를 가하고 상온에서 5시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 142mg (quant.)를 수득하였다.tert-butyl (S)-4-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H After -pyrazol-1-yl)piperidine-1-carboxylate (100mg, 0.17mmol) was suspended in DCM (1.7ml), 4M HCl in dioxane (0.26ml) was added and stirred at room temperature for 5 hours. The reaction solution was concentrated to obtain 142 mg (quant.) of a white solid.
단계 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)benzamide의 합성 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzamide hydrochloride (10mg, 0.02 mmol), 및 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (중간체 3-25, 7.4mg, 0.02mmol)를 DCM (0.2ml)와 MeOH (0.03ml)에 현탁 시킨 후 sodium triacetoxyborohydride (8.5mg, 0.04mmol)를 가하고 상온에서 12시간 동안 교반 하였다. 반응액에 NaHCO3 수용액 (1.0ml)를 가한 뒤 DCM (2.0ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 5mg (30%)를 수득하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(piperidin-4-yl)-1H- pyrazol-4-yl)benzamide hydrochloride (10 mg, 0.02 mmol), and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (intermediate 3-25, 7.4mg, 0.02mmol) was suspended in DCM (0.2ml) and MeOH (0.03ml), sodium triacetoxyborohydride (8.5mg, 0.04mmol) was added and stirred at room temperature for 12 hours. An aqueous solution of NaHCO 3 (1.0ml) was added to the reaction mixture, followed by extraction with DCM (2.0ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 5 mg (30%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000078
Figure PCTKR2022013646-appb-img-000078
1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (중간체 3-25) 대신 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (중간체 3-26)을 사용하여 실시예 31의 합성법과 동일한 방법으로 실시예 32를 합성하였다. 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (intermediate 3-25) instead of 1-(2-(2,6-dioxopiperidin) 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).
실시예 33: 4-(1-(1-(2-(1-(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)benzamideExample 33: 4-(1-(1-(2-(1-(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
Figure PCTKR2022013646-appb-img-000079
Figure PCTKR2022013646-appb-img-000079
1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (중간체 3-25) 대신 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (중간체 3-27)을 사용하여 실시예 31의 합성법과 동일한 방법으로 실시예 33을 합성하였다. 2-(1-(2-(2, 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). .
실시예 34: 4-(1-(1-(2-(1-(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)benzamideExample 34: 4-(1-(1-(2-(1-(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
Figure PCTKR2022013646-appb-img-000080
Figure PCTKR2022013646-appb-img-000080
1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carbaldehyde (중간체 3-25) 대신 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (중간체 3-28)을 사용하여 실시예 31의 합성법과 동일한 방법으로 실시예 34를 합성하였다. 2-(1-(2-(2, 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). .
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000081
Figure PCTKR2022013646-appb-img-000081
단계 1: tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate
4-bromo-1H-pyrazole (97mg, 0.67mmol), tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288, 257mg, 0.67mmol), 및 K2CO3 (138mg, 1mmol)를 DMF (1.7ml)에 현탁 시킨 후 70℃에서 4시간 동안 교반 하였다. 반응물에 증류수 (2.0ml)를 가한 뒤 EtOAc (3.0ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (20% EtOAc/Hexane)하여 투명한 오일 200mg (83%)를 수득하였다.4-bromo-1H-pyrazole (97mg, 0.67mmol), tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288, 257mg, 0.67mmol), and K 2 CO 3 (138mg , 1 mmol) was suspended in DMF (1.7ml) and then stirred at 70°C for 4 hours. After adding distilled water (2.0ml) to the reactant, extraction was performed with EtOAc (3.0ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (20% EtOAc/Hexane) to give 200 mg (83%) of a clear oil.
단계 2: tert-butyl 4-(2-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(2-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate
tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (74mg, 0.21mmol), (4-(methoxycarbonyl)phenyl)boronic acid (38mg, 0.21mmol), Xantphos (36mg, 0.063mmol), PdCl2(dppf)CH2Cl2 (51mg, 0.063mmol), 및 Cs2CO3 (103mg, 0.315mmol)를 1,4-dioxane (4ml)와 H2O (1ml)에 현탁 시킨 후 90℃에서 2시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 갈색 오일 53 mg (61%)를 수득하였다.tert-butyl 4-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (74mg, 0.21mmol), (4-(methoxycarbonyl)phenyl)boronic acid (38mg, 0.21mmol) ), Xantphos (36 mg, 0.063 mmol), PdCl 2 (dppf)CH 2 Cl 2 (51 mg, 0.063 mmol), and Cs 2 CO 3 (103 mg, 0.315 mmol) were mixed with 1,4-dioxane (4 ml) and H 2 O (1ml) and stirred for 2 hours at 90 ℃. The reaction product was filtered and then concentrated under reduced pressure. The obtained residue was subjected to MPLC (50% EtOAc/Hexane) to give 53 mg (61%) of a brown oil.
단계 3: 4-(1-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 3: Synthesis of 4-(1-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzoic acid
tert-butyl 4-(2-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (75mg, 0.18mmol), 및 lithium hydroxide monohydrate (43mg, 1.1mmol)를 THF (0.9ml)와 H2O (0.9ml)에 현탁 시킨 후 50℃에서 20시간 동안 교반 하였다. 반응액에 1N HCl 수용액 (10ml)을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 연한 갈색 고체 50mg (70%)를 수득하였다. tert-butyl 4-(2-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (75mg, 0.18mmol), and lithium hydroxide monohydrate (43mg, 1.1 mmol) was suspended in THF (0.9ml) and H 2 O (0.9ml) and stirred at 50°C for 20 hours. 1N HCl aqueous solution (10ml) was added to the reaction solution to adjust pH = 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 50 mg (70%) of a light brown solid.
단계 4: tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 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
4-(1-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzoic acid (50mg, 0.125mmol), EDCI (29mg, 0.15mmol), HOBt (20mg, 0.15mmol)를 DMF (1.25ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 29mg, 0.125mmol), DIPEA (0.088ml, 0.5mmol)를 가한 후 상온에서 48시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 연한 갈색 고체 50mg (65%)을 수득하였다.4-(1-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzoic acid (50mg, 0.125mmol), EDCI (29mg, 0.15mmol), HOBt (20mg, 0.15mmol) was suspended in DMF (1.25ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 29 mg, 0.125 mmol), DIPEA (0.088 ml, 0.5 mmol) was added, and the mixture was stirred at room temperature for 48 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 50 mg (65%) of a pale brown solid.
단계 5: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (47mg, 0.08mmol)를 DCM (0.8ml)에 현탁 시킨 후 4M HCl in dioxane (0.12ml)를 가하고 상온에서 24시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 50mg (quant.)를 수득하였다.tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (47mg, 0.08mmol) was suspended in DCM (0.8ml), 4M HCl in dioxane (0.12ml) was added, and the mixture was stirred at room temperature for 24 hours. . The reaction solution was concentrated to obtain 50 mg (quant.) of a white solid.
단계 6: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl)ethyl)-1H-pyrazol-4-yl)benzamide hydrochloride (30mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 15mg, 0.05mmol), 및 DIPEA (0.02ml, 0.16mmol)를 DMSO (0.05ml)에 현탁 시킨 후 90℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (1.5ml)를 가한 뒤 EtOAc (2.5ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 황색 고체 13mg (31%)을 수득하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl) ethyl)-1H-pyrazol-4-yl)benzamide hydrochloride (30mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 15mg, 0.05mmol), and DIPEA (0.02ml, 0.16mmol) were suspended in DMSO (0.05ml) and then stirred at 90°C for 16 hours. After adding distilled water (1.5ml) to the reaction mixture, extraction was performed with EtOAc (2.5ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 13 mg (31%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000082
Figure PCTKR2022013646-appb-img-000082
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 36을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 36 was synthesized in the same manner as in Example 35 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000083
Figure PCTKR2022013646-appb-img-000083
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 37을 합성하였다. tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) instead of tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) Example 37 was synthesized in the same manner as in Example 35.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000084
Figure PCTKR2022013646-appb-img-000084
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 38을 합성하였다. Use tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) instead of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) , 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1, Example 38 was synthesized in the same manner as in Example 35 using 3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000085
Figure PCTKR2022013646-appb-img-000085
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하고 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4)을 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 39를 합성하였다.Use tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) instead of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 2-(pyrrolidin-1-ylmethyl)-1H-benzo instead of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1) Example 39 was synthesized in the same manner as in Example 35 using [d]imidazol-5-amine (Intermediate 1-4).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000086
Figure PCTKR2022013646-appb-img-000086
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하고 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 40을 합성하였다.Use tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) instead of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) (3S,5S)-1-((5-amino Example 40 was synthesized in the same manner as in Example 35 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000087
Figure PCTKR2022013646-appb-img-000087
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하고 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3R,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-3)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 41을 합성하였다.Use tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) instead of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) (3R,5S)-1-((5-amino Example 41 was synthesized in the same manner as in Example 35 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-3).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000088
Figure PCTKR2022013646-appb-img-000088
tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) 대신 tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458)를 사용하고 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-amine (중간체 1-5)를 사용하여 실시예 35의 합성법과 동일한 방법으로 실시예 42를 합성하였다.Use tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) instead of tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (US2010/016288) (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1) instead of (S)-2-((2-methylpyrrolidin-1 Example 42 was synthesized in the same manner as in Example 35 using -yl)methyl)benzo[d]oxazol-5-amine (Intermediate 1-5).
실시예 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 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
Figure PCTKR2022013646-appb-img-000089
Figure PCTKR2022013646-appb-img-000089
Figure PCTKR2022013646-appb-img-000090
Figure PCTKR2022013646-appb-img-000090
단계 1: tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate의 합성 Step 1: Synthesis of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate
3-(piperidin-4-yl)propan-1-ol (1g, 7mmol), 및 Boc2O (1.6g, 7.3mmol)를 DCM (23ml)에 현탁 시킨 후 0℃에서 TEA (1.46ml, 10.5mmol)를 천천히 가하고 상온에서 2시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (33% EtOAc/Hexane)하여 투명한 오일 1.27g (75%)를 수득하였다.After suspending 3-(piperidin-4-yl)propan-1-ol (1g, 7mmol) and Boc 2 O (1.6g, 7.3mmol) in DCM (23ml), TEA (1.46ml, 10.5mmol) at 0℃. ) was slowly added and stirred at room temperature for 2 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (33% EtOAc/Hexane) to give 1.27 g (75%) of a clear oil.
단계 2: tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate의 합성 Step 2: Synthesis of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate
tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (500mg, 2.1mmol)를 DCM (21ml)에 현탁 시킨 후 DMP (1.05g, 2.5mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액에 NaHCO3 수용액 (20ml)를 가한 뒤 DCM (30ml x 2)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 투명한 오일 348mg (69%)를 수득하였다.After tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (500mg, 2.1mmol) was suspended in DCM (21ml), DMP (1.05g, 2.5mmol) was added and stirred at room temperature for 2 hours. An aqueous solution of NaHCO 3 (20ml) was added to the reaction solution, followed by extraction with DCM (30ml x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to give 348 mg (69%) of a clear oil.
단계 3: tert-butyl 4-(3-hydroxybutyl)piperidine-1-carboxylate의 합성 Step 3: Synthesis of tert-butyl 4-(3-hydroxybutyl)piperidine-1-carboxylate
tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (350mg, 1.46mmol)를 THF (1.46ml)에 현탁 시킨 후 MeMgBr (1.56ml, 2.19mmol)를 -78℃에서 천천히 가하였다. 이후, -78℃에서 30분 동안 교반 하였다. 반응액에 NH4Cl 수용액 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 노란색 오일 286mg (76%)를 수득하였다.After tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (350mg, 1.46mmol) was suspended in THF (1.46ml), MeMgBr (1.56ml, 2.19mmol) was slowly added at -78℃. Then, the mixture was stirred at -78°C for 30 minutes. After adding NH 4 Cl aqueous solution (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 286 mg (76%) of a yellow oil.
단계 4: tert-butyl 4-(3-((methylsulfonyl)oxy)butyl)piperidine-1-carboxylate의 합성Step 4: Synthesis of tert-butyl 4-(3-((methylsulfonyl)oxy)butyl)piperidine-1-carboxylate
tert-butyl 4-(3-hydroxybutyl)piperidine-1-carboxylate (120mg, 0.47mmol)를 DCM (4.7ml)에 현탁 시킨 후 MsCl (0.047ml, 0.14mmol), 및 TEA (0.13ml, 0.86mmol)를 0℃에서 천천히 가하고 상온에서 1시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 DCM (30ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 투명한 오일 104.5mg (65%)를 수득하였다.After tert-butyl 4-(3-hydroxybutyl)piperidine-1-carboxylate (120mg, 0.47mmol) was suspended in DCM (4.7ml), MsCl (0.047ml, 0.14mmol) and TEA (0.13ml, 0.86mmol) were added. It was added slowly at 0°C and stirred for 1 hour at room temperature. After adding distilled water (20ml) to the reaction mixture, extraction was performed with DCM (30ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to give 104.5 mg (65%) of a clear oil.
단계 5: tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate의 합성 Step 5: Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate
4-bromo-1H-pyrazole (47mg, 0.32mmol), tert-butyl 4-(3-((methylsulfonyl)oxy)butyl)piperidine-1-carboxylate (104.5mg, 0.32mmol), 및 K2CO3 (138mg, 1mmol)를 DMF (3.2ml)에 현탁 시킨 후 80℃에서 13시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (16% EtOAc/Hexane)하여 투명한 오일 77mg (63%)를 수득하였다.4-bromo-1H-pyrazole (47mg, 0.32mmol), tert-butyl 4-(3-((methylsulfonyl)oxy)butyl)piperidine-1-carboxylate (104.5mg, 0.32mmol), and K 2 CO 3 (138mg , 1 mmol) was suspended in DMF (3.2ml) and then stirred at 80°C for 13 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (16% EtOAc/Hexane) to give 77 mg (63%) of a clear oil.
단계 6: tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate의 합성Step 6: Synthesis of tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate
tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate (75mg, 0.19mmol), (4-(methoxycarbonyl)phenyl)boronic acid (35mg, 0.19mmol), Xantphos (34mg, 0.06mmol), PdCl2(dppf) (49mg, 0.06mmol), 및 Cs2CO3 (95mg, 0.29mmol)를 1,4-dioxane (1.5ml)와 H2O (0.4ml)에 현탁 시킨 후 90℃에서 2시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하였다. 얻어진 잔사를 MPLC (15% EtOAc/Hexane)하여 갈색 오일 52mg (61%)를 수득하였다. tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate (75mg, 0.19mmol), (4-(methoxycarbonyl)phenyl)boronic acid (35mg, 0.19mmol) ), Xantphos (34 mg, 0.06 mmol), PdCl 2 (dppf) (49 mg, 0.06 mmol), and Cs 2 CO 3 (95 mg, 0.29 mmol) were mixed with 1,4-dioxane (1.5 ml) and H 2 O (0.4 ml). ) and then stirred at 90 ° C for 2 hours. The reaction product was filtered and then concentrated under reduced pressure. The obtained residue was subjected to MPLC (15% EtOAc/Hexane) to give 52mg (61%) of a brown oil.
단계 7: 4-(1-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzoic acid의 합성 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), 및 lithium hydroxide monohydrate (48mg, 0.12mmol)를 THF (0.6ml), 및 H2O (0.6ml)에 현탁 시킨 후 50℃에서 4시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 연한 갈색 고체 53mg (quant.)를 수득하였다. 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.
단계 8: tert-butyl 4-(3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate의 합성 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
4-(1-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzoic acid (54mg, 0.126mmol), EDCI (49mg, 0.26mmol), 및 HOBt (21mg, 0.15mmol)를 DMF (1.26ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 30mg, 0.126mmol), 및 DIPEA (0.07ml, 0.38mmol)를 가한 후 상온에서 21시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 갈색 고체 24mg (30%)을 수득하였다. 4-(1-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzoic acid (54mg, 0.126mmol), EDCI (49mg, 0.26mmol), and HOBt (21mg, 0.15mmol) were suspended in DMF (1.26ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 30mg, 0.126mmol), and DIPEA (0.07ml, 0.38 mmol) was added and stirred at room temperature for 21 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed 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 (10% MeOH/DCM) to give 24 mg (30%) of a brown solid.
단계 9: N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(4-(piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzamide hydrochloride의 합성Step 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
tert-butyl 4-(3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate (20mg, 0.03mmol)를 DCM (0.3ml)에 현탁 시킨 후 4M HCl in dioxane (0.08ml)를 가하고 상온에서 4시간 동안 교반 하였다. 반응액을 농축하여 갈색 고체 18mg (quant.)를 수득하였다.tert-butyl 4-(3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1H-pyrazol-1-yl)butyl)piperidine-1-carboxylate (20mg, 0.03mmol) was suspended in DCM (0.3ml), 4M HCl in dioxane (0.08ml) was added, and the mixture was stirred at room temperature for 4 hours. . The reaction solution was concentrated to obtain 18 mg (quant.) of a brown solid.
단계 10: 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)benzamide의 합성Step 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
N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(4-(piperidin-4-yl)butan-2-yl)-1H-pyrazol-4-yl)benzamide hydrochloride (18mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 8.7mg, 0.03mmol), 및 DIPEA (0.03ml, 0.16mmol)를 DMSO (0.3ml)에 현탁 시킨 후 100℃에서 19시간 동안 교반 하였다. 반응액에 증류수 (2.0ml)를 가한 뒤 EtOAc (2.0ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 7.5mg (30%)를 수득하였다.N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(4-(piperidin-4-yl) butan-2-yl)-1H-pyrazol-4-yl)benzamide hydrochloride (18mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/ 160845, 8.7mg, 0.03mmol), and DIPEA (0.03ml, 0.16mmol) were suspended in DMSO (0.3ml) and then stirred at 100°C for 19 hours. After adding distilled water (2.0ml) to the reaction mixture, extraction was performed with EtOAc (2.0ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 7.5 mg (30%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000091
Figure PCTKR2022013646-appb-img-000091
단계 1: tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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 (334mg, 1.27mmol), 4-bromo-1H-pyrazole (169mg, 1.15mmol), 및 Cs2CO3 (497mg, 1.5mmol)를 acetonitrile (12.7ml)와 THF (2ml)에 현탁 시킨 후 80℃에서 15시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 노란색 오일 423mg (89%)를 수득하였다.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℃ 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.
단계 2: tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (200mg, 0.54mmol), (4-(methoxycarbonyl)phenyl)boronic acid (97mg, 0.54mmol), Pd(dppf)Cl2 (131mg, 0.16mmol), Xantphos (93mg, 0.16mmol), 및 Cs2CO3 (262mg, 0.8mmol)를 1,4-dioxane (9ml)와 H2O (1.8ml)에 현탁 시킨 후 80℃에서 1시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 갈색 고체 176mg (77%)를 수득하였다.tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (200mg, 0.54mmol), (4-(methoxycarbonyl)phenyl)boronic acid (97mg, 0.54mmol) ), Pd(dppf)Cl 2 (131mg, 0.16mmol), Xantphos (93mg, 0.16mmol), and Cs 2 CO 3 (262mg, 0.8mmol) were mixed with 1,4-dioxane (9ml) and H 2 O (1.8ml). ) and then stirred at 80 ° C for 1 hour. 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 176 mg (77%) of a brown solid.
단계 3: 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 3: Synthesis of 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzoic acid
tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (174mg, 0.41mmol), 및 lithium hydroxide monohydrate (103mg, 2.4mmol)를 THF (2ml), H2O (2ml)에 현탁 시킨 후 50℃에서 26시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 6으로 조정하였다. 그 뒤 EtOAc (20ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 연한 갈색 고체 119mg (70%)를 수득하였다. tert-butyl 4-(3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (174 mg, 0.41 mmol), and lithium hydroxide monohydrate (103 mg, 2.4 mmol) was suspended in THF (2ml) and H 2 O (2ml) and stirred at 50°C for 26 hours. 1N HCl aqueous solution was added to the reaction solution to adjust the pH to 6. After extraction with EtOAc (20ml x 2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 119mg (70%) of a light brown solid.
단계 4: tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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
4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzoic acid (115mg, 0.28mmol), EDCI (107mg, 0.56mmol), 및 HOBt (46mg, 0.34mmol)를 DMF (2.8ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 51mg, 0.22mmol), 및 DIPEA (0.15ml, 0.84mmol)를 가한 후 상온에서 24시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% MeOH/DCM)하여 갈색 고체 37mg (21%)을 수득하였다.4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzoic acid (115mg, 0.28mmol), EDCI (107mg, 0.56mmol), and HOBt (46mg, 0.34mmol) were suspended in DMF (2.8ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 51mg, 0.22mmol), and DIPEA (0.15ml, 0.84 mmol) was added and stirred at room temperature for 24 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed 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 (8% MeOH/DCM) to give 37 mg (21%) of a brown solid.
단계 5: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (35mg, 0.05mmol)를 DCM (0.5ml)에 현탁 시킨 후 4M HCl in dioxane (0.09ml, 0.36mmol)를 가하고 상온에서 30분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 31mg (98%)를 수득하였다.tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl After suspending )-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (35mg, 0.05mmol) in DCM (0.5ml), 4M HCl in dioxane (0.09ml, 0.36mmol) was added and incubated at room temperature for 30 minutes. while stirring. The reaction solution was concentrated to obtain 31 mg (98%) of a white solid.
단계 6: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)benzamide hydrochloride (29mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 15mg, 0.05mmol), 및 DIPEA (0.04ml, 0.34mmol)를 DMSO (0.5ml)에 현탁 시킨 후 100℃에서 14시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 13.3mg (33%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl) propyl)-1H-pyrazol-4-yl)benzamide hydrochloride (29mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 15mg, 0.05mmol), and DIPEA (0.04ml, 0.34mmol) were suspended in DMSO (0.5ml) and then stirred at 100°C for 14 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 13.3 mg (33%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000092
Figure PCTKR2022013646-appb-img-000092
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4)를 사용하여 실시예 44의 합성법과 동일한 방법으로 실시예 45를 합성하였다.2-(pyrrolidin-1-ylmethyl)-1H-benzo instead of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1) Example 45 was synthesized in the same manner as in Example 44 using [d]imidazol-5-amine (Intermediate 1-4).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000093
Figure PCTKR2022013646-appb-img-000093
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)를 사용하여 실시예 44의 합성법과 동일한 방법으로 실시예 46을 합성하였다.(3S,5S)-1-((5-amino Example 46 was synthesized in the same manner as in Example 44 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000094
Figure PCTKR2022013646-appb-img-000094
단계 1: tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2,2-difluoropropyl)piperazine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2,2-difluoropropyl)piperazine-1-carboxylate
tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (중간체 2-3, 100mg, 0.23mmol), 4-bromo-1H-pyrazole (41mg, 0.27mmol), 및 K2CO3 (48mg, 0.35mmol)를 DMF (2ml)에 현탁 시킨 후 80℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 투명한 오일 119mg을 수득하였다.tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (Intermediate 2-3, 100mg, 0.23mmol), 4-bromo-1H-pyrazole (41mg, 0.27mmol), And K 2 CO 3 (48mg, 0.35mmol) was suspended in DMF (2ml) and then stirred at 80°C for 16 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 to obtain 119 mg of a clear oil.
단계 2: tert-butyl 4-(2,2-difluoro-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(2,2-difluoro-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2,2-difluoropropyl)piperazine-1-carboxylate (195mg, 0.48mmol), (4-(methoxycarbonyl)phenyl)boronic acid (96mg, 0.53mmol), Pd(PPh3)4 (12mg, 0.01mmol), 및 Na2CO3 (155mg, 1.3mmol)를 1,4-dioxane (4ml)와 H2O (1ml)에 현탁 시킨 후 microwave 150℃에서 15분 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (15% EtOAc/Hexane)하여 투명한 오일 117mg (53%)를 수득하였다.tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2,2-difluoropropyl)piperazine-1-carboxylate (195mg, 0.48mmol), (4-(methoxycarbonyl)phenyl)boronic acid (96mg, 0.53mmol), Pd(PPh 3 ) 4 (12mg, 0.01mmol), and Na 2 CO 3 (155mg, 1.3mmol) suspended in 1,4-dioxane (4ml) and H 2 O (1ml) After stirring at 150 ℃ in the microwave for 15 minutes. 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 (15% EtOAc/Hexane) to give 117 mg (53%) of a clear oil.
단계 3: 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2-difluoropropyl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 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), 및 lithium hydroxide monohydrate (63mg, 1.5mmol)를 THF (1.2ml)와 H2O (1.2ml)에 현탁 시킨 후 50℃에서 17시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (10ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 투명한 오일 107mg (95%)를 수득하였다. 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℃ 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.
단계 4: tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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
4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2-difluoropropyl)-1H-pyrazol-4-yl)benzoic acid (50mg, 0.11mmol), EDCI (42mg, 0.22mmol), 및 HOBt (18mg, 0.13mmol)를 DMF (1.1ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 25mg, 0.11mmol), 및 DIPEA (0.05ml, 0.33mmol)를 가한 후 상온에서 19시간 동안 교반 하였다. 반응물에 증류수 (2.0ml)를 가한 뒤 EtOAc (3.0ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (7% MeOH/DCM)하여 흰색 고체 14.4mg (20%)을 수득하였다.4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,2-difluoropropyl)-1H-pyrazol-4-yl)benzoic acid (50mg, 0.11mmol), EDCI (42mg , 0.22mmol), and HOBt (18mg, 0.13mmol) were suspended in DMF (1.1ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 25mg, 0.11mmol), and DIPEA (0.05ml, 0.33 mmol) was added and stirred at room temperature for 19 hours. After adding distilled water (2.0ml) to the reaction mixture, the mixture was extracted with EtOAc (3.0ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (7% MeOH/DCM) to give 14.4 mg (20%) of a white solid.
단계 5: (S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (14mg, 0.02mmol)를 DCM (0.2ml)에 현탁 시킨 후 4M HCl in dioxane (0.05ml, 0.2mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 17mg (quant.)를 수득하였다.tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5 After -yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (14mg, 0.02mmol) was suspended in DCM (0.2ml), 4M HCl in dioxane (0.05ml, 0.2mmol) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 17 mg (quant.) of a white solid.
단계 6: 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)benzamide의 합성Step 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
(S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (17mg, 0.02mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 6mg, 0.02mmol), 및 DIPEA (0.02ml, 0.1mmol)를 DMSO (0.2ml)에 현탁 시킨 후 100℃에서 17시간 동안 교반 하였다. 반응액에 증류수 (10ml)를 가한 뒤 EtOAc (10ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 7.8mg (48%)를 수득하였다.(S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-((2-methylpyrrolidin-1- yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (17mg, 0.02mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione ( WO2015/160845, 6mg, 0.02mmol), and DIPEA (0.02ml, 0.1mmol) were suspended in DMSO (0.2ml) and then stirred at 100°C for 17 hours. After adding distilled water (10ml) to the reaction solution, extraction was performed with EtOAc (10ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH/DCM) to give 7.8 mg (48%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000095
Figure PCTKR2022013646-appb-img-000095
tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (중간체 2-3) 대신 tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1-carboxylate (중간체 2-1)을 사용하여 실시예 47의 합성법과 동일한 방법으로 실시예 48을 합성하였다. tert-butyl 4-((1-(chloromethyl)cyclopropyl)methyl)piperazine-1 instead of tert-butyl 4-(2,2-difluoro-3-(tosyloxy)propyl)piperazine-1-carboxylate (intermediate 2-3) Example 48 was synthesized in the same manner as in Example 47 using -carboxylate (intermediate 2-1).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000096
Figure PCTKR2022013646-appb-img-000096
단계 1: 4-bromo-1-(oxiran-2-ylmethyl)-1H-pyrazole의 합성Step 1: Synthesis of 4-bromo-1-(oxiran-2-ylmethyl)-1H-pyrazole
2-(chloromethyl)oxirane (2.4ml, 30mmol), 및 4-bromo-1H-pyrazole (300mg, 2.04mmol)의 혼합물에 0℃에서 TEA (0.57ml, 4.08mmol)를 천천히 첨가하였다. 이후, 70℃에서 3시간 동안 교반 하였다. 반응액에 증류수 (30ml)를 가한 뒤 DCM (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (20% EtOAc/Hexane)하여 투명한 오일 321mg (78%)를 수득하였다.TEA (0.57ml, 4.08mmol) was slowly added to a mixture of 2-(chloromethyl)oxirane (2.4ml, 30mmol) and 4-bromo-1H-pyrazole (300mg, 2.04mmol) at 0°C. Thereafter, the mixture was stirred at 70° C. for 3 hours. After adding distilled water (30ml) to the reaction mixture, the mixture was extracted with DCM (30ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (20% EtOAc/Hexane) to give 321 mg (78%) of a clear oil.
단계 2: tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2-hydroxypropyl)piperazine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2-hydroxypropyl)piperazine-1-carboxylate
4-bromo-1-(oxiran-2-ylmethyl)-1H-pyrazole (315mg, 1.55mmol), 및 tert-butyl piperazine-1-carboxylate (318mg, 1.71mmol)를 EtOH (7.7ml)에 현탁 시킨 후 80℃에서 15시간 동안 교반 하였다. 반응액을 농축하여 얻어진 잔사를 MPLC (67% EtOAc/Hexane)하여 투명한 오일 468mg (76%)를 수득하였다.4-bromo-1-(oxiran-2-ylmethyl)-1H-pyrazole (315mg, 1.55mmol), and tert-butyl piperazine-1-carboxylate (318mg, 1.71mmol) were suspended in EtOH (7.7ml) and then 80 It was stirred for 15 hours at °C. The residue obtained by concentrating the reaction solution was subjected to MPLC (67% EtOAc/Hexane) to obtain 468mg (76%) of a clear oil.
단계 3: tert-butyl 4-(2-hydroxy-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(2-hydroxy-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate
tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2-hydroxypropyl)piperazine-1-carboxylate (150mg, 0.39mmol), (4-(methoxycarbonyl)phenyl)boronic acid (70mg, 0.39mmol), Xantphos (70mg, 0.12mmol), Pd(dppf)Cl2 (98mg, 0.12mmol), 및 Cs2CO3 (193mg, 0.59mmol)를 1,4-dioxane (3ml)와 H2O (0.6ml)에 현탁 시킨 후 90℃에서 1시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 갈색 고체 128mg (74%)를 수득하였다.tert-butyl 4-(3-(4-bromo-1H-pyrazol-1-yl)-2-hydroxypropyl)piperazine-1-carboxylate (150mg, 0.39mmol), (4-(methoxycarbonyl)phenyl)boronic acid (70mg , 0.39 mmol), Xantphos (70 mg, 0.12 mmol), Pd(dppf)Cl 2 (98 mg, 0.12 mmol), and Cs 2 CO 3 (193 mg, 0.59 mmol) were mixed with 1,4-dioxane (3 ml) and H 2 O. (0.6ml) and stirred at 90℃ for 1 hour. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (5% MeOH/DCM) to obtain 128 mg (74%) of a brown solid.
단계 4: 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-hydroxypropyl)-1H-pyrazol-4-yl)benzoic acid의 합성Step 4: Synthesis of 4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-hydroxypropyl)-1H-pyrazol-4-yl)benzoic acid
tert-butyl 4-(2-hydroxy-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (126mg, 0.28mmol), 및 lithium hydroxide monohydrate (118mg, 2.8mmol)를 THF (1.4ml)와 H2O (1.4ml)에 현탁 시킨 후 50℃에서 17시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 갈색 고체 57mg (48%)를 수득하였다. tert-butyl 4-(2-hydroxy-3-(4-(4-(methoxycarbonyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (126mg, 0.28mmol), and lithium hydroxide monohydrate (118mg, 2.8mmol) was suspended in THF (1.4ml) and H 2 O (1.4ml) and stirred at 50℃ for 17 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 6, followed by extraction with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 57 mg (48%) of a brown solid.
단계 5: tert-butyl 4-(2-hydroxy-3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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
4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-hydroxypropyl)-1H-pyrazol-4-yl)benzoic acid (55mg, 0.128mmol), EDCI (30mg, 0.15mmol), 및 HOBt (21mg, 0.15mmol)를 DMF (1.26ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 30mg, 0.128mmol), 및 DIPEA (0.07ml, 0.38mmol)를 가한 후 상온에서 21시간 동안 교반 하였다. 반응물에 증류수 (2.0ml)를 가한 뒤 EtOAc (3.0ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 갈색 고체 30mg (38%)을 수득하였다.4-(1-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-hydroxypropyl)-1H-pyrazol-4-yl)benzoic acid (55 mg, 0.128 mmol), EDCI (30 mg, 0.15 mmol), and HOBt (21mg, 0.15mmol) were suspended in DMF (1.26ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 30mg, 0.128mmol), and DIPEA (0.07ml, 0.38 mmol) was added and stirred at room temperature for 21 hours. After adding distilled water (2.0ml) to the reaction mixture, the mixture was extracted with EtOAc (3.0ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 30 mg (38%) of a brown solid.
단계 6: 4-(1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl 4-(2-hydroxy-3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (30mg, 0.05mmol)를 DCM (0.5ml)에 현탁 시킨 후 4M HCl in dioxane (0.12ml)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 갈색 고체 27mg (99%)를 수득하였다.tert-butyl 4-(2-hydroxy-3-(4-(4-((2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl )carbamoyl)phenyl)-1H-pyrazol-1-yl)propyl)piperazine-1-carboxylate (30mg, 0.05mmol) was suspended in DCM (0.5ml), 4M HCl in dioxane (0.12ml) was added, and 1 Stir for an hour. The reaction solution was concentrated to obtain 27 mg (99%) of a brown solid.
단계 7: 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)benzamide의 합성Step 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
4-(1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (25mg, 0.043mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 12mg, 0.043mmol), 및 DIPEA (0.038ml, 0.22mmol)를 DMSO (0.43ml)에 현탁 시킨 후 100℃에서 19시간 동안 교반 하였다. 반응액에 증류수 (1.0ml)를 가한 뒤 EtOAc (1.0ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 3.6mg (10%)를 수득하였다.4-(1-(2-hydroxy-3-(piperazin-1-yl)propyl)-1H-pyrazol-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl) methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (25mg, 0.043mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/ 160845, 12mg, 0.043mmol), and DIPEA (0.038ml, 0.22mmol) were suspended in DMSO (0.43ml) and then stirred at 100°C for 19 hours. After adding distilled water (1.0ml) to the reaction mixture, extraction was performed with EtOAc (1.0ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 3.6 mg (10%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000097
Figure PCTKR2022013646-appb-img-000097
단계 1: (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 1: Synthesis of (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 1g, 4.3mmol), EDCI (1.6g, 8.6mmol), 및 HOBt (1.3g, 8.6mmol)를 DMF (10ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 4-ethynylbenzoic acid (940mg, 6.45mmol), 및 DIPEA (2.25ml, 13mmol)를 가한 후 상온에서 16시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 연한 갈색 고체 780mg (52%)을 수득하였다.(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (Intermediate 1-1, 1g, 4.3mmol), EDCI (1.6g, 8.6mmol) , and HOBt (1.3 g, 8.6 mmol) were suspended in DMF (10 ml) and stirred at room temperature for 10 minutes. After adding 4-ethynylbenzoic acid (940mg, 6.45mmol) and DIPEA (2.25ml, 13mmol) to the reaction mixture, the mixture was stirred at room temperature for 16 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (10% MeOH/DCM) to give 780 mg (52%) of a pale brown solid.
단계 2: 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)benzamide의 합성Step 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
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38, 60mg, 0.15mmol), (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide (56mg, 0.15mmol), CuSO4·5H2O (0.4mg, 1 mol%), 및 sodium ascorbate (3mg, 10 mol %)를 t-BuOH : water = 1 : 1 (2ml)에 현탁 시킨 후 상온에서 24시간 동안 교반 하였다. 반응물을 감압 농축하여 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 연한 황색 고체 13mg (11%)을 수득하였다.4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-38, 60mg, 0.15mmol), (S)-4-ethynyl -N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide (56mg, 0.15mmol), CuSO 4 5H 2 O (0.4mg, 1 mol%), and sodium ascorbate (3mg, 10 mol%) were suspended in t-BuOH : water = 1 : 1 (2ml) and stirred at room temperature for 24 hours. The residue obtained by concentrating the reaction product under reduced pressure was subjected to MPLC (10% MeOH/DCM) to obtain 13 mg (11%) of a pale yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000098
Figure PCTKR2022013646-appb-img-000098
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38) 대신 4-((6-azidohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-36)를 사용하여 실시예 50의 합성법과 동일한 방법으로 실시예 51을 합성하였다. 4-((6-azidohexyl)amino)-2 instead of 4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-38) 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).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000099
Figure PCTKR2022013646-appb-img-000099
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38) 대신 5-((6-azidohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-37)를 사용하여 실시예 50의 합성법과 동일한 방법으로 실시예 52를 합성하였다. 5-((6-azidohexyl)amino)-2 instead of 4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-38) 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).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000100
Figure PCTKR2022013646-appb-img-000100
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38) 대신 4-((10-azidodecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-35)를 사용하여 실시예 50의 합성법과 동일한 방법으로 실시예 53을 합성하였다. 4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate 3-38) instead of 4-((10-azidodecyl)amino)-2 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).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000101
Figure PCTKR2022013646-appb-img-000101
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38) 대신 N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (중간체 3-39)를 사용하여 실시예 50의 합성법과 동일한 방법으로 실시예 54를 합성하였다. N-(2-(2-(2-( Using 2-azidoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (intermediate 3-39) Thus, Example 54 was synthesized in the same manner as in Example 50.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000102
Figure PCTKR2022013646-appb-img-000102
4-((5-azidopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (중간체 3-38) 대신 N-(10-azidodecyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (중간체 3-40)를 사용하여 실시예 50의 합성법과 동일한 방법으로 실시예 55를 합성하였다. N-(10-azidodecyl)-2-(( Example 55 was synthesized in the same manner as Example 50 using 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (Intermediate 3-40) did
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000103
Figure PCTKR2022013646-appb-img-000103
단계 1: 4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 1: Synthesis of 4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4, 148mg, 0.68mmol), 4-ethynylbenzoic acid (150mg, 1.03mmol), EDC (262mg, 1.37mmol), 및 HOBt (111mg, 0.82mmol)를 DMF (7ml)에 녹인 후 DIPEA (0.36ml, 2.05mmol)를 가하고 상온에서 15시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% DCM/MeOH)하여 노란색 고체 142 mg (60%)을 수득하였다.2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4, 148mg, 0.68mmol), 4-ethynylbenzoic acid (150mg, 1.03mmol), EDC (262mg, 1.37mmol ), and HOBt (111mg, 0.82mmol) were dissolved in DMF (7ml), DIPEA (0.36ml, 2.05mmol) was added, and the mixture was stirred at room temperature for 15 hours. After adding EtOAc (40ml) to the reaction solution, it was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% DCM/MeOH) to give 142 mg (60%) of a yellow solid.
단계 2: tert-butyl 4-(2-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 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
4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide (44mg, 0.13mmol), 및 tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) (42mg, 0.17mmol)를 DMF : H2O = 1 : 1 (1.3ml)에 녹였다. 이후, 각각 0.1ml의 물에 녹인 copper(II) sulfate pentahydrate (3.2mg, 0.013mmol), 및 sodium L-ascorbate (26mg, 0.13mmol)를 가하고 40℃에서 16시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (7% DCM/MeOH)하여 분홍색 고체 16mg (21%)을 수득하였다.4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide (44 mg, 0.13 mmol), and tert-butyl 4-(2-azidoethyl) piperidine- 1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) (42mg, 0.17mmol) was dissolved in DMF:H 2 O = 1:1 (1.3ml). Thereafter, copper(II) sulfate pentahydrate (3.2mg, 0.013mmol) and sodium L-ascorbate (26mg, 0.13mmol) dissolved in 0.1ml of water were added and stirred at 40°C for 16 hours. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (7% DCM/MeOH) to obtain 16 mg (21%) of a pink solid.
단계 3: 4-(1-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl 4-(2-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)ethyl)piperidine-1-carboxylate (16mg, 0.03mmol)를 DCM (0.3ml)에 녹인 후 4M HCl in dioxane (0.10ml)를 가하고 상온에서 90분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 18 mg (quant.)을 수득하였다.tert-butyl 4-(2-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3 After dissolving -triazol-1-yl)ethyl)piperidine-1-carboxylate (16mg, 0.03mmol) in DCM (0.3ml), 4M HCl in dioxane (0.10ml) was added and stirred at room temperature for 90 minutes. The reaction solution was concentrated to obtain 18 mg (quant.) of a white solid.
단계 4: 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)benzamide의 합성Step 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
4-(1-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (18mg, 0.03mmol), 및 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036, 9mg, 0.03mmol)을 DMSO (0.3ml)에 녹인 후 DIPEA (0.03ml, 0.17mmol)를 가하고 100℃에서 18시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 H2O (20ml x 4)와 brine (20ml)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (7% DCM/MeOH(10% NH3))하여 노란색 고체 3.4mg (13%)을 수득하였다.4-(1-(2-(piperidin-4-yl)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[ d]imidazol-5-yl)benzamide hydrochloride (18mg, 0.03mmol), and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036, 9mg, 0.03mmol ) was dissolved in DMSO (0.3ml), DIPEA (0.03ml, 0.17mmol) was added, and the mixture was stirred at 100°C for 18 hours. After adding EtOAc (40ml) to the reaction solution, it was washed with H 2 O (20ml x 4) and brine (20ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (7% DCM/MeOH (10% NH 3 )) to give 3.4 mg (13%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000104
Figure PCTKR2022013646-appb-img-000104
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1)을 사용하고 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) 대신 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845)를 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 57을 합성하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) Use [d]imidazol-5-amine (intermediate 1-1) and replace 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) Example 57 was synthesized in the same manner as in Example 56 using ,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione (WO2015/160845).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000105
Figure PCTKR2022013646-appb-img-000105
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1)을 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 58을 합성하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) Example 58 was synthesized in the same manner as in Example 56 using [d]imidazol-5-amine (Intermediate 1-1).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000106
Figure PCTKR2022013646-appb-img-000106
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1)을 사용하고 tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 대신 tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167)를 사용하고 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) 대신 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845)를 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 59를 합성하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) [d]imidazol-5-amine (intermediate 1-1) was used and tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) was used instead of tert-butyl Use 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167) and use 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) instead of 2 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).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000107
Figure PCTKR2022013646-appb-img-000107
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1)을 사용하고 tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 대신 tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167)를 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 60을 합성하였다. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) [d]imidazol-5-amine (intermediate 1-1) was used and tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) was used instead of tert-butyl Example 60 was synthesized in the same manner as in Example 56 using 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000108
Figure PCTKR2022013646-appb-img-000108
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)을 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 61을 합성하였다.(3S,5S)-1-((5-amino-1H-benzo[d]imidazol- Example 61 was synthesized in the same manner as in Example 56 using 2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000109
Figure PCTKR2022013646-appb-img-000109
tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 대신 tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167)를 사용하고 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) 대신 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845)를 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 62를 합성하였다. Tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167) instead of tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) instead of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline- Example 62 was synthesized in the same manner as in Example 56 using 1,3-dione (WO2015/160845).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000110
Figure PCTKR2022013646-appb-img-000110
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)을 사용하고 tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 대신 tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167)를 사용하고 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) 대신 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845)를 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 63을 합성하였다. (3S,5S)-1-((5-amino-1H-benzo[d]imidazol- 2-yl)methyl)-5-methylpyrrolidin-3-ol (intermediate 1-2) was used and tert-butyl 4-(2-azidoethyl) piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728- 741) instead of tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione ( 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
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000111
Figure PCTKR2022013646-appb-img-000111
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-amine (중간체 1-5)을 사용하고 tert-butyl 4-(2-azidoethyl)piperidine-1-carboxylate (Bioconjugate Chem. 2009, 20, 4, 728-741) 대신 tert-butyl 4-(3-azidopropyl)piperidine-1-carboxylate (WO2008/050167)을 사용하고 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) 대신 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845)을 사용하여 실시예 56의 합성법과 동일한 방법으로 실시예 64를 합성하였다.(S)-2-((2-methylpyrrolidin-1-yl)methyl)benzo[d] instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) oxazol-5-amine (intermediate 1-5) was used and tert-butyl 4-( Use 3-azidopropyl)piperidine-1-carboxylate (WO2008/050167) and replace 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) Example 64 was synthesized in the same manner as in Example 56 using ,6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1,3-dione (WO2015/160845).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000112
Figure PCTKR2022013646-appb-img-000112
단계 1: tert-butyl 4-(3-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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
4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide (54mg, 0.16mmol), 및 tert-butyl 4-(3-azidopropyl)piperazine-1-carboxylate (WO2007/092095, 46mg, 0.17mmol)를 DMF : H2O = 1 : 1 (1.6ml)에 녹였다. 이후 각각 0.1ml의 물에 녹인 copper(II) sulfate pentahydrate (2mg, 0.008mmol), 및 sodium L-ascorbate (16mg, 0.08mmol)를 가하고 40℃에서 16시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (10% DCM/MeOH)하여 분홍색 고체 50mg (52%)을 수득하였다.4-ethynyl-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide (54mg, 0.16mmol), and tert-butyl 4-(3-azidopropyl)piperazine- 1-carboxylate (WO2007/092095, 46mg, 0.17mmol) was dissolved in DMF:H 2 O = 1:1 (1.6ml). Then, copper(II) sulfate pentahydrate (2mg, 0.008mmol) and sodium L-ascorbate (16mg, 0.08mmol) dissolved in 0.1ml of water were added and stirred at 40℃ for 16 hours. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (10% DCM/MeOH) to obtain 50 mg (52%) of a pink solid.
단계 2: 4-(1-(3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl 4-(3-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate (46mg, 0.07mmol)를 DCM (0.7ml)에 녹인 후 4M HCl in dioxane (0.28ml)를 가하고 상온에서 90분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 55mg (quant.)을 수득하였다.tert-butyl 4-(3-(4-(4-((2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3 After dissolving -triazol-1-yl)propyl)piperazine-1-carboxylate (46mg, 0.07mmol) in DCM (0.7ml), 4M HCl in dioxane (0.28ml) was added and stirred at room temperature for 90 minutes. The reaction solution was concentrated to obtain 55 mg (quant.) of a white solid.
단계 3: 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)benzamide의 합성Step 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
4-(1-(3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (55mg, 0.10mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 28mg, 0.10mmol)을 DMSO (1.0ml)에 녹인 후 DIPEA (0.09ml, 0.50mmol)를 가하고 100℃에서 18시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4)와 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 17.5mg (23%)을 수득하였다.4-(1-(3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[ d]imidazol-5-yl)benzamide hydrochloride (55mg, 0.10mmol), and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 28mg, 0.10mmol ) was dissolved in DMSO (1.0ml), DIPEA (0.09ml, 0.50mmol) was added, and the mixture was stirred at 100°C for 18 hours. After adding EtOAc (40ml) to the reaction solution, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 17.5 mg (23%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000113
Figure PCTKR2022013646-appb-img-000113
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1)을 사용하여 실시예 56 및 실시예 65의 합성법을 이용한 방법으로 실시예 66을 합성하였다.(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo instead of 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-4) [d]imidazol-5-amine (Intermediate 1-1) was used to synthesize Example 66 in the same manner as in Examples 56 and 65.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000114
Figure PCTKR2022013646-appb-img-000114
2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)을 사용하여 실시예 56 및 실시예 65의 합성법을 이용한 방법으로 실시예 67을 합성하였다.(3S,5S)-1-((5-amino-1H-benzo[d]imidazol- Example 67 was synthesized by the method using the synthesis methods of Examples 56 and 65 using 2-yl) methyl) -5-methylpyrrolidin-3-ol (intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000115
Figure PCTKR2022013646-appb-img-000115
단계 1: (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 1: Synthesis of (S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 151mg, 0.66mmol), 4-ethnylbenzoic acid (144mg, 0.98mmol), EDC (251mg, 1.31mmol), 및 HOBt (106mg, 0.79mmol)를 DMF (6.6ml)에 녹인 후 DIPEA (0.34ml, 1.97mmol)를 가하고 상온에서 15시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4)와 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% DCM/MeOH)하여 갈색 고체 152mg (65%)을 수득하였다.(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 151mg, 0.66mmol), 4-ethnylbenzoic acid (144mg, 0.98 mmol), EDC (251mg, 1.31mmol), and HOBt (106mg, 0.79mmol) were dissolved in DMF (6.6ml), DIPEA (0.34ml, 1.97mmol) was added, and the mixture was stirred at room temperature for 15 hours. After adding EtOAc (40ml) to the reaction solution, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% DCM/MeOH) to give 152 mg (65%) of a brown solid.
단계 2: tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate의 합성Step 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
(S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide (43mg, 0.12mmol), 및 tert-butyl 4-(3-azido-2,2-difluoropropyl)piperazine-1-carboxylate (중간체 2-4, 55mg, 0.18mmol)를 DMF : H2O = 1 : 1 (1.2ml)에 녹였다. 이후, 각각 0.1ml의 물에 녹인 copper(II) sulfate pentahydrate (3mg, 0.01mmol), 및 sodium L-ascorbate (24mg, 0.12mmol)를 가하고 40℃에서 16시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (7% DCM/MeOH)하여 분홍색 고체 56mg (71%)을 수득하였다.(S)-4-ethynyl-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide (43mg, 0.12mmol), and tert-butyl 4-(3-azido-2,2-difluoropropyl)piperazine-1-carboxylate (intermediate 2-4, 55 mg, 0.18 mmol) was dissolved in DMF:H 2 O = 1:1 (1.2 ml). Subsequently, copper(II) sulfate pentahydrate (3mg, 0.01mmol) and sodium L-ascorbate (24mg, 0.12mmol) dissolved in 0.1ml of water were added and stirred at 40°C for 16 hours. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (7% DCM/MeOH) to obtain 56 mg (71%) of a pink solid.
단계 3: (S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate (52mg, 0.08mmol)를 DCM (0.8ml)에 녹인 후 4M HCl in dioxane (0.3ml)를 가하고 상온에서 90분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 59mg (quant.)을 수득하였다.tert-butyl (S)-4-(2,2-difluoro-3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5 After dissolving -yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)propyl)piperazine-1-carboxylate (52mg, 0.08mmol) in DCM (0.8ml), 4M HCl in dioxane (0.3 ml) was added and stirred at room temperature for 90 minutes. The reaction solution was concentrated to obtain 59 mg (quant.) of a white solid.
단계 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-yl)benzamide의 합성Step 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
(S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (47mg, 0.08mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 22mg, 0.08mmol)을 DMSO (0.8ml)에 녹인 후 DIPEA (0.07ml, 0.39mmol)를 가하고 100℃에서 18시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4)와 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 30mg (47%)을 수득하였다.(S)-4-(1-(2,2-difluoro-3-(piperazin-1-yl)propyl)-1H-1,2,3-triazol-4-yl)-N-(2-(( 2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (47mg, 0.08mmol), and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline After dissolving -1,3-dione (WO2015/160845, 22mg, 0.08mmol) in DMSO (0.8ml), DIPEA (0.07ml, 0.39mmol) was added and stirred at 100℃ for 18 hours. After adding EtOAc (40ml) to the reaction solution, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 30 mg (47%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000116
Figure PCTKR2022013646-appb-img-000116
tert-butyl 4-(3-azido-2,2-difluoropropyl)piperazine-1-carboxylate (중간체 2-4) 대신 tert-butyl 4-((1-(azidomethyl)cyclopropyl)methyl)piperazine-1-carboxylate (중간체 2-2)를 사용하여 실시예 68의 합성법과 동일한 방법으로 실시예 69를 합성하였다.tert-butyl 4-((1-(azidomethyl)cyclopropyl)methyl)piperazine-1-carboxylate ( Example 69 was synthesized in the same manner as in Example 68 using Intermediate 2-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000117
Figure PCTKR2022013646-appb-img-000117
단계 1: tert-butyl 4-(3-(3-bromo-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate의 합성 Step 1: Synthesis of tert-butyl 4-(3-(3-bromo-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
3-bromo-1H-1,2,4-triazole (200mg, 1.35mmol), tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458, 537mg, 1.35mmol), 및 K2CO3 (280mg, 2.03mmol)를 DMF (4.5ml)에 현탁 시킨 후 80℃에서 40분 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (33% EtOAc/Hexane)하여 연한 노란색 오일 197mg (39%)를 수득하였다.3-bromo-1H-1,2,4-triazole (200mg, 1.35mmol), tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458, 537mg, 1.35mmol), and K 2 CO 3 (280mg, 2.03mmol) was suspended in DMF (4.5ml) and stirred at 80°C for 40 minutes. After adding distilled water (20ml) to the reaction solution, extraction was performed 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 (33% EtOAc/Hexane) to give 197 mg (39%) of a pale yellow oil.
단계 2: tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate의 합성 Step 2: Synthesis of tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate
tert-butyl 4-(3-(3-bromo-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (150mg, 0.4mmol), (4-(methoxycarbonyl)phenyl)boronic acid (73mg, 0.4mmol), Xantphos (70mg, 0.12mmol), Pd(dppf)Cl2 (98mg, 0.12mmol), 및 Cs2CO3 (196mg, 0.6mmol)를 1,4-dioxane (6.7ml)와 H2O (1.3ml)에 현탁 시킨 후 90℃에서 2시간 동안 교반 하였다. 반응물을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 갈색 고체 87mg (51%)를 수득하였다.tert-butyl 4-(3-(3-bromo-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (150mg, 0.4mmol), (4-(methoxycarbonyl)phenyl)boronic acid (73mg, 0.4mmol), Xantphos (70mg, 0.12mmol), Pd(dppf)Cl 2 (98mg, 0.12mmol), and Cs 2 CO 3 (196mg, 0.6mmol) were mixed with 1,4-dioxane (6.7ml). and H 2 O (1.3ml) and then stirred at 90 ℃ for 2 hours. The reaction product was filtered and concentrated under reduced pressure, and the resulting residue was subjected to MPLC (50% EtOAc/Hexane) to obtain 87 mg (51%) of a brown solid.
단계 3: 4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzoic acid의 합성Step 3: Synthesis of 4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzoic acid
tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (85mg, 0.2mmol), 및 lithium hydroxide monohydrate (42mg, 1mmol)를 THF (1ml)와 H2O (1ml)에 현탁 시킨 후 상온에서 17시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 4로 조정한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 갈색 고체 79mg (96%)를 수득하였다.tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (85mg, 0.2mmol), and lithium Hydroxide monohydrate (42mg, 1mmol) was suspended in THF (1ml) and H 2 O (1ml) 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 x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 79 mg (96%) of a brown solid.
단계 4: tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate의 합성 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
4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzoic acid (77mg, 0.186mmol), 및 HATU (85mg, 0.23mmol)를 DMF (1.25ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 43mg, 0.186mmol), 및 DIPEA (0.07ml, 0.37mmol)를 가한 후 상온에서 6시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% MeOH/DCM)하여 갈색 고체 67mg (58%)을 수득하였다.4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzoic acid (77mg, 0.186mmol), and HATU (85mg, 0.23mmol) was suspended in DMF (1.25ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 43mg, 0.186mmol), and DIPEA (0.07ml, 0.37 mmol) was added and stirred at room temperature for 6 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% MeOH/DCM) to give 67 mg (58%) of a brown solid.
단계 5: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (65mg, 0.1mmol)를 DCM (1ml)에 현탁 시킨 후 4M HCl in dioxane (0.16ml)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 갈색 고체 55mg (98%)를 수득하였다.tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (65mg, 0.1mmol) was suspended in DCM (1ml), and 4M HCl in dioxane (0.16ml) was added thereto at room temperature. Stir for 2 hours. The reaction solution was concentrated to obtain 55 mg (98%) of a brown solid.
단계 6: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)benzamide hydrochloride (53mg, 0.09mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 26mg, 0.09mmol), 및 DIPEA (0.08ml, 0.47mmol)를 DMSO (0.9ml)에 현탁 시킨 후 100℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% MeOH/DCM)하여 노란색 고체 23.7mg (33%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperidin-4-yl) propyl)-1H-1,2,4-triazol-3-yl)benzamide hydrochloride (53mg, 0.09mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione ( WO2015/160845, 26mg, 0.09mmol), and DIPEA (0.08ml, 0.47mmol) were suspended in DMSO (0.9ml) and then stirred at 100°C for 16 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (20ml x 2), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% MeOH/DCM) to give 23.7 mg (33%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000118
Figure PCTKR2022013646-appb-img-000118
Figure PCTKR2022013646-appb-img-000119
Figure PCTKR2022013646-appb-img-000119
단계 1: methyl 4-(hydrazinecarbonyl)benzoate의 합성 Step 1: Synthesis of methyl 4-(hydrazinecarbonyl)benzoate
dimethyl terephthalate (1g, 5.15mmol), 및 N2H4-H2O (181mg, 5.66mmol)를 EtOH (10.3ml)에 현탁 시킨 후 90℃에서 16시간 동안 교반 하였다. 반응액을 감압 농축하여 흰색 고체 750mg을 수득하였다.After dimethyl terephthalate (1g, 5.15mmol) and N 2 H 4 -H 2 O (181mg, 5.66mmol) were suspended in EtOH (10.3ml), the mixture was stirred at 90℃ for 16 hours. The reaction solution was concentrated under reduced pressure to obtain 750 mg of a white solid.
단계 2: methyl 4-(2-(1-iminoethyl)hydrazine-1-carbonyl)benzoate의 합성 Step 2: Synthesis of methyl 4-(2-(1-iminoethyl)hydrazine-1-carbonyl)benzoate
ethyl acetimidate hydrochloride (706mg, 5.72mmol), 및 20% NaOEt in EtOH (2.21ml, 5.72mmol)를 EtOH (8.5ml)에 현탁 시킨 후 상온에서 20분 동안 교반 하였다. 반응액을 여과한 후 여과액에 methyl 4-(hydrazinecarbonyl)benzoate (740mg, 3.81mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 감압 농축하여 흰색 고체 660mg을 수득하였다.Ethyl acetimidate hydrochloride (706mg, 5.72mmol) and 20% NaOEt in EtOH (2.21ml, 5.72mmol) were suspended in EtOH (8.5ml) and stirred at room temperature for 20 minutes. After filtering the reaction solution, methyl 4-(hydrazinecarbonyl)benzoate (740mg, 3.81mmol) was added to the filtrate and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 660 mg of a white solid.
단계 3: methyl 4-(5-methyl-1H-1,2,4-triazol-3-yl)benzoate의 합성Step 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)를 180℃에서 40분 동안 교반 하였다. 반응액을 감압 농축하여 얻어진 잔사를 MPLC (70% EtOAc/Hexane)하여 흰색 고체 283mg (43%)를 수득하였다.Methyl 4-(2-(1-iminoethyl)hydrazine-1-carbonyl)benzoate (660mg, 3.04mmol) was stirred at 180℃ 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.
단계 4: tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate의 합성 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
methyl 4-(5-methyl-1H-1,2,4-triazol-3-yl)benzoate (283mg, 1.3mmol), tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458, 516mg, 1.3mmol), 및 K2CO3 (270mg, 1.95mmol)를 DMF (4.5ml)에 현탁 시킨 후 80℃에서 2시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 연한 노란색 오일 376mg (65%)를 수득하였다.methyl 4-(5-methyl-1H-1,2,4-triazol-3-yl)benzoate (283mg, 1.3mmol), tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000 /037458, 516mg, 1.3mmol), and K 2 CO 3 (270mg, 1.95mmol) were suspended in DMF (4.5ml) and then stirred at 80°C for 2 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed 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 (50% EtOAc/Hexane) to give 376 mg (65%) of a pale yellow oil.
단계 5: 4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-5-methyl-1H-1,2,4-triazol-3-yl)benzoic acid의 합성 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), 및 lithium hydroxide monohydrate (178mg, 4.23mmol)를 THF (4.3ml)와 H2O (4.3ml)에 현탁 시킨 후 상온에서 17시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 4로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 348mg (96%)를 수득하였다. 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.
단계 6: tert-butyl (S)-4-(3-(5-methyl-3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate의 합성Step 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
4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-5-methyl-1H-1,2,4-triazol-3-yl)benzoic acid (70mg, 0.164mmol), 및 HATU (46mg, 0.2mmol)를 DMF (1.2ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 46mg, 0.2mmol), 및 DIPEA (0.06ml, 0.33mmol)를 가한 후 상온에서 15시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% MeOH/DCM)하여 갈색 고체 72mg (69%)을 수득하였다.4-(1-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-5-methyl-1H-1,2,4-triazol-3-yl)benzoic acid (70mg, 0.164mmol ), and HATU (46mg, 0.2mmol) were suspended in DMF (1.2ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 46mg, 0.2mmol), and DIPEA (0.06ml, 0.33 mmol) was added and stirred at room temperature for 15 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% MeOH/DCM) to give 72 mg (69%) of a brown solid.
단계 7: (S)-4-(5-methyl-1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride의 합성 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
tert-butyl (S)-4-(3-(5-methyl-3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (70mg, 0.11mmol)를 DCM (1.1ml)에 현탁 시킨 후 4M HCl in dioxane (0.16ml)를 가하고 상온에서 4시간 동안 교반 하였다. 반응액을 농축하여 갈색 고체 63mg (99%)를 수득하였다.tert-butyl (S)-4-(3-(5-methyl-3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl After suspending )carbamoyl)phenyl)-1H-1,2,4-triazol-1-yl)propyl)piperidine-1-carboxylate (70mg, 0.11mmol) in DCM (1.1ml), 4M HCl in dioxane (0.16ml ) was added and stirred at room temperature for 4 hours. The reaction solution was concentrated to obtain 63 mg (99%) of a brown solid.
단계 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)benzamide의 합성 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
(S)-4-(5-methyl-1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (63mg, 0.11mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 31mg, 0.11mmol), 및 DIPEA (0.1ml, 0.55mmol)를 DMSO (1ml)에 현탁 시킨 후 100℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 22.6mg (26%)를 수득하였다.(S)-4-(5-methyl-1-(3-(piperidin-4-yl)propyl)-1H-1,2,4-triazol-3-yl)-N-(2-((2- methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (63mg, 0.11mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1, After suspending 3-dione (WO2015/160845, 31mg, 0.11mmol) and DIPEA (0.1ml, 0.55mmol) in DMSO (1ml), the mixture was stirred at 100°C for 16 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 22.6 mg (26%) of a yellow solid.
실시예 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)nicotinamideExample 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
Figure PCTKR2022013646-appb-img-000120
Figure PCTKR2022013646-appb-img-000120
단계 1: methyl 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinate의 합성 Step 1: Synthesis of methyl 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinate
methyl 6-chloronicotinate (346mg, 2.02mmol), tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (중간체 2-5, 500mg, 1.68mmol), 및 DIPEA (0.74ml, 4.14mmol)를 DMSO (10ml)에 현탁 시킨 후 120℃에서 2시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 연한 갈색 고체 418mg (58%)를 수득하였다.methyl 6-chloronicotinate (346mg, 2.02mmol), tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (intermediate 2-5, 500mg, 1.68mmol), and DIPEA (0.74ml , 4.14mmol) was suspended in DMSO (10ml) and stirred at 120°C for 2 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EtOAc/Hexane) to give 418 mg (58%) of a pale brown solid.
단계 2: 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinic acid의 합성Step 2: Synthesis of 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinic acid
methyl 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinate (410mg, 0.95mmol), 및 lithium hydroxide monohydrate (398mg, 9.5mmol)를 THF (2.5ml)와 H2O (2.5ml)에 현탁 시킨 후 50℃에서 16시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 연한 갈색 고체 368mg (93%)를 수득하였다.methyl 6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinate (410mg, 0.95mmol), and lithium hydroxide monohydrate (398mg, 9.5mmol) After suspension in THF (2.5ml) and H 2 O (2.5ml), the mixture was stirred at 50°C for 16 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 5, followed by extraction with EtOAc (20ml), drying the organic layer over anhydrous sodium sulfate, filtration, and concentration under reduced pressure to obtain 368mg (93%) of a light brown solid.
단계 3: tert-butyl (S)-4-(2-(4-(5-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate의 합성Step 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
6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinic acid (100mg, 0.24mmol), HATU (110mg, 0.15mmol), 및 DIPEA (0.09ml, 0.48mmol)를 DMF (1ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 55mg, 0.24mmol)를 가한 후 상온에서 48시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml x 2)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 연한 갈색 고체 36mg (24%)을 수득하였다.6-(4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)piperazin-1-yl)nicotinic acid (100mg, 0.24mmol), HATU (110mg, 0.15mmol), and DIPEA ( 0.09ml, 0.48mmol) was suspended in DMF (1ml) and stirred at room temperature for 10 minutes. After adding (S) -2-((2-methylpyrrolidin-1-yl)methyl) -1H-benzo[d]imidazol-5-amine (intermediate 1-1, 55mg, 0.24mmol) to the reactant, it was left at room temperature for 48 hours while stirring. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 36 mg (24%) of a pale brown solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-6-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)nicotinamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(2-(4-(5-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (36mg, 0.06mmol)를 DCM (0.57ml)에 현탁 시킨 후 4M HCl in dioxane (0.09ml)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 연한 갈색 고체 31mg (96%)를 수득하였다.tert-butyl (S)-4-(2-(4-(5-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)pyridin After -2-yl)piperazin-1-yl)ethyl)piperidine-1-carboxylate (36mg, 0.06mmol) was suspended in DCM (0.57ml), 4M HCl in dioxane (0.09ml) was added and stirred for 2 hours at room temperature. did The reaction mixture was concentrated to obtain 31 mg (96%) of a pale brown solid.
단계 5: 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)nicotinamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-6-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)nicotinamide hydrochloride (17.5mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 8.3mg, 0.03mmol), 및 DIPEA (0.016ml, 0.09mmol)를 DMSO (0.3ml)에 현탁 시킨 후 100℃에서 15시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 8mg (34%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-6-(4-(2-(piperidin-4-yl) ethyl)piperazin-1-yl)nicotinamide hydrochloride (17.5mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 8.3mg, 0.03 mmol), and DIPEA (0.016ml, 0.09mmol) were suspended in DMSO (0.3ml) and then stirred at 100°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 (10% MeOH/DCM) to give 8 mg (34%) of a yellow solid.
실시예 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)nicotinamideExample 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
Figure PCTKR2022013646-appb-img-000121
Figure PCTKR2022013646-appb-img-000121
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 72의 합성법과 동일한 방법으로 실시예 73을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 73 was synthesized in the same manner as in Example 72 using -dione (WO2010/081036).
실시예 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)nicotinamideExample 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
Figure PCTKR2022013646-appb-img-000122
Figure PCTKR2022013646-appb-img-000122
tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (중간체 2-5) 대신 tert-butyl 4-(3-(piperazin-1-yl)propyl)piperidine-1-carboxylate (중간체 2-6)를 사용하여 실시예 72의 합성법과 동일한 방법으로 실시예 74를 합성하였다. tert-butyl 4-(3-(piperazin-1-yl)propyl)piperidine-1- instead of tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (intermediate 2-5) Example 74 was synthesized in the same manner as in Example 72 using carboxylate (intermediate 2-6).
실시예 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)nicotinamideExample 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
Figure PCTKR2022013646-appb-img-000123
Figure PCTKR2022013646-appb-img-000123
tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (중간체 2-5) 대신 tert-butyl 4-(3-(piperazin-1-yl)propyl)piperidine-1-carboxylate (중간체 2-6)를 사용하고 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 72의 합성법과 동일한 방법으로 실시예 75를 합성하였다. tert-butyl 4-(3-(piperazin-1-yl)propyl)piperidine-1- instead of tert-butyl 4-(2-(piperazin-1-yl)ethyl)piperidine-1-carboxylate (intermediate 2-5) Use carboxylate (intermediate 2-6) and replace 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) with 2-(2,6-dioxopiperidin-3-yl) Example 75 was synthesized in the same manner as in Example 72 using yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000124
Figure PCTKR2022013646-appb-img-000124
Figure PCTKR2022013646-appb-img-000125
Figure PCTKR2022013646-appb-img-000125
단계 1: methyl (E)-4-(N'-hydroxycarbamimidoyl)benzoate의 합성Step 1: Synthesis of methyl (E)-4-(N'-hydroxycarbamimidoyl)benzoate
methyl 4-cyano benzoate (500mg, 3.1mmol), hydroxylamine hydrochloride (216mg, 3.1mmol), 및 NaHCO3 (260mg, 3.1mmol)를 MeOH (6.2ml)에 현탁 시킨 후 60℃에서 2시간 동안 교반 하였다. 반응물을 감압 농축한 후 증류수를 사용하여 고체화하여 흰색 고체 501mg (84%)를 수득하였다.Methyl 4-cyano benzoate (500mg, 3.1mmol), hydroxylamine hydrochloride (216mg, 3.1mmol), and NaHCO 3 (260mg, 3.1mmol) were suspended in MeOH (6.2ml) and stirred at 60℃ for 2 hours. After concentrating the reactant under reduced pressure, it was solidified using distilled water to obtain 501 mg (84%) of a white solid.
단계 2: tert-butyl 4-(4-((4-(methoxycarbonyl)benzimidamido)oxy)-4-oxobutyl)piperidine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(4-((4-(methoxycarbonyl)benzimidamido)oxy)-4-oxobutyl)piperidine-1-carboxylate
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) (48mg, 0.18mmol), methyl (E)-4-(N'-hydroxycarbamimidoyl)benzoate (35mg, 0.18mmol), EDCI (42mg, 0.22mmol), HOBt (30mg, 0.22mmol), 및 DIPEA (0.12ml, 0.66mmol)를 DMF (1.8ml)에 현탁 시킨 후 상온에서 15시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 연한 노란색 오일 148mg을 수득하였다.4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) (48mg, 0.18mmol), methyl (E)-4 After suspending -(N'-hydroxycarbamimidoyl)benzoate (35mg, 0.18mmol), EDCI (42mg, 0.22mmol), HOBt (30mg, 0.22mmol), and DIPEA (0.12ml, 0.66mmol) in DMF (1.8ml) It was stirred for 15 hours at room temperature. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 148mg of a pale yellow oil.
단계 3: tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate
tert-butyl 4-(4-((4-(methoxycarbonyl)benzimidamido)oxy)-4-oxobutyl)piperidine-1-carboxylate (148mg, 1.8mmol), 및 Cs2CO3 (129mg, 0.4mmol)를 THF (1.8ml)에 현탁 시킨 후 50℃에서 1시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 흰색 고체 65mg (84%)를 수득하였다.tert-butyl 4-(4-((4-(methoxycarbonyl)benzimidamido)oxy)-4-oxobutyl)piperidine-1-carboxylate (148 mg, 1.8 mmol), and Cs 2 CO 3 (129 mg, 0.4 mmol) were mixed with THF ( 1.8ml) and then stirred at 50°C for 1 hour. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to give 65 mg (84%) of a white solid.
단계 4: 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzoic acid의 합성Step 4: Synthesis of 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzoic acid
tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate (62mg, 0.15mmol), 및 lithium hydroxide monohydrate (37mg, 0.87mmol)를 THF (0.7ml), H2O (0.7ml)에 현탁 시킨 후 상온에서 18시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 54mg (90%)를 수득하였다.tert-butyl 4-(3-(3-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate (62mg, 0.15mmol), and lithium hydroxide monohydrate (37mg, 0.87mmol) was suspended in THF (0.7ml) and H 2 O (0.7ml) and stirred at room temperature for 18 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 54 mg (90%) of a white solid.
단계 5: tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate의 합성Step 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
4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzoic acid (52mg, 0.12mmol), EDCI (48mg, 0.24mmol), 및 HOBt (21mg, 0.15mmol)를 DMF (1.2ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 28mg, 0.12mmol), 및 DIPEA (0.06ml, 0.37mmol)를 가한 후 상온에서 24시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (7% MeOH/DCM)하여 연한 갈색 고체 37mg (47%)을 수득하였다.4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzoic acid (52mg, 0.12mmol), EDCI (48mg, 0.24mmol) and HOBt (21mg, 0.15mmol) were suspended in DMF (1.2ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 28mg, 0.12mmol), and DIPEA (0.06ml, 0.37 mmol) was added and stirred at room temperature for 24 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (7% MeOH/DCM) to give 37 mg (47%) of a pale brown solid.
단계 6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate (35mg, 0.05mmol)를 DCM (0.56ml)에 현탁 시킨 후 4M HCl in dioxane (0.14ml)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 연한 갈색 고체 31mg (99%)를 수득하였다.tert-butyl (S)-4-(3-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1,2,4-oxadiazol-5-yl)propyl)piperidine-1-carboxylate (35mg, 0.05mmol) was suspended in DCM (0.56ml), 4M HCl in dioxane (0.14ml) was added, and 1 Stir for an hour. The reaction mixture was concentrated to obtain 31 mg (99%) of a pale brown solid.
단계 7: 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)benzamide의 합성 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl)propyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride (29mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 14mg, 0.05mmol), 및 DIPEA (0.05ml, 0.26mmol)를 DMSO (0.5ml)에 현탁 시킨 후 100℃에서 17시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 26mg (64%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl) propyl)-1,2,4-oxadiazol-3-yl)benzamide hydrochloride (29mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/ 160845, 14mg, 0.05mmol), and DIPEA (0.05ml, 0.26mmol) were suspended in DMSO (0.5ml) and then stirred at 100°C for 17 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 26 mg (64%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000126
Figure PCTKR2022013646-appb-img-000126
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 76의 합성법과 동일한 방법으로 실시예 77을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 77 was synthesized in the same manner as in Example 76 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000127
Figure PCTKR2022013646-appb-img-000127
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)을 사용하여 실시예 76의 합성법과 동일한 방법으로 실시예 78을 합성하였다.(3S,5S)-1-((5-amino Example 78 was synthesized in the same manner as in Example 76 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000128
Figure PCTKR2022013646-appb-img-000128
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry,　1994, vol. 37, #16, 2537 - 2551) 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하여 실시예 76의 합성법과 동일한 방법으로 실시예 79를 합성하였다.3-(1-(tert-butoxycarbonyl)piperidin- Example 79 was synthesized in the same manner as in Example 76 using 4-yl)propanoic acid (WO1994/027965).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000129
Figure PCTKR2022013646-appb-img-000129
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry,　1994, vol. 37, #16, 2537 - 2551) 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 76의 합성법과 동일한 방법으로 실시예 80을 합성하였다. 3-(1-(tert-butoxycarbonyl)piperidin- 4-yl)propanoic acid (WO1994/027965) is used, and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) is used instead. Example 80 was synthesized in the same manner as in Example 76 using -dioxopiperidin-3-yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000130
Figure PCTKR2022013646-appb-img-000130
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry,　1994, vol. 37, #16, 2537 - 2551) 대신 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)butanoic acid (WO2014/135244)를 사용하여 실시예 76의 합성법과 동일한 방법으로 실시예 81을 합성하였다. 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 　1994, vol. 37, #16, 2537 - 2551) instead of 4-(4-(tert-butoxycarbonyl)piperazin- Example 81 was synthesized in the same manner as in Example 76 using 1-yl)butanoic acid (WO2014/135244).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000131
Figure PCTKR2022013646-appb-img-000131
단계 1: tert-butyl 4-(3-cyanopropyl)piperidine-1-carboxylate의 합성Step 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), 및 sodium cyanide (148mg, 3mmol)를 EtOH (3ml)에 현탁 시킨 후 80℃에서 2시간 동안 교반 하였다. 반응액을 감압 농축한 후 증류수 (20ml)를 가하고 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (30% EtOAc/Hexane)하여 투명한 오일 333mg (88%)를 수득하였다. 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℃ 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.
단계 2: tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperidine-1-carboxylate의 합성Step 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), 및 K2CO3 (122mg, 0.88mmol)를 EtOH (0.66ml)와 H2O (0.17ml)에 현탁 시킨 후 90℃에서 24시간 동안 교반 하였다. 반응액을 감압 농축한 후 증류수 (20ml)를 가하고 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 투명한 오일 95mg을 수득하였다. tert-butyl 4-(3-cyanopropyl)piperidine-1-carboxylate (100mg, 0.4mmol), hydroxylamine hydrochloride (56mg, 0.8mmol), and K 2 CO 3 (122mg, 0.88mmol) were mixed with EtOH (0.66ml) and H After suspension in 2 O (0.17ml), the mixture was stirred at 90℃ for 24 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 to obtain 95 mg of a clear oil.
단계 3: tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate
tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperidine-1-carboxylate (64mg, 0.23mmol), methyl 4-(chlorocarbonyl)benzoate (45mg, 0.23mmol), 및 DIPEA (0.05ml, 0.28mmol)를 THF (2.3ml)에 현탁 시킨 후 상온에서 1시간 동안 교반 하였다. Cs2CO3 (165mg, 0.51mmol)를 첨가한 후 50℃에서 3시간 동안 교반 하였다. 반응액을 감압 농축한 후 증류수 (10ml)를 가하고 EtOAc (10ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 흰색 고체 85mg (77%)를 수득하였다. tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperidine-1-carboxylate (64mg, 0.23mmol), methyl 4-(chlorocarbonyl)benzoate (45mg, 0.23mmol), and DIPEA ( 0.05ml, 0.28mmol) was suspended in THF (2.3ml) and stirred at room temperature for 1 hour. After adding Cs 2 CO 3 (165mg, 0.51mmol), the mixture was stirred at 50°C for 3 hours. After concentrating the reaction solution under reduced pressure, distilled water (10ml) was added and extracted with EtOAc (10ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to obtain 85 mg (77%) of a white solid.
단계 4: 4-(3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid의 합성Step 4: Synthesis of 4-(3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid
tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate (81mg, 0.19mmol), 및 lithium hydroxide monohydrate (48mg, 1.13mmol)를 THF (0.9ml), H2O (0.9ml)에 현탁 시킨 후 상온에서 18시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 78mg (99%)를 수득하였다. tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate (81mg, 0.19mmol), and lithium hydroxide monohydrate (48mg, 1.13mmol) was suspended in THF (0.9ml) and H 2 O (0.9ml) and stirred at room temperature for 18 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 78 mg (99%) of a white solid.
단계 5: tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate의 합성Step 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
4-(3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid (76mg, 0.18mmol), EDCI (69mg, 0.36mmol), 및 HOBt (30mg, 0.22mmol)를 DMF (1.8ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 42mg, 0.18mmol), DIPEA (0.09ml, 0.54mmol)를 가한 후 상온에서 24시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 연한 갈색 고체 60mg (54%)을 수득하였다.4-(3-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid (76mg, 0.18mmol), EDCI (69mg, 0.36mmol), and HOBt (30mg, 0.22mmol) were suspended in DMF (1.8ml) and stirred at room temperature for 10 minutes. (S) -2-((2-methylpyrrolidin-1-yl)methyl) -1H-benzo[d]imidazol-5-amine (intermediate 1-1, 42mg, 0.18mmol), DIPEA (0.09ml, 0.54 mmol) was added, and the mixture was stirred at room temperature for 24 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 60 mg (54%) of a pale brown solid.
단계 6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate (38mg, 0.06mmol)를 DCM (0.6ml)에 현탁 시킨 후 4M HCl in dioxane (0.15ml, 0.61mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 34mg (99%)를 수득하였다.tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl After suspending )-1,2,4-oxadiazol-3-yl)propyl)piperidine-1-carboxylate (38mg, 0.06mmol) in DCM (0.6ml), 4M HCl in dioxane (0.15ml, 0.61mmol) was added. It was stirred for 2 hours at room temperature. The reaction solution was concentrated to obtain 34 mg (99%) of a white solid.
단계 7: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperidin-4-yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride (36mg, 0.06mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 18mg, 0.06mmol), 및 DIPEA (0.06ml, 0.32mmol)를 DMSO (0.6ml)에 현탁 시킨 후 100℃에서 17시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 36mg (72%)를 수득하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperidin-4-yl) propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride (36mg, 0.06mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/ 160845, 18mg, 0.06mmol), and DIPEA (0.06ml, 0.32mmol) were suspended in DMSO (0.6ml) and then stirred at 100°C for 17 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 (10% MeOH/DCM) to give 36 mg (72%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000132
Figure PCTKR2022013646-appb-img-000132
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 82의 합성법과 동일한 방법으로 실시예 83을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 83 was synthesized in the same manner as in Example 82 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000133
Figure PCTKR2022013646-appb-img-000133
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)를 사용하여 실시예 82의 합성법과 동일한 방법으로 실시예 84를 합성하였다.(3S,5S)-1-((5-amino Example 84 was synthesized in the same manner as in Example 82 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000134
Figure PCTKR2022013646-appb-img-000134
tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) 대신 tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (Journal of Medicinal Chemistry, 2002, vol. 45, #6, 1300 - 1312)를 사용하여 실시예 82의 합성법과 동일한 방법으로 실시예 85를 합성하였다.Tert-butyl 4-(2-(tosyloxy)propyl)piperidine-1-carboxylate (Journal of Medicinal Chemistry, 2002, vol. 45, #6, 1300 - 1312) was synthesized in Example 85 in the same manner as in Example 82.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000135
Figure PCTKR2022013646-appb-img-000135
tert-butyl 4-(3-(tosyloxy)propyl)piperidine-1-carboxylate (WO2000/037458) 대신 tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (Journal of Medicinal Chemistry, 2002, vol. 45, #6, 1300 - 1312)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 82의 합성법과 동일한 방법으로 실시예 86을 합성하였다. Tert-butyl 4-(2-(tosyloxy)propyl)piperidine-1-carboxylate (Journal of Medicinal Chemistry, 2002, vol. 45, #6, 1300 - 1312), and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead Example 86 was synthesized in the same manner as in Example 82 using -dioxopiperidin-3-yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000136
Figure PCTKR2022013646-appb-img-000136
단계 1: tert-butyl 4-(3-cyanopropyl)piperazine-1-carboxylate의 합성Step 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), 및 Na2CO3 (0.569mg, 5.4mmol)를 acetonitrile (2.68ml)에 현탁 시킨 후 85℃에서 5시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 투명한 오일 665mg (98%)를 수득하였다. tert-butyl piperazine-1-carboxylate (500mg, 2.7mmol), 4-bromobutanenitrile (0.54ml, 5.4mmol), and Na 2 CO 3 (0.569mg, 5.4mmol) were suspended in acetonitrile (2.68ml) and then heated to 85℃. was stirred for 5 hours. After adding distilled water (20ml) to the reaction solution, extraction was performed with EtOAc (20ml), and 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.
단계 2: tert-butyl (Z)-4-(4-amino-4-(hydroxyimino)butyl)piperazine-1-carboxylate의 합성Step 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), 및 K2CO3 (792mg, 5.73mmol)를 EtOH (3.2ml)와 H2O (0.8ml)에 현탁 시킨 후 90℃에서 14시간 동안 교반 하였다. 반응액을 감압 농축하여 연한 노란색 오일 696mg을 수득하였다. 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℃ for 14 hours. The reaction solution was concentrated under reduced pressure to obtain 696 mg of pale yellow oil.
단계 3: tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate의 합성Step 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), 및 DIPEA (0.5ml, 2.78mmol)를 THF (10ml)에 현탁 시킨 후 상온에서 1시간 동안 교반 하였다. Cs2CO3 (1.49g, 4.6mmol)를 첨가한 후 60℃에서 4시간 동안 교반 하였다. 반응액을 감압 농축한 후 증류수 (20ml)를 가하고 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (50% EtOAc/Hexane)하여 갈색 오일 231mg을 수득하였다. 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.
단계 4: 4-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid의 합성Step 4: Synthesis of 4-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid
tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate (50mg, 0.12mmol), 및 lithium hydroxide monohydrate (29mg, 0.7mmol)를 THF (0.6ml)와 H2O (0.6ml)에 현탁 시킨 후 상온에서 1시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 갈색 고체 22.3mg (45%)를 수득하였다. tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate (50mg, 0.12mmol), and lithium hydroxide monohydrate (29mg, 0.7mmol) was suspended in THF (0.6ml) and H 2 O (0.6ml) and stirred at room temperature for 1 hour. 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 22.3 mg (45%) of a brown solid.
단계 5: tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate의 합성Step 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
4-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid (51mg, 0.13mmol), EDCI (50mg, 0.26mmol), 및 HOBt (21mg, 0.15mmol)를 DMF (1.3ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 28mg, 0.13mmol), 및 DIPEA (0.07ml, 0.39mmol)를 가한 후 상온에서 15시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% MeOH/DCM)하여 연한 노란색 고체 48mg (59%)을 수득하였다.4-(3-(3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzoic acid (51mg, 0.13mmol), EDCI (50mg, 0.26mmol), and HOBt (21mg, 0.15mmol) were suspended in DMF (1.3ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 28mg, 0.13mmol), and DIPEA (0.07ml, 0.39 mmol) was added and stirred at room temperature for 15 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% MeOH/DCM) to give 48 mg (59%) of a pale yellow solid.
단계 6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate (45mg, 0.07mmol)를 DCM (0.7ml)에 현탁 시킨 후 4M HCl in dioxane (0.18ml, 0.7mmol)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 49mg (quant.)를 수득하였다.tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1,2,4-oxadiazol-3-yl)propyl)piperazine-1-carboxylate (45mg, 0.07mmol) was suspended in DCM (0.7ml), and 4M HCl in dioxane (0.18ml, 0.7mmol) was added. It was stirred for 1 hour at room temperature. The reaction solution was concentrated to obtain 49 mg (quant.) of a white solid.
단계 7: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperazin-1-yl)propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride (46mg, 0.08mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 23mg, 0.08mmol), 및 DIPEA (0.07ml, 0.4mmol)를 DMSO (0.8ml)에 현탁 시킨 후 100℃에서 18시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 28mg (45%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(3-(piperazin-1-yl) propyl)-1,2,4-oxadiazol-5-yl)benzamide hydrochloride (46mg, 0.08mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/ 160845, 23mg, 0.08mmol), and DIPEA (0.07ml, 0.4mmol) were suspended in DMSO (0.8ml) and stirred at 100°C for 18 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 28 mg (45%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000137
Figure PCTKR2022013646-appb-img-000137
단계 1: methyl 4-(hydrazinecarbonyl)benzoate의 합성Step 1: Synthesis of methyl 4-(hydrazinecarbonyl)benzoate
dimethyl terephthalate (500mg, 2.58mmol), 및 hydrazine hydrate (90mg, 2.83mmol)를 EtOH (5ml)에 현탁 시킨 후 90℃에서 19시간 동안 교반 하였다. 반응액을 감압 농축하여 흰색 고체 507mg을 수득하였다. After dimethyl terephthalate (500mg, 2.58mmol) and hydrazine hydrate (90mg, 2.83mmol) were suspended in EtOH (5ml), the mixture was stirred at 90℃ for 19 hours. The reaction solution was concentrated under reduced pressure to obtain 507 mg of a white solid.
단계 2: tert-butyl 4-(4-(2-(4-(methoxycarbonyl)benzoyl)hydrazineyl)-4-oxobutyl)piperidine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(4-(2-(4-(methoxycarbonyl)benzoyl)hydrazineyl)-4-oxobutyl)piperidine-1-carboxylate
methyl 4-(hydrazinecarbonyl)benzoate (322mg, 0.1.66mmol), 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) (300mg, 1.11mmol), HBTU (631mg, 1.7mmol), 및 TEA (0.31ml, 2.22mmol)를 DMF (2.22ml)에 현탁 시킨 후 상온에서 18시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 연한 갈색 고체 676mg을 수득하였다.methyl 4-(hydrazinecarbonyl)benzoate (322mg, 0.1.66mmol), 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) (300mg, 1.11mmol), HBTU (631mg, 1.7mmol), and TEA (0.31ml, 2.22mmol) were suspended in DMF (2.22ml) and stirred at room temperature for 18 hours. After adding distilled water (20ml) to the reaction mixture, the mixture was extracted with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 676 mg of a light brown solid.
단계 3: tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate의 합성Step 3: Synthesis of tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate
tert-butyl 4-(4-(2-(4-(methoxycarbonyl)benzoyl)hydrazineyl)-4-oxobutyl)piperidine-1-carboxylate (496mg, 1.11mmol), 및 p-toluenesulfonyl chloride (317mg, 1.67mmol)를 DCM (10ml)에 현탁 시킨 후 0℃에서 TEA (0.77ml, 5.55mmol)를 천천히 가하고 상온에서 2시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 DCM (30ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (30% EtOAc/Hexane)하여 흰색 고체 309mg (65%)를 수득하였다. tert-butyl 4-(4-(2-(4-(methoxycarbonyl)benzoyl)hydrazineyl)-4-oxobutyl)piperidine-1-carboxylate (496mg, 1.11mmol) and p-toluenesulfonyl chloride (317mg, 1.67mmol) After suspension in DCM (10ml), TEA (0.77ml, 5.55mmol) was slowly added at 0°C and stirred at room temperature for 2 hours. After adding distilled water (20ml) to the reaction mixture, the mixture was extracted with DCM (30ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (30% EtOAc/Hexane) to give 309 mg (65%) of a white solid.
단계 4: 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzoic acid의 합성Step 4: Synthesis of 4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzoic acid
tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate (60mg, 0.14mmol), 및 lithium hydroxide monohydrate (36mg, 0.84mmol)를 THF (0.7ml)와 H2O (0.7ml)에 현탁 시킨 후 상온에서 18시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 59mg (100%)를 수득하였다. tert-butyl 4-(3-(5-(4-(methoxycarbonyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate (60mg, 0.14mmol), and lithium hydroxide monohydrate (36mg, 0.84mmol) was suspended in THF (0.7ml) and H 2 O (0.7ml) and stirred at room temperature for 18 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 59 mg (100%) of a white solid.
단계 5: tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate의 합성Step 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
4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzoic acid (57mg, 0.13mmol), EDCI (53mg, 0.26mmol), 및 HOBt (23mg, 0.15mmol)를 DMF (1.3ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 31mg, 0.13mmol), 및 DIPEA (0.07ml, 0.41mmol)를 가한 후 상온에서 24시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 연한 갈색 고체 51mg (59%)을 수득하였다.4-(5-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzoic acid (57mg, 0.13mmol), EDCI (53mg, 0.26mmol), and HOBt (23mg, 0.15mmol) were suspended in DMF (1.3ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 31mg, 0.13mmol), and DIPEA (0.07ml, 0.41 mmol) was added and stirred at room temperature for 24 hours. After adding distilled water (20ml) to the reactant, extraction was performed with EtOAc (20ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 51 mg (59%) of a pale brown solid.
단계 6: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate (49mg, 0.07mmol)를 DCM (0.7ml)에 현탁 시킨 후 4M HCl in dioxane (0.2ml, 0.7mmol)를 가하고 상온에서 45분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 43mg (98%)를 수득하였다.tert-butyl (S)-4-(3-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl )-1,3,4-oxadiazol-2-yl)propyl)piperidine-1-carboxylate (49mg, 0.07mmol) was suspended in DCM (0.7ml), and then 4M HCl in dioxane (0.2ml, 0.7mmol) was added. It was stirred for 45 minutes at room temperature. The reaction solution was concentrated to obtain 43mg (98%) of a white solid.
단계 7: 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)benzamide의 합성Step 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
((S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl)propyl)-1,3,4-oxadiazol-2-yl)benzamide hydrochloride (41mg, 0.07mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 20mg, 0.07mmol), 및 DIPEA (0.06ml, 0.37mmol)를 DMSO (0.7ml)에 현탁 시킨 후 100℃에서 17시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 38mg (67%)를 수득하였다.((S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(5-(3-(piperidin-4-yl) )propyl)-1,3,4-oxadiazol-2-yl)benzamide hydrochloride (41mg, 0.07mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015 / 160845, 20mg, 0.07mmol), and DIPEA (0.06ml, 0.37mmol) were suspended in DMSO (0.7ml) and stirred for 17 hours at 100 ° C. After adding distilled water (20ml) to the reaction solution, EtOAc (20ml) ), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was subjected to MPLC (10% MeOH/DCM) to obtain 38 mg (67%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000138
Figure PCTKR2022013646-appb-img-000138
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 88의 합성법과 동일한 방법으로 실시예 89를 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 89 was synthesized in the same manner as in Example 88 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000139
Figure PCTKR2022013646-appb-img-000139
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry,　1994, vol. 37, #16, 2537 - 2551) 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하여 실시예 88의 합성법과 동일한 방법으로 실시예 90을 합성하였다.3-(1-(tert-butoxycarbonyl)piperidin- Example 90 was synthesized in the same manner as in Example 88 using 4-yl)propanoic acid (WO1994/027965).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000140
Figure PCTKR2022013646-appb-img-000140
4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 88의 합성법과 동일한 방법으로 실시예 91을 합성하였다. Instead of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551) Use 4-yl)propanoic acid (WO1994/027965) and replace 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) with 2-(2,6- Example 91 was synthesized in the same manner as in Example 88 using dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000141
Figure PCTKR2022013646-appb-img-000141
단계 1: tert-butyl 4-(2-(5-bromopyridin-2-yl)ethyl)piperidine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(2-(5-bromopyridin-2-yl)ethyl)piperidine-1-carboxylate
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192, 400mg, 1.9mmol)를 9-borabicyclo[3.3.1]nonane solution 0.5M in THF (4.5ml, 2.3 mmol)에 현탁 시킨 후 60℃에서 1시간 동안 교반 하였다. 반응물을 식힌 후 2,5-dibromopyridine (540mg, 2.3mmol), K2CO3 (394mg, 2.85mmol), Pd(dppf)Cl2 (695mg, 0.95mmol), DMF (9.5ml), 및 H2O (0.95ml)를 첨가하고 60℃에서 14시간 동안 교반 하였다. 반응물에 1N NaOH (5ml)를 첨가하고 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (30% EtOAc/Hexane)하여 노란색 오일 427mg (61%)를 수득하였다.After tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192, 400mg, 1.9mmol) was suspended in 9-borabicyclo[3.3.1]nonane solution 0.5M in THF (4.5ml, 2.3mmol), 1 Stir for an hour. After cooling the reaction mass, 2,5-dibromopyridine (540mg, 2.3mmol), K 2 CO 3 (394mg, 2.85mmol), Pd(dppf)Cl 2 (695mg, 0.95mmol), DMF (9.5ml), and H 2 O (0.95ml) was added and stirred at 60°C for 14 hours. 1N NaOH (5ml) was added to the reaction mixture, distilled water (20ml) was added, and 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 (30% EtOAc/Hexane) to give 427 mg (61%) of a yellow oil.
단계 2: tert-butyl 4-(2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate의 합성Step 2: Synthesis of tert-butyl 4-(2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate
tert-butyl 4-(2-(5-bromopyridin-2-yl)ethyl)piperidine-1-carboxylate (421mg, 1.14mmol), (4-(methoxycarbonyl)phenyl)boronic acid (205mg, 1.14mmol), Pd(dppf)Cl2 (278mg, 0.34mmol), Xantphos (198mg, 0.34mmol), 및 Cs2CO3 (558mg, 1.71mmol)를 1,4-dioxane (10ml)와 H2O (2ml)에 현탁 시킨 후 80℃에서 2시간 동안 교반 하였다. 반응액을 여과한 후 감압 농축하여 얻어진 잔사를 MPLC (30% EtOAc/Hexane)하여 녹색 고체 285mg (59%)를 수득하였다.tert-butyl 4-(2-(5-bromopyridin-2-yl)ethyl)piperidine-1-carboxylate (421mg, 1.14mmol), (4-(methoxycarbonyl)phenyl)boronic acid (205mg, 1.14mmol), Pd( dppf) Cl 2 (278mg, 0.34mmol), Xantphos (198mg, 0.34mmol), and Cs 2 CO 3 (558mg, 1.71mmol) were suspended in 1,4-dioxane (10ml) and H 2 O (2ml) Stirred at 80 °C for 2 hours. After filtering the reaction solution, the residue obtained by concentration under reduced pressure was subjected to MPLC (30% EtOAc/Hexane) to obtain 285 mg (59%) of a green solid.
단계 3: 4-(6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)pyridin-3-yl)benzoic acid의 합성Step 3: Synthesis of 4-(6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)pyridin-3-yl)benzoic acid
tert-butyl 4-(2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate (280mg, 0.66mmol), 및 lithium hydroxide monohydrate (277mg, 6.6mmol)를 THF (3.3ml)와 H2O (3.3ml)에 현탁 시킨 후 50℃에서 16시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 6으로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 254mg (94%)를 수득하였다. tert-butyl 4-(2-(5-(4-(methoxycarbonyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate (280mg, 0.66mmol), and lithium hydroxide monohydrate (277mg, 6.6mmol) After being suspended in THF (3.3ml) and H 2 O (3.3ml), the mixture was stirred at 50°C for 16 hours. 1N HCl aqueous solution was added to the reaction mixture to adjust the pH to 6, followed by extraction with EtOAc (20ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 254 mg (94%) of a white solid.
단계 4: tert-butyl (S)-4-(2-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate의 합성Step 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
4-(6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)pyridin-3-yl)benzoic acid (251mg, 0.61mmol), EDCI (234mg, 1.22mmol), 및 HOBt (99mg, 0.73mmol)를 DMF (6.1ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 141mg, 0.61mmol), 및 DIPEA (0.17ml, 1.83mmol)를 가한 후 상온에서 21시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 289mg (76%)을 수득하였다.4-(6-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)pyridin-3-yl)benzoic acid (251 mg, 0.61 mmol), EDCI (234 mg, 1.22 mmol), and HOBt ( 99mg, 0.73mmol) was suspended in DMF (6.1ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 141mg, 0.61mmol), and DIPEA (0.17ml, 1.83 mmol) was added and stirred at room temperature for 21 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed 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 (10% MeOH/DCM) to give 289 mg (76%) of a yellow solid.
단계 5: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(6-(2-(piperidin-4-yl)ethyl)pyridin-3-yl)benzamide hydrochloride의 합성Step 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
tert-butyl (S)-4-(2-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)pyridin-2-yl)ethyl)piperidine-1-carboxylate (286mg, 0.46mmol)를 DCM (4.6ml)에 현탁 시킨 후 4M HCl in dioxane (1.15ml, 4.6mmol)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 연한 갈색 고체 288mg (quant.)를 수득하였다.tert-butyl (S)-4-(2-(5-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl After )pyridin-2-yl)ethyl)piperidine-1-carboxylate (286mg, 0.46mmol) was suspended in DCM (4.6ml), 4M HCl in dioxane (1.15ml, 4.6mmol) was added and stirred at room temperature for 1 hour. . The reaction solution was concentrated to obtain 288 mg (quant.) of a pale brown solid.
단계 6: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(6-(2-(piperidin-4-yl)ethyl)pyridin-3-yl)benzamide hydrochloride (50mg, 0.09mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 25mg, 0.09mmol), 및 DIPEA (0.08ml, 0.45mmol)를 DMSO (0.9ml)에 현탁 시킨 후 100℃에서 13시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 8.3mg (12%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(6-(2-(piperidin-4-yl) ethyl)pyridin-3-yl)benzamide hydrochloride (50mg, 0.09mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 25mg, 0.09mmol) , and DIPEA (0.08ml, 0.45mmol) were suspended in DMSO (0.9ml) and then stirred at 100°C for 13 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 (10% MeOH/DCM) to give 8.3 mg (12%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000142
Figure PCTKR2022013646-appb-img-000142
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 92의 합성법과 동일한 방법으로 실시예 93을 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 93 was synthesized in the same manner as in Example 92 using -dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000143
Figure PCTKR2022013646-appb-img-000143
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192) 대신 tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380)를 사용하여 실시예 92의 합성법과 동일한 방법으로 실시예 94를 합성하였다. 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.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000144
Figure PCTKR2022013646-appb-img-000144
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192) 대신 tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 92의 합성법과 동일한 방법으로 실시예 95를 합성하였다. tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380) was used instead of tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192), and 2-(2,6-dioxopiperidin 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) instead of -3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) Example 95 was synthesized in the same manner as in Example 92 using
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000145
Figure PCTKR2022013646-appb-img-000145
단계 1: tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperidine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperidine-1-carboxylate
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192, 472mg, 2.23mmol), 및 9-BBN 0.5M in THF (5.36ml, 2.68mmol)의 혼합물을 60℃에서 1시간 동안 교반 하였다. 반응물에 methyl 4-bromobenzoate (576mg, 2.68mmol), K2CO3 (463mg, 3.35mmol), Pd(dppf)Cl2 (490mg, 0.3mmol), DMF (8.9ml), 및 H2O (0.89ml)를 가하고 80℃에서 20시간 동안 교반 하였다. 반응액에 EtOAc (70ml)를 가한 뒤 1 N NaOH 수용액 (30ml x 1), 물 (30ml x 4), 및 brine (30ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% EtOAc/Hexane)하여 투명한 액체 477mg (62%)을 수득하였다.A mixture of tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192, 472mg, 2.23mmol) and 9-BBN 0.5M in THF (5.36ml, 2.68mmol) was stirred at 60°C for 1 hour. To the reactants were methyl 4-bromobenzoate (576mg, 2.68mmol), K 2 CO 3 (463mg, 3.35mmol), Pd(dppf)Cl 2 (490mg, 0.3mmol), DMF (8.9ml), and H 2 O (0.89ml). ) was added and stirred at 80 ° C for 20 hours. After adding EtOAc (70ml) to the reaction mixture, the mixture was washed with 1 N NaOH aqueous solution (30ml x 1), water (30ml x 4), and brine (30ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% EtOAc/Hexane) to give 477 mg (62%) of a clear liquid.
단계 2: 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)benzoic acid의 합성Step 2: Synthesis of 4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)benzoic acid
tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperidine-1-carboxylate (463mg, 1.33mmol)을 THF : H2O = 1 : 1 (13ml)에 녹인 후 lithium hydroxide monohydrate (839mg, 20mmol)를 가하고 50℃에서 17시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조절한 뒤 EtOAc (30ml x 2)로 추출하였다. 추출한 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 하얀색 고체 388mg (87%)을 수득하였다.After dissolving tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperidine-1-carboxylate (463mg, 1.33mmol) in THF : H 2 O = 1 : 1 (13ml), lithium hydroxide monohydrate (839mg, 20mmol) was added. Stirred at 50 °C for 17 hours. 1N HCl aqueous solution was added to the reaction solution to adjust the pH to 5, followed by extraction with EtOAc (30ml x 2). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 388mg (87%) of a white solid.
단계 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperidine-1-carboxylate의 합성Step 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperidine- Synthesis of 1-carboxylate
4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)benzoic acid (120mg, 0.36mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 83mg, 0.36mmol), EDC (138mg, 0.72mmol), 및 HOBt (58mg, 0.43mmol)를 DMF (4ml)에 녹인 후 DIPEA (0.19ml, 1.08mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% DCM/MeOH)하여 하얀색 고체 124mg (63%)을 수득하였다.4-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)ethyl)benzoic acid (120mg, 0.36mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H After dissolving -benzo[d]imidazol-5-amine (intermediate 1-1, 83mg, 0.36mmol), EDC (138mg, 0.72mmol), and HOBt (58mg, 0.43mmol) in DMF (4ml), DIPEA (0.19ml , 1.08 mmol) was added and stirred at room temperature for 16 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% DCM/MeOH) to give 124 mg (63%) of a white solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride의 합성Step 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperidin-4-yl) Synthesis of ethyl)benzamide hydrochloride
tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperidine-1-carboxylate (123mg, 0.23mmol)를 DCM (2.3ml)에 녹인 후 4M HCl in dioxane (0.56ml)를 가하고 상온에서 3시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 143mg (quant.)을 수득하였다.tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperidine-1-carboxylate (123mg, 0.23mmol) was dissolved in DCM (2.3ml), 4M HCl in dioxane (0.56ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated to obtain 143 mg (quant.) of a white solid.
단계 5: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride (50mg, 0.10mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 29mg, 0.10mmol)을 DMSO (1.0ml)에 녹인 후 DIPEA (0.09ml, 0.52mmol)를 가하고 100℃에서 18시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 주황색 고체 39mg (53%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperidin-4-yl)ethyl)benzamide hydrochloride (50mg, 0.10mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 29mg, 0.10mmol) dissolved in DMSO (1.0ml) After adding DIPEA (0.09ml, 0.52mmol), the mixture was stirred at 100°C for 18 hours. After adding EtOAc (40ml) to the reaction solution, it was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 39 mg (53%) of an orange solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000146
Figure PCTKR2022013646-appb-img-000146
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845 A2) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 96의 합성법과 동일한 방법으로 실시예 97을 합성하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845 A2) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1, Example 97 was synthesized in the same manner as in Example 96 using 3-dione (WO2010/081036).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000147
Figure PCTKR2022013646-appb-img-000147
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 (3S,5S)-1-((5-amino-1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (중간체 1-2)을 사용하여 실시예 96의 합성법과 동일한 방법으로 실시예 98을 합성하였다.(3S,5S)-1-((5-amino Example 98 was synthesized in the same manner as in Example 96 using -1H-benzo[d]imidazol-2-yl)methyl)-5-methylpyrrolidin-3-ol (Intermediate 1-2).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000148
Figure PCTKR2022013646-appb-img-000148
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4)을 사용하여 실시예 96의 합성법과 동일한 방법으로 실시예 99를 합성하였다.2-(pyrrolidin-1-ylmethyl)-1H-benzo instead of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1) Example 99 was synthesized in the same manner as in Example 96 using [d]imidazol-5-amine (Intermediate 1-4).
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000149
Figure PCTKR2022013646-appb-img-000149
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192) 대신 tert-butyl 4-allylpiperidine-1-carboxylate (Synlett,　1998, #4, 379 - 380)를 사용하여 실시예 96의 합성법과 동일한 방법으로 실시예 100을 합성하였다.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 96. Example 100 was synthesized.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000150
Figure PCTKR2022013646-appb-img-000150
tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192) 대신 tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 96의 합성법과 동일한 방법으로 실시예 101을 합성하였다.tert-butyl 4-allylpiperidine-1-carboxylate (Synlett, 1998, #4, 379 - 380) was used instead of tert-butyl 4-vinylpiperidine-1-carboxylate (WO1996/020192), and 2-(2,6-dioxopiperidin 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036) instead of -3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) Example 101 was synthesized in the same manner as in Example 96 using the same method.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000151
Figure PCTKR2022013646-appb-img-000151
단계 1: tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperazine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperazine-1-carboxylate
methyl 4-(2-bromoethyl)benzoate (500mg, 2.06mmol), tert-butyl piperazine-1-carboxylate (460mg, 2.47mmol), 및 DIPEA (0.72ml, 4.12mmol)를 DMF (7ml)에 현탁 시킨 후 상온에서 23시간 동안 교반 하였다. 증류수 (20ml)를 가한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (60% EtOAc/Hexane)하여 흰색 고체 316mg (44%)를 수득하였다.After suspending methyl 4-(2-bromoethyl)benzoate (500mg, 2.06mmol), tert-butyl piperazine-1-carboxylate (460mg, 2.47mmol), and DIPEA (0.72ml, 4.12mmol) in DMF (7ml), room temperature was stirred for 23 hours. After adding distilled water (20ml), the mixture was 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 (60% EtOAc/Hexane) to give 316mg (44%) of a white solid.
단계 2: 4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)benzoic acid의 합성Step 2: Synthesis of 4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)benzoic acid
tert-butyl 4-(4-(methoxycarbonyl)phenethyl)piperazine-1-carboxylate (306mg, 0.88mmol), 및 lithium hydroxide monohydrate (221mg, 5.3mmol)를 THF (2ml)와 H2O (2ml)에 현탁 시킨 후 50℃에서 6시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조정한 뒤 EtOAc (20ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 304mg (quant.)를 수득하였다. 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 ℃ 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.
단계 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperazine-1-carboxylate의 합성Step 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperazine- Synthesis of 1-carboxylate
4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)benzoic acid (60mg, 0.18mmol), EDCI (69mg, 0.36mmol), 및 HOBt (29mg, 0.22mmol)를 DMF (1.8ml)에 현탁 시킨 후 상온에서 10분 동안 교반 하였다. 반응물에 (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 41mg, 0.18mmol), 및 DIPEA (0.1ml, 0.54mmol)를 가한 후 상온에서 14시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 흰색 고체 30mg (31%)을 수득하였다.4-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)benzoic acid (60 mg, 0.18 mmol), EDCI (69 mg, 0.36 mmol), and HOBt (29 mg, 0.22 mmol) were mixed with DMF (1.8 ml) and stirred at room temperature for 10 minutes. (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 41mg, 0.18mmol), and DIPEA (0.1ml, 0.54 mmol) was added and stirred at room temperature for 14 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed 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 (5% MeOH/DCM) to give 30 mg (31%) of a white solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperazin-1-yl)ethyl)benzamide hydrochloride의 합성Step 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperazin-1-yl) Synthesis of ethyl)benzamide hydrochloride
tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperazine-1-carboxylate (28mg, 0.05mmol)를 DCM (0.5ml)에 현탁 시킨 후 4M HCl in dioxane (0.12ml, 0.5mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 연한 노란색 고체 25mg (quant.)를 수득하였다.tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenethyl)piperazine-1-carboxylate (28mg, 0.05mmol) was suspended in DCM (0.5ml), 4M HCl in dioxane (0.12ml, 0.5mmol) was added, and stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain 25 mg (quant.) of a pale yellow solid.
단계 5: 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)benzamide의 합성Step 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
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperazin-1-yl)ethyl)benzamide hydrochloride (28mg, 0.05mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 14mg, 0.05mmol), 및 DIPEA (0.04ml, 0.25mmol)를 DMSO (0.5ml)에 현탁 시킨 후 100℃에서 14시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 13mg (37%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(2-(piperazin-1-yl)ethyl)benzamide hydrochloride (28 mg, 0.05 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 14 mg, 0.05 mmol), and DIPEA (0.04 ml, 0.25 mmol) ) was suspended in DMSO (0.5ml) and then stirred at 100°C for 14 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 13 mg (37%) of a yellow solid.
실시예 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)benzamideExample 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
Figure PCTKR2022013646-appb-img-000152
Figure PCTKR2022013646-appb-img-000152
(S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1) 대신 2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-amine (중간체 1-4)를 사용하여 실시예 102의 합성법과 동일한 방법으로 실시예 103을 합성하였다.2-(pyrrolidin-1-ylmethyl)-1H-benzo instead of (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1) Example 103 was synthesized in the same manner as in Example 102 using [d]imidazol-5-amine (Intermediate 1-4).
실시예 104: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 104: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000153
Figure PCTKR2022013646-appb-img-000153
단계 1: tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate의 합성Step 1: tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6, 163mg, 0.36mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (105mg, 0.43mmol), HATU (327mg, 0.86mmol), 및 DIPEA (0.38ml, 2.15mmol)를 DMF (4.3ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (5% MeOH/DCM)하여 갈색 고체 45mg (20%)을 수득하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6, 163mg, 0.36mmol), 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (105mg, 0.43mmol), HATU (327mg, 0.86mmol), and DIPEA (0.38ml, 2.15mmol) was suspended in DMF (4.3ml) and stirred at room temperature for 16 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to give 45 mg (20%) of a brown solid.
단계 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)benzamide hydrochloride의 합성Step 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4 Synthesis of -yl)acetyl)piperidin-4-yl)benzamide hydrochloride
tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate (43mg, 0.07mmol)를 DCM (0.7ml)에 현탁 시킨 후 4M HCl in dioxane (0.18ml, 0.7mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액을 농축하여 연한 갈색 고체 45mg (quant.)를 수득하였다.tert-butyl (S)-4-(2-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl After suspending )piperidin-1-yl)-2-oxoethyl)piperidine-1-carboxylate (43mg, 0.07mmol) in DCM (0.7ml), 4M HCl in dioxane (0.18ml, 0.7mmol) was added and incubated at room temperature for 2 hours. while stirring. The reaction solution was concentrated to obtain 45 mg (quant.) of a light brown solid.
단계 3: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 3: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperidin-4 Synthesis of -yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)benzamide hydrochloride (21mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 10mg, 0.03mmol), 및 DIPEA (0.03ml, 0.18mmol)를 DMSO (0.3ml)에 현탁 시킨 후 100℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20ml)를 가한 뒤 EtOAc (20ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% MeOH/DCM)하여 노란색 고체 9.7mg (34%)를 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(2-(piperidin-4-yl) acetyl)piperidin-4-yl)benzamide hydrochloride (21mg, 0.03mmol), 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 10mg, 0.03mmol) , and DIPEA (0.03ml, 0.18mmol) were suspended in DMSO (0.3ml) and then stirred at 100°C for 16 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (20ml x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% MeOH/DCM) to give 9.7 mg (34%) of a yellow solid.
실시예 105: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 105: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000154
Figure PCTKR2022013646-appb-img-000154
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 105를 합성하였다. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 105 was synthesized in the same manner as in Example 104 using -dione (WO2010/081036).
실시예 106: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 106: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000155
Figure PCTKR2022013646-appb-img-000155
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 106을 합성하였다. Synthesis method of Example 104 using 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid Example 106 was synthesized in the same manner as above.
실시예 107: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 107: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000156
Figure PCTKR2022013646-appb-img-000156
2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 107을 합성하였다.3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) is used instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid, and 2-(2 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010 / 081036) was used to synthesize Example 107 in the same manner as in Example 104.
실시예 108: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 108: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000157
Figure PCTKR2022013646-appb-img-000157
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-7)를 사용하고, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 108을 합성하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Instead of N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4 -yl)benzamide hydrochloride (intermediate 1-7) is used, 3-(1-(tert-butoxycarbonyl)piperidin-4-yl) instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid Example 108 was synthesized in the same manner as in Example 104 using propanoic acid (WO1994/027965).
실시예 109: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 109: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000158
Figure PCTKR2022013646-appb-img-000158
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-7)를 사용하고, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 109를 합성하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Instead of N-(2-(((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4 -yl)benzamide hydrochloride (intermediate 1-7) is used, 3-(1-(tert-butoxycarbonyl)piperidin-4-yl) instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid Propanoic acid (WO1994/027965) is used, and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) is used instead of 2-(2,6-dioxopiperidin-3-yl) Example 109 was synthesized in the same manner as in Example 104 using -yl) -5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 110: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 110: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000159
Figure PCTKR2022013646-appb-img-000159
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (중간체 1-8)를 사용하고, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 110을 합성하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Use 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (intermediate 1-8) instead, Synthesis method of Example 104 using 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid Example 110 was synthesized in the same manner as above.
실시예 111: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 111: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000160
Figure PCTKR2022013646-appb-img-000160
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (중간체 1-8)를 사용하고, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 111을 합성하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Use 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (intermediate 1-8) instead, 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) is used instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid, and 2-(2 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010 / 081036) was used to synthesize Example 111 in the same manner as in Example 104.
실시예 112: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)benzamideExample 112: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000161
Figure PCTKR2022013646-appb-img-000161
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-9)를 사용하고, 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 대신 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)를 사용하여 실시예 104의 합성법과 동일한 방법으로 실시예 112를 합성하였다. (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Instead of (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)benzo[d]oxazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 9), and 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) is used instead of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1 Example 112 was synthesized in the same manner as in Example 104 using ,3-dione (WO2010/081036).
실시예 113: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperazin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 113: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000162
Figure PCTKR2022013646-appb-img-000162
단계 1: tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate
methyl 4-fluorobenzoate (1g, 6.49mmol), 및 tert-butyl piperazine-1-carboxylate (1.2g, 6.49mmol)를 DMSO (22ml)에 녹인 후 K2CO3 (1.34g, 9.74mmol)를 가하고 120℃에서 18시간 동안 교반 하였다. 반응액에 EtOAc (70ml)를 가한 뒤 물 (40ml x 1), 및 brine (40ml x 5)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% EtOAc/Hexane)하여 하얀색 고체 589mg (28%)을 수득하였다.After dissolving methyl 4-fluorobenzoate (1g, 6.49mmol) and tert-butyl piperazine-1-carboxylate (1.2g, 6.49mmol) in DMSO (22ml), K 2 CO 3 (1.34g, 9.74mmol) was added and heated to 120℃. was stirred for 18 hours. After adding EtOAc (70ml) to the reaction solution, the mixture was washed with water (40ml x 1) and brine (40ml x 5). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% EtOAc/Hexane) to give 589mg (28%) of a white solid.
단계 2: 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid의 합성Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid
tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (587mg, 1.83mmol)을 THF : H2O = 1 : 1 (9ml)에 녹인 후 lithium hydroxide monohydrate (462mg, 11mmol)를 가하고 50℃에서 6시간 동안 교반 하였다. 반응액에 1 N HCl 수용액을 가하여 pH = 5로 조절한 뒤 EtOAc (30ml x 2)로 추출하였다. 추출한 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 하얀색 고체 517mg (93%)을 수득하였다.After dissolving tert-butyl 4-(4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (587mg, 1.83mmol) in THF : H 2 O = 1 : 1 (9ml), lithium hydroxide monohydrate (462mg, 11mmol) was added. It was stirred at 50 °C for 6 hours. 1 N HCl aqueous solution was added to the reaction mixture to adjust the pH to 5, followed by extraction with EtOAc (30ml x 2). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 517 mg (93%) of a white solid.
단계 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperazine-1-carboxylate의 합성Step 3: tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperazine- Synthesis of 1-carboxylate
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (133mg, 0.43mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 100mg, 0.43mmol), EDC (166mg, 0.87mmol), 및 HOBt (70mg, 0.52mmol)를 DMF (4.3ml)에 녹인 후 DIPEA (0.23ml, 1.30mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (6% DCM/MeOH)하여 하얀색 고체 123mg (55%)을 수득하였다.4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (133mg, 0.43mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d] After dissolving imidazol-5-amine (intermediate 1-1, 100mg, 0.43mmol), EDC (166mg, 0.87mmol), and HOBt (70mg, 0.52mmol) in DMF (4.3ml), DIPEA (0.23ml, 1.30mmol) was added and stirred at room temperature for 16 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (6% DCM/MeOH) to give 123 mg (55%) of a white solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperazin-1-yl)benzamide의 합성Step 4: Synthesis of (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperazin-1-yl)benzamide
tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperazine-1-carboxylate (121mg, 0.23mmol)를 DCM (2.3ml)에 녹인 후 4M HCl in dioxane (0.58ml)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액을 가하여 pH = 7로 조절한 뒤 EtOAc (20ml x 5)로 추출하였다. 추출한 유기층을 brine (30ml x 1)으로 세척하고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 하얀색 고체 72mg (74%)을 수득하였다.tert-butyl (S)-4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperazine-1-carboxylate (121mg, 0.23mmol) was dissolved in DCM (2.3ml), 4M HCl in dioxane (0.58ml) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of NaHCO 3 was added to the reaction mixture to adjust the pH to 7, followed by extraction with EtOAc (20ml x 5). The extracted organic layer was washed with brine (30ml x 1), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 72mg (74%) of a white solid.
단계 5: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperazin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 5: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetyl)piperazin-1 Synthesis of -yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperazin-1-yl)benzamide (26mg, 0.06mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (중간체 3-33, 37mg, 0.09mmol), 및 HATU (47mg, 0.12mmol)를 DMF (0.6ml)에 녹인 후 DIPEA (0.03ml, 0.19mmol)를 가하고 상온에서 22시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 29mg (59%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperazin-1-yl)benzamide (26mg, 0.06mmol ), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (Intermediate 3-33, 37mg, 0.09mmol ), and HATU (47mg, 0.12mmol) were dissolved in DMF (0.6ml), DIPEA (0.03ml, 0.19mmol) was added, and the mixture was stirred at room temperature for 22 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 29 mg (59%) of a yellow solid.
실시예 114: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperazin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 114: 4-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000163
Figure PCTKR2022013646-appb-img-000163
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (중간체 3-33) 대신 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetic acid (중간체 3-34)를 사용하여 실시예 113의 합성법과 동일한 방법으로 실시예 114를 합성하였다.2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (intermediate 3-33) instead of 2-(1- The same method as the synthesis method of Example 113 using (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetic acid (Intermediate 3-34) Example 114 was synthesized with
실시예 115: 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperazin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 115: 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000164
Figure PCTKR2022013646-appb-img-000164
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (중간체 3-33) 대신 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (중간체 3-31)를 사용하여 실시예 113의 합성법과 동일한 방법으로 실시예 115를 합성하였다.2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (intermediate 3-33) instead of 3-(1- The same method as the synthesis method of Example 113 using (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (Intermediate 3-31) Example 115 was synthesized with
실시예 116: 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperazin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 116: 4-(4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)piperazin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000165
Figure PCTKR2022013646-appb-img-000165
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (중간체 3-33) 대신 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoic acid (중간체 3-32)를 사용하여 실시예 113의 합성법과 동일한 방법으로 실시예 116을 합성하였다.2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetic acid (intermediate 3-33) instead of 3-(1- The same method as the synthesis method of Example 113 using (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoic acid (Intermediate 3-32) Example 116 was synthesized with
실시예 117: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 117: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000166
Figure PCTKR2022013646-appb-img-000166
단계 1: tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate의 합성Step 1: tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl) Synthesis of carbamoyl)phenyl)piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6, 112mg, 0.25mmol), 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoic acid (64mg, 0.25mmol), EDC (95mg, 0.49mmol), 및 HOBt (40mg, 0.30mmol)를 DMF (2.5ml)에 녹인 후 DIPEA (0.13ml, 0.74mmol)를 가하고 상온에서 15시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% DCM/MeOH)하여 하얀색 고체 59mg (37%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6, 112mg, 0.25mmol), 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoic acid (64mg, 0.25mmol), EDC (95mg, 0.49mmol), and HOBt (40mg, 0.30mmol) After dissolving in DMF (2.5ml), DIPEA (0.13ml, 0.74mmol) was added and stirred at room temperature for 15 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% DCM/MeOH) to give 59 mg (37%) of a white solid.
단계 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl)propanoyl)piperidin-4-yl)benzamide hydrochloride의 합성Step 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1 Synthesis of -yl)propanoyl)piperidin-4-yl)benzamide hydrochloride
tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate (56mg, 0.08mmol)를 DCM (0.8ml)에 녹인 후 4M HCl in dioxane (0.31ml)를 가하고 상온에서 30분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 74mg (quant.)을 수득하였다.tert-butyl (S)-4-(3-(4-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl After dissolving )piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate (56mg, 0.08mmol) in DCM (0.8ml), 4M HCl in dioxane (0.31ml) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain 74 mg (quant.) of a white solid.
단계 3: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 3: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin-4 Synthesis of -yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl)propanoyl)piperidin-4-yl)benzamide hydrochloride (74mg, 0.12mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 34mg, 0.12mmol)을 DMSO (1.2ml)에 녹인 후 DIPEA (0.11ml, 0.62mmol)를 가하고 100℃에서 14시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (2.0ml x 4), 및 brine (2.0ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 38mg (55%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(1-(3-(piperazin-1-yl) propanoyl)piperidin-4-yl)benzamide hydrochloride (74mg, 0.12mmol), and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 34mg, 0.12mmol ) was dissolved in DMSO (1.2ml), DIPEA (0.11ml, 0.62mmol) was added, and the mixture was stirred at 100°C for 14 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (2.0ml x 4) and brine (2.0ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 38 mg (55%) of a yellow solid.
실시예 118: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 118: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000167
Figure PCTKR2022013646-appb-img-000167
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2020/264172) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 117의 합성법과 동일한 방법으로 실시예 118을 합성하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2020/264172) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 118 was synthesized in the same manner as in Example 117 using -dione (WO2010/081036).
실시예 119: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 119: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)piperidin- 4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000168
Figure PCTKR2022013646-appb-img-000168
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (중간체 1-8)를 사용하여 실시예 117의 합성법과 동일한 방법으로 실시예 119를 합성하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Instead of 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (Intermediate 1-8) Example 119 was synthesized in the same manner as in Example 117.
실시예 120: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 120: 4-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)piperidin- 4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000169
Figure PCTKR2022013646-appb-img-000169
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6) 대신 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (중간체 1-8)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 117의 합성법과 동일한 방법으로 실시예 120을 합성하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6) Use 4-(piperidin-4-yl)-N-(2-(pyrrolidin-1-ylmethyl)-1H-benzo[d]imidazol-5-yl)benzamide hydrochloride (intermediate 1-8) instead, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 120 was synthesized in the same manner as in Example 117 using -dione (WO2010/081036).
실시예 121: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 121: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)ethyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000170
Figure PCTKR2022013646-appb-img-000170
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (중간체 1-6, 60mg, 0.13mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (중간체 3-27, 50mg, 0.13mmol)을 DCM : MeOH = 10 : 1 (2ml)에 녹인 후 sodium triacetoxyborohydride (56mg, 0.26mmol)를 가하고 상온에서 2시간 동안 교반 하였다. 반응액에 DCM (40ml)를 가한 뒤 NaHCO3 포화수용액 (20ml x 3)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 67mg (64%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(piperidin-4-yl)benzamide hydrochloride (intermediate 1- 6, 60mg, 0.13mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (Intermediate 3-27 , 50mg, 0.13mmol) was dissolved in DCM : MeOH = 10 : 1 (2ml), sodium triacetoxyborohydride (56mg, 0.26mmol) was added and stirred at room temperature for 2 hours. After adding DCM (40ml) to the reaction solution, the mixture was washed with a saturated NaHCO 3 aqueous solution (20ml x 3). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% DCM/MeOH (10% NH 3 )) to give 67 mg (64%) of a yellow solid.
실시예 122: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 122: 4-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000171
Figure PCTKR2022013646-appb-img-000171
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (중간체 3-27) 대신 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (중간체 3-28)를 사용하여 실시예 121의 합성법과 동일한 방법으로 실시예 122를 합성하였다.2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (intermediate 3-27) instead of 2-(1-( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (Intermediate 3-28) was used and carried out in the same manner as in Example 121 synthesis Example 122 was synthesized.
실시예 123: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 123: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000172
Figure PCTKR2022013646-appb-img-000172
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (중간체 3-27) 대신 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanal (중간체 3-29)을 사용하여 실시예 121의 합성법과 동일한 방법으로 실시예 123을 합성하였다.3-(1-( instead of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (intermediate 3-27) 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanal (intermediate 3-29) was carried out in the same manner as in Example 121 synthesis Example 123 was synthesized.
실시예 124: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidin-4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 124: 4-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidin- 4-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000173
Figure PCTKR2022013646-appb-img-000173
2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (중간체 3-27) 대신 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal (중간체 3-30)을 사용하여 실시예 121의 합성법과 동일한 방법으로 실시예 124를 합성하였다. 3-(1-( instead of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (intermediate 3-27) 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal (Intermediate 3-30) was carried out in the same manner as in Example 121 synthesis Example 124 was synthesized.
실시예 125: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 125: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000174
Figure PCTKR2022013646-appb-img-000174
단계 1: tert-butyl 4-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (중간체 2-7, 469mg, 1.65mmol), 및 methyl 4-fluorobenzoate (0.19ml, 1.50mmol)를 DMSO (8ml)에 녹인 후 DIPEA (0.79ml, 4.51mmol)를 가하고 100℃에서 16시간 동안 교반 하였다. 반응액에 EtOAc (70ml)를 가한 뒤 물 (30ml x 3), 및 brine (30ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (30% EtOAc /hexane)하여 하얀색 고체 270mg (44%)을 수득하였다.After dissolving tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (intermediate 2-7, 469mg, 1.65mmol), and methyl 4-fluorobenzoate (0.19ml, 1.50mmol) in DMSO (8ml), DIPEA (0.79ml, 4.51mmol) was added and stirred at 100℃ for 16 hours. After adding EtOAc (70ml) to the reaction solution, it was washed with water (30ml x 3) and brine (30ml x 1). 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 obtain 270 mg (44%) of a white solid.
단계 2: 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid의 합성Step 2: Synthesis of 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid
tert-butyl 4-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (266mg, 0.64mmol)을 THF : H2O = 1 : 1 (6.6ml)에 녹인 후 lithium hydroxide monohydrate (134mg, 3.19mmol)를 가하고 60℃에서 7시간 동안 교반 하였다. 반응액에 1N HCl 수용액을 가하여 pH = 5로 조절한 뒤 EtOAc (50ml)를 가하여 생기는 침전물을 여과하여 하얀색 고체 75mg (29%)을 수득하였다.tert-butyl 4-((1-(4-(methoxycarbonyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (266mg, 0.64mmol) was added as THF: HO = 1:1 (6.6ml) After dissolving it, lithium hydroxide monohydrate (134mg, 3.19mmol) was added and stirred at 60℃ for 7 hours. 1N HCl aqueous solution was added to the reaction solution to adjust pH = 5, and EtOAc (50ml) was added to obtain a precipitate formed by filtration to obtain 75mg (29%) of a white solid.
단계 3: tert-butyl (S)-4-((1-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate의 합성Step 3: tert-butyl (S)-4-((1-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl) Synthesis of phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate
4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid (75mg, 0.19mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 43mg, 0.19mmol), EDC (72mg, 0.37mmol), 및 HOBt (30mg, 0.22mmol)를 DMF (2ml)에 녹인 후 DIPEA (0.1ml, 0.56mmol)를 가하고 상온에서 14시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (7% DCM/MeOH)하여 연한 갈색 고체 67mg (59%)을 수득하였다.4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)piperidin-1-yl)benzoic acid (75mg, 0.19mmol), (S)-2-((2-methylpyrrolidin-1 -yl)methyl)-1H-benzo[d]imidazol-5-amine (intermediate 1-1, 43mg, 0.19mmol), EDC (72mg, 0.37mmol), and HOBt (30mg, 0.22mmol) in DMF (2ml) After dissolving it, DIPEA (0.1ml, 0.56mmol) was added and stirred at room temperature for 14 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to MPLC (7% DCM/MeOH) to give 67 mg (59%) of a pale brown solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)benzamide hydrochloride의 합성Step 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(4-(piperazin-1-ylmethyl) Synthesis of piperidin-1-yl)benzamide hydrochloride
tert-butyl (S)-4-((1-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (65mg, 0.10mmol)를 DCM (1.1ml)에 녹인 후 4M HCl in dioxane (0.26ml)를 가하고 상온에서 30분 동안 교반 하였다. 반응액을 농축하여 흰색 고체 75mg (quant.)을 수득하였다.tert-butyl (S)-4-((1-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)piperidin After dissolving -4-yl)methyl)piperazine-1-carboxylate (65mg, 0.10mmol) in DCM (1.1ml), 4M HCl in dioxane (0.26ml) was added and stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain 75 mg (quant.) of a white solid.
단계 5: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 5: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl Synthesis of )-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(4-(piperazin-1-ylmethyl)piperidin-1-yl)benzamide hydrochloride (34mg, 0.06mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 17mg, 0.06mmol)을 DMSO (0.6ml)에 녹인 후 DIPEA (0.05ml, 0.31mmol)를 가하고 100℃에서 14시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 20mg (42%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(4-(piperazin-1-ylmethyl)piperidin-1 DMSO (0.6 ml), DIPEA (0.05ml, 0.31mmol) was added, and the mixture was stirred at 100°C for 14 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 20 mg (42%) of a yellow solid.
실시예 126: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 126: 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1- yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000175
Figure PCTKR2022013646-appb-img-000175
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 125 합성법과 동일한 방법으로 실시예 126을 합성하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 126 was synthesized in the same manner as in Example 125 synthesis using -dione (WO2010/081036).
실시예 127: 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 127: 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)ethyl)piperidin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000176
Figure PCTKR2022013646-appb-img-000176
tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (중간체 2-7) 대신 tert-butyl 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate (중간체 2-8)을 사용하여 실시예 125의 합성법과 동일한 방법으로 실시예 127을 합성하였다.tert-butyl 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate (intermediate 2-7) instead of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (intermediate 2-7) 8) was used to synthesize Example 127 in the same manner as in Example 125.
실시예 128: 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 128: 4-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin- 1-yl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000177
Figure PCTKR2022013646-appb-img-000177
tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (중간체 2-7) 대신 tert-butyl 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate (중간체 2-8)을 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 125의 합성법과 동일한 방법으로 실시예 128을 합성하였다.tert-butyl 4-(2-(piperidin-4-yl)ethyl)piperazine-1-carboxylate (intermediate 2-7) instead of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (intermediate 2-7) 8) is used, and 2-(2,6-dioxopiperidin-3-yl)-5 instead of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) Example 128 was synthesized in the same manner as in Example 125 using -fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 129: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanamido)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 129: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanamido)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000178
Figure PCTKR2022013646-appb-img-000178
단계 1: tert-butyl 4-(3-((4-(methoxycarbonyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate의 합성Step 1: Synthesis of tert-butyl 4-(3-((4-(methoxycarbonyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate
methyl 4-aminobenzoate (294mg, 1.95mmol), 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965, 500mg, 1.95mmol), 및 HATU (1. 49g, 3.9mmol)를 DMF (3.2ml)에 녹인 후 DIPEA (1.02ml, 5.85mmol)를 가하고 상온에서 15시간 동안 교반 하였다. 반응액에 EtOAc (70ml)를 가한 뒤 물 (30ml x 3), 및 brine (30ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (30% EtOAc /hexane)하여 하얀색 고체 480mg (63%)을 수득하였다.methyl 4-aminobenzoate (294mg, 1.95mmol), 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965, 500mg, 1.95mmol), and HATU (1.49g, 3.9mmol) After dissolving in DMF (3.2ml), DIPEA (1.02ml, 5.85mmol) was added and stirred at room temperature for 15 hours. After adding EtOAc (70ml) to the reaction solution, it was washed with water (30ml x 3) and brine (30ml x 1). 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 obtain 480mg (63%) of a white solid.
단계 2: 4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanamido)benzoic acid의 합성Step 2: Synthesis of 4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanamido)benzoic acid
tert-butyl 4-(3-((4-(methoxycarbonyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate (475mg, 1.22mmol)을 THF : H2O = 1 : 1 (12ml)에 녹인 후 lithium hydroxide monohydrate (766mg, 18.25mmol)를 가하고 60℃에서 24시간 동안 교반 하였다. 반응액에 1 N HCl 수용액을 가하여 pH = 5로 조절한 뒤 EtOAc (30ml x 2)로 추출하였다. 추출한 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 하얀색 고체 440mg (96%)을 수득하였다.tert-butyl 4-(3-((4-(methoxycarbonyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate (475mg, 1.22mmol) dissolved in THF:H 2 O = 1:1 (12ml) After adding lithium hydroxide monohydrate (766mg, 18.25mmol), the mixture was stirred at 60℃ for 24 hours. 1 N HCl aqueous solution was added to the reaction mixture to adjust the pH to 5, followed by extraction with EtOAc (30ml x 2). The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 440 mg (96%) of a white solid.
단계 3: tert-butyl (S)-4-(3-((4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate의 합성Step 3: tert-butyl (S)-4-(3-((4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl) Synthesis of phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate
4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanamido)benzoic acid (150mg, 0.40mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-amine (중간체 1-1, 92mg, 0.40mmol), EDC (153mg, 0.80mmol), 및 HOBt (65mg, 0.48mmol)를 DMF (4ml)에 녹인 후 DIPEA (0.2ml, 1.20mmol)를 가하고 상온에서 16시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (8% DCM/MeOH)하여 노란색 고체 121mg (52%)을 수득하였다.4-(3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanamido)benzoic acid (150mg, 0.40mmol), (S)-2-((2-methylpyrrolidin-1-yl)methyl)-1H After dissolving -benzo[d]imidazol-5-amine (intermediate 1-1, 92mg, 0.40mmol), EDC (153mg, 0.80mmol), and HOBt (65mg, 0.48mmol) in DMF (4ml), DIPEA (0.2ml , 1.20 mmol) was added and stirred at room temperature for 16 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (8% DCM/MeOH) to give 121 mg (52%) of a yellow solid.
단계 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(piperidin-4-yl)propanamido)benzamide hydrochloride의 합성Step 4: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(piperidin-4-yl) Synthesis of propanamido)benzamide hydrochloride
tert-butyl (S)-4-(3-((4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)amino)-3-oxopropyl)piperidine-1-carboxylate (121mg, 0.21mmol)를 DCM (2.1ml)에 녹인 후 4M HCl in dioxane (0.5ml)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 131mg (quant.)을 수득하였다.tert-butyl (S)-4-(3-((4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)phenyl)amino After dissolving )-3-oxopropyl)piperidine-1-carboxylate (121mg, 0.21mmol) in DCM (2.1ml), 4M HCl in dioxane (0.5ml) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 131 mg (quant.) of a white solid.
단계 5: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanamido)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide의 합성Step 5: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanamido)-N-(2- Synthesis of (((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(piperidin-4-yl)propanamido)benzamide hydrochloride (50mg, 0.10mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 26mg, 0.10mmol)을 DMSO (1.0ml)에 녹인 후 DIPEA (0.08ml, 0.48mmol)를 가하고 100℃에서 15시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 32mg (45%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-4-(3-(piperidin-4-yl)propanamido)benzamide hydrochloride (50mg, 0.10mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 26mg, 0.10mmol) dissolved in DMSO (1.0ml) After adding DIPEA (0.08ml, 0.48mmol), the mixture was stirred at 100°C for 15 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 32 mg (45%) of a yellow solid.
실시예 130: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanamido)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 130: 4-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanamido)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000179
Figure PCTKR2022013646-appb-img-000179
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 129의 합성법과 동일한 방법으로 실시예 130을 합성하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 130 was synthesized in the same manner as in Example 129 using -dione (WO2010/081036).
실시예 131: 4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)butanamido)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 131: 4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)butanamido)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000180
Figure PCTKR2022013646-appb-img-000180
3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) 대신 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551)를 사용하여 실시예 129의 합성법과 동일한 방법으로 실시예 131을 합성하였다.4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid instead of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) vol. 37, #16, 2537-2551) was synthesized in Example 131 in the same manner as in Example 129.
실시예 132: 4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)butanamido)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamideExample 132: 4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)butanamido)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)benzamide
Figure PCTKR2022013646-appb-img-000181
Figure PCTKR2022013646-appb-img-000181
3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) 대신 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid (Journal of Medicinal Chemistry, 1994, vol. 37, #16, 2537 - 2551)를 사용하고, 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 129의 합성법과 동일한 방법으로 실시예 132를 합성하였다.4-(1-(tert-butoxycarbonyl)piperidin-4-yl)butanoic acid instead of 3-(1-(tert-butoxycarbonyl)piperidin-4-yl)propanoic acid (WO1994/027965) vol. 37, #16, 2537 - 2551) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead. Example 132 was synthesized in the same manner as in Example 129 using -dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036).
실시예 133: 1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamideExample 133: 1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide
Figure PCTKR2022013646-appb-img-000182
Figure PCTKR2022013646-appb-img-000182
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide hydrochloride (중간체 1-10, 30mg, 0.08mmol), 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (중간체 3-31, 33mg, 0.08mmol), HATU (61mg, 0.16mmol), 및 DIPEA (0.04ml, 0.24mmol)를 DMF (0.8ml)에 현탁 시킨 후 상온에서 15시간 동안 교반 하였다. 반응물에 증류수 (20ml)를 가한 뒤 EtOAc (30ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% (10% NH4OH/MeOH)/DCM)하여 노란색 고체 8.5mg (14%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide hydrochloride (Intermediate 1-10, 30mg, 0.08mmol ), 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (intermediate 3-31, 33mg, 0.08mmol ), HATU (61mg, 0.16mmol), and DIPEA (0.04ml, 0.24mmol) were suspended in DMF (0.8ml) and stirred at room temperature for 15 hours. After adding distilled water (20ml) to the reaction mixture, extraction was performed with EtOAc (30ml), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% (10% NH 4 OH/MeOH)/DCM) to give 8.5 mg (14%) of a yellow solid.
실시예 134: 1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamideExample 134: 1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide
Figure PCTKR2022013646-appb-img-000183
Figure PCTKR2022013646-appb-img-000183
3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (중간체 3-31) 대신 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoic acid (중간체 3-32)를 사용하여 실시예 133의 합성법과 동일한 방법으로 실시예 134를 합성하였다. 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanoic acid (intermediate 3-31) instead of 3-(1- The same method as the synthesis method of Example 133 using (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanoic acid (Intermediate 3-32) Example 134 was synthesized with
실시예 135: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamideExample 135: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide
Figure PCTKR2022013646-appb-img-000184
Figure PCTKR2022013646-appb-img-000184
단계 1: tert-butyl (S)-4-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate의 합성Step 1: tert-butyl (S)-4-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)piperidin Synthesis of -1-yl)-3-oxopropyl)piperazine-1-carboxylate
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide hydrochloride (중간체 1-10, 202mg, 0.53mmol), 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoic acid (138mg, 0.53mmol), EDC (205mg, 1.07mmol), 및 HOBt (87mg, 0.64mmol)를 DMF (5.3ml)에 녹인 후 DIPEA (0.28ml, 1.60mmol)를 가하고 상온에서 19시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (20ml x 4), 및 brine (20ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 MPLC (10% DCM/MeOH(10% NH3))하여 하얀색 고체 84mg (27%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide hydrochloride (Intermediate 1-10, 202mg, 0.53mmol ), 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propanoic acid (138 mg, 0.53 mmol), EDC (205 mg, 1.07 mmol), and HOBt (87 mg, 0.64 mmol) in DMF (5.3 ml). After melting, DIPEA (0.28ml, 1.60mmol) was added and stirred at room temperature for 19 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (20ml x 4) and brine (20ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (10% DCM/MeOH (10% NH 3 )) to give 84 mg (27%) of a white solid.
단계 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1-(3-(piperazin-1-yl)propanoyl)piperidine-4-carboxamide hydrochloride의 합성Step 2: (S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1-(3-(piperazin-1-yl) Synthesis of propanoyl)piperidine-4-carboxamide hydrochloride
tert-butyl (S)-4-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)piperidin-1-yl)-3-oxopropyl)piperazine-1-carboxylate (78mg, 0.13mmol)를 DCM (1.3ml)에 녹인 후 4M HCl in dioxane (0.5ml)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액을 농축하여 흰색 고체 128mg (quant.)을 수득하였다.tert-butyl (S)-4-(3-(4-((2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)carbamoyl)piperidin-1- After dissolving yl)-3-oxopropyl)piperazine-1-carboxylate (78mg, 0.13mmol) in DCM (1.3ml), 4M HCl in dioxane (0.5ml) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 128 mg (quant.) of a white solid.
단계 3: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide의 합성Step 3: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)propanoyl)-N-(2- Synthesis of (((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide
(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1-(3-(piperazin-1-yl)propanoyl)piperidine-4-carboxamide hydrochloride (58mg, 0.11mmol), 및 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845, 31mg, 0.11mmol)을 DMSO (1.1ml)에 녹인 후 DIPEA (0.09ml, 0.56mmol)를 가하고 100℃에서 15시간 동안 교반 하였다. 반응액에 EtOAc (40ml)를 가한 뒤 물 (2.0ml x 4), 및 brine (2.0ml x 1)으로 세척하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하였다. 얻어진 잔사를 PTLC (10% DCM/MeOH(10% NH3))하여 노란색 고체 20mg (24%)을 수득하였다.(S)-N-(2-((2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)-1-(3-(piperazin-1-yl)propanoyl)piperidine DMSO (1.1 ml), DIPEA (0.09ml, 0.56mmol) was added, and the mixture was stirred at 100°C for 15 hours. After adding EtOAc (40ml) to the reaction mixture, the mixture was washed with water (2.0ml x 4) and brine (2.0ml x 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% DCM/MeOH (10% NH 3 )) to give 20 mg (24%) of a yellow solid.
실시예 136: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)-N-(2-(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamideExample 136: 1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)propanoyl)-N-(2 -(((S)-2-methylpyrrolidin-1-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidine-4-carboxamide
Figure PCTKR2022013646-appb-img-000185
Figure PCTKR2022013646-appb-img-000185
2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) 대신 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (WO2010/081036)을 사용하여 실시예 135의 합성법과 동일한 방법으로 실시예 136을 합성하였다.2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (WO2015/160845) instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3 Example 136 was synthesized in the same manner as in Example 135 using -dione (WO2010/081036).
실시예 35 내지 41의 합성법 또는 실시예 44 내지 46의 합성법과 유사한 방법으로 실시예(example) 137 내지 141을 합성하였다. IUPAC 명칭과 구조를 하기에 종합하여 나타내었다.Examples 137 to 141 were synthesized in a manner similar to the synthesis method of Examples 35 to 41 or the synthesis method of Examples 44 to 46. The IUPAC names and structures are presented collectively below.
Figure PCTKR2022013646-appb-img-000186
Figure PCTKR2022013646-appb-img-000186
Figure PCTKR2022013646-appb-img-000187
Figure PCTKR2022013646-appb-img-000187
앞서 합성한 화합물들의 NMR 및/또는 LC/MS 측정 결과를 하기 표 11에 종합하여 나타내었다. The NMR and/or LC/MS measurement results of the previously synthesized compounds are summarized in Table 11 below.
Figure PCTKR2022013646-appb-img-000188
Figure PCTKR2022013646-appb-img-000188
Figure PCTKR2022013646-appb-img-000189
Figure PCTKR2022013646-appb-img-000189
Figure PCTKR2022013646-appb-img-000190
Figure PCTKR2022013646-appb-img-000190
Figure PCTKR2022013646-appb-img-000191
Figure PCTKR2022013646-appb-img-000191
Figure PCTKR2022013646-appb-img-000192
Figure PCTKR2022013646-appb-img-000192
Figure PCTKR2022013646-appb-img-000193
Figure PCTKR2022013646-appb-img-000193
Figure PCTKR2022013646-appb-img-000194
Figure PCTKR2022013646-appb-img-000194
Figure PCTKR2022013646-appb-img-000195
Figure PCTKR2022013646-appb-img-000195
Figure PCTKR2022013646-appb-img-000196
Figure PCTKR2022013646-appb-img-000196
Figure PCTKR2022013646-appb-img-000197
Figure PCTKR2022013646-appb-img-000197
Figure PCTKR2022013646-appb-img-000198
Figure PCTKR2022013646-appb-img-000198
Figure PCTKR2022013646-appb-img-000199
Figure PCTKR2022013646-appb-img-000199
Figure PCTKR2022013646-appb-img-000200
Figure PCTKR2022013646-appb-img-000200
Figure PCTKR2022013646-appb-img-000201
Figure PCTKR2022013646-appb-img-000201
Figure PCTKR2022013646-appb-img-000202
Figure PCTKR2022013646-appb-img-000202
Figure PCTKR2022013646-appb-img-000203
Figure PCTKR2022013646-appb-img-000203
실험예 1: ENL 단백질 분해능 측정 Experimental Example 1: Measurement of ENL protein degradation
합성된 실시예 화합물을 MOLM13 세포에 처리하여 세포내에 존재하는 ENL 단백질의 양을 western blotting 검출법을 사용하여 측정하였다. MOLM13 세포를 사용하여 진행된 실험의 protocol은 다음과 같았다. MOLM13 cells were treated with the synthesized example compounds, and the amount of ENL protein present in the cells was measured using a western blotting detection method. The protocol of the experiment using MOLM13 cells was as follows.
[배양] MOLM13 세포를 RPMI1640 MEDIUM (Hyclone, SH30027.01), 10% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02) media에 resuspend하여 1 x 106/mL로 12-well plate에 1 mL씩 seeding하였다. [Culture] MOLM13 cells were resuspended in RPMI1640 MEDIUM (Hyclone, SH30027.01), 10% FBS (Hyclone, SV30207.02), and 1% Penicillin-streptomycin (Welgene, LS 202-02) media to 1 x 10 6 /mL 1 mL each was seeded in a 12-well plate.
[화합물 처리] 12-well plate에 다음과 같이 처리하였다. 10 mM stock을 DMSO로 1/10씩 serial dilution하여 (3 μL + 27 μL DMSO) 최종 농도 0.1, 1, 10 μM 또는 0.0001, 0.001, 0.01, 0.1 μM로 화합물을 세포에 처리하고 24 시간 후 harvest하였다. 음성대조군에는 media에 1/10으로 희석한 DMSO를 넣어주었다 (3 μL DMSO + 27 μL media). [Compound treatment] A 12-well plate was treated as follows. A 10 mM stock was serially diluted with DMSO by 1/10 (3 μL + 27 μL DMSO), and the cells were treated with compounds at final concentrations of 0.1, 1, 10 μM, or 0.0001, 0.001, 0.01, 0.1 μM, and harvested after 24 hours. . In the negative control group, 1/10 diluted DMSO was added to the media (3 μL DMSO + 27 μL media).
[Harvest] 각 well을 1 mL pipette으로 pipetting하여 1.5 mL microtube에 모아 centrifuge (500 g, 5 min, 4℃)하였다. 상층액 제거 후 PBS washing하여 다시 centrifuge (500 g, 5 min, 4℃) 한 후 상층액을 제거하여 pellet을 준비하였다. [Harvest] Each well was pipetted with a 1 mL pipette, collected in a 1.5 mL microtube, and centrifuged (500 g, 5 min, 4°C). After removing the supernatant, washing with PBS and centrifuging (500 g, 5 min, 4 ℃) again, the supernatant was removed to prepare a pellet.
[Cell lysis 및 Sample 준비] Iysis buffer는 다음과 같이 준비하였다. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1x Protease/Phosphatase Inhibitor (Cell signaling, 5872S) = well 당 100 μL씩 넣고 30분간 얼음위에 두었다. (0, 30분에 각각 vortexing) 이후 sonication 과정을 (10초 pulse, 30초 rest, 5 cycles, 70% amplification) 진행하고 centrifuge (15000 g, 15 min, 4℃)하여 상층액만 따서 새 microtube로 옮겼다. 96-well plate에 RIPA buffer로 샘플을 1/2 희석해서 넣고 BCA Protein Assay Kit (iNtRON, 21071)의 A:B = 50:1로 섞어 200 μL씩 넣어 37℃에서 30분 동안 두고 10분간 식혀주었다. 이후 BioTek 사의 SYNERGY H1 microplate reader로 562 nm에서 absorbance를 측정하였다. 측정값으로 단백질을 정량하여 샘플을 만든 후, 70℃에서 10분간 boiling하였다. 이때 사용되는 Sample buffer는 사용할 gel에 맞추어 NuPAGE 혹은 Bolt 4x sample buffer (Invitrogen)와 각각의 10x sample reducing agent를 섞어서 사용하였다. 단백질 희석은 RIPA buffer를 이용하였다. [Cell lysis and sample preparation] Isis buffer was prepared as follows. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1x Protease/Phosphatase Inhibitor (Cell signaling, 5872S) = 100 μL per well and left on ice for 30 minutes. (Vortexing at 0 and 30 minutes respectively), proceed with sonication process (10 seconds pulse, 30 seconds rest, 5 cycles, 70% amplification), and centrifuge (15000 g, 15 min, 4℃) to collect only the supernatant and transfer it to a new microtube. moved A 1/2 dilution of the sample with RIPA buffer was added to a 96-well plate, mixed with A:B = 50:1 of the BCA Protein Assay Kit (iNtRON, 21071), and 200 μL of each was placed at 37 ° C for 30 minutes and cooled for 10 minutes. . Then, absorbance was measured at 562 nm using a SYNERGY H1 microplate reader from BioTek. After making a sample by quantifying the protein with the measured value, it was boiled at 70 ° C. for 10 minutes. At this time, the sample buffer used was a mixture of NuPAGE or Bolt 4x sample buffer (Invitrogen) and each 10x sample reducing agent according to the gel to be used. RIPA buffer was used for protein dilution.
[Western blotting 검출법] NuPAGE 혹은 Bolt Bis-tris 4-12% gradient gel에 같은 양의 샘플을 loading하여 running 하였다. (200 V, 35분) Trans-blot Turbo (BIO-RAD)로 0.2 mm NC membrane에 transfer하였다. (1.3 A constant, 25 V limit, 15분) Skim milk 혹은 Intercept Blocking Buffer (LI-COR, 927-60001):0.1% TBST = 1:1 로 1시간 동안 상온에서 blocking해주었다. Anti ENL Rabbit (1:1,000 in 5% skim milk/0.2% TBST, size: 62 kDa, Abcam)은 4℃에서 O/N 혹은 상온에서 3 시간 동안 붙여주고 Anti GAPDH Rabbit (1:2,500 in 5% BSA/0.2% TBST, size: 36 kDa, GENETEX)과 Anti β-actin mouse (1:2,500 in 5% BSA/0.2% TBST, RT, size: 43 kDa, GENETEX)는 상온에서 1시간 30분 혹은 3시간 동안 붙여주었다. 0.5% TBST로 각 5분씩 3회 washing 해주고 2차 antibody인 Anti-Rabbit IgG (1:5,000 in 5% Skim milk/TBST, CST), IRDye® 800CW Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 5% skim/TBST, RT 45 min), 및 IRDye® 680RD Goat anti-Mouse IgG Secondary Antibody (1:10,000 in 5% skim/TBST, RT 45 min)를 넣어주고 상온의 rocker 위에 45분간 두었다. 0.5% TBST로 각 5분씩 5회 washing 해주고 LI-COR사의 Odyssey로 detection 해주었다. 이때 ENL은 SuperSignal West Pico PLUS Chemiluminescent Substrate 혹은 SuperSignal West femto Maximum Sensitivity Substrate를 이용해 detection하고 house-keeping gene들은 그대로 detection하였다. [Western blotting detection method] The same amount of sample was loaded on NuPAGE or Bolt Bis-tris 4-12% gradient gel and run. (200 V, 35 minutes) Trans-blot Turbo (BIO-RAD) was used to transfer to a 0.2 mm NC membrane. (1.3 A constant, 25 V limit, 15 minutes) Skim milk or Intercept Blocking Buffer (LI-COR, 927-60001): 0.1% TBST = 1: 1 was blocked at room temperature for 1 hour. Anti ENL Rabbit (1:1,000 in 5% skim milk/0.2% TBST, size: 62 kDa, Abcam) was applied O/N at 4℃ or at room temperature for 3 hours, and Anti GAPDH Rabbit (1:2,500 in 5% BSA /0.2% TBST, size: 36 kDa, GENETEX) and Anti β-actin mouse (1:2,500 in 5% BSA/0.2% TBST, RT, size: 43 kDa, GENETEX) for 1 hour 30 minutes or 3 hours at room temperature attached during After washing with 0.5% TBST three times for 5 minutes each, secondary antibody Anti-Rabbit IgG (1:5,000 in 5% Skim milk/TBST, CST), IRDye® 800CW Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 5 % skim/TBST, RT 45 min), and IRDye® 680RD Goat anti-Mouse IgG Secondary Antibody (1:10,000 in 5% skim/TBST, RT 45 min) and placed on a rocker at room temperature for 45 minutes. After washing with 0.5% TBST 5 times for 5 minutes each, detection was performed with LI-COR's Odyssey. At this time, ENL was detected using SuperSignal West Pico PLUS Chemiluminescent Substrate or SuperSignal West femto Maximum Sensitivity Substrate, and house-keeping genes were detected as they were.
이러한 평가 결과를 하기 표 12에 종합하여 나타내었다.These evaluation results are summarized and shown in Table 12 below.
Figure PCTKR2022013646-appb-img-000204
Figure PCTKR2022013646-appb-img-000204
Figure PCTKR2022013646-appb-img-000205
Figure PCTKR2022013646-appb-img-000205
Figure PCTKR2022013646-appb-img-000206
Figure PCTKR2022013646-appb-img-000206
상기 표 12에 나타나는 바와 같이, 본 발명에 따른 화합물들은 ENL 단백질을 분해하는데 있어 우수한 활성을 나타내었다. As shown in Table 12, the compounds according to the present invention exhibited excellent activity in degrading ENL protein.
특히, ENL 단백질 분해 활성 등 다양한 측면에서 실시예 13-15, 32, 34-37, 39, 40, 41, 43-49, 56-59, 61-63, 65-70, 76, 78, 81, 82, 84, 87, 88, 90, 91, 96, 98-100, 102, 104, 106-111, 117, 119, 121, 131, 및 137-141의 화합물이 바람직하였다.In particular, in various aspects such as ENL proteolytic activity, Examples 13-15, 32, 34-37, 39, 40, 41, 43-49, 56-59, 61-63, 65-70, 76, 78, 81, Compounds of 82, 84, 87, 88, 90, 91, 96, 98-100, 102, 104, 106-111, 117, 119, 121, 131, and 137-141 were preferred.

Claims (15)

  1. 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염.A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
    [화학식 1][Formula 1]
    Figure PCTKR2022013646-appb-img-000207
    Figure PCTKR2022013646-appb-img-000207
    상기 화학식 1에서, In Formula 1,
    R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고,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,
    X는 NH 또는 O이고,X is NH or O;
    A는 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며, 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;
    n은 0, 1, 또는 2이고, n is 0, 1, or 2;
    L은 하기 화학식 2이고,L is Formula 2 below,
    [화학식 2][Formula 2]
    Figure PCTKR2022013646-appb-img-000208
    Figure PCTKR2022013646-appb-img-000208
    상기 화학식 2에 있어서, In Formula 2,
    A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고,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-,
    B1, B2 및 B3은 서로 독립적으로 직접 결합, C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 C3-12사이클로알킬, 헤테로사이클, 아릴, 또는 헤테로아릴 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며, 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;
    R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH이며,R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, or -OH;
    q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
    E는 하기 화학식 3 또는 4임.E is Formula 3 or 4.
    [화학식 3][Formula 3]
    Figure PCTKR2022013646-appb-img-000209
    Figure PCTKR2022013646-appb-img-000209
    상기 화학식 3에 있어서, In Formula 3,
    R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-, wherein R 5 and R 5 'are mutually independently H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    [화학식 4][Formula 4]
    Figure PCTKR2022013646-appb-img-000210
    Figure PCTKR2022013646-appb-img-000210
    화학식 4에서, In Formula 4,
    R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고,R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    X1, X2 및 X3는 서로 독립적으로 CH 또는 N이며, X 1 , X 2 and X 3 are independently of each other CH or N,
    Z는 직접 결합, -C(R5)(R5')-, -N(R5)-, -O-, 또는 -C(O)NH-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시임.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.
  2. 제1항에 있어서, 상기 화학식 1에서, The method of claim 1, wherein in Formula 1,
    R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고, 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,
    X는 NH이고,X is NH;
    A는 헤테로사이클, 아릴, 또는 헤테로아릴이며, 여기에서 헤테로사이클, 아릴, 또는 헤테로아릴은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며, 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;
    n은 0 또는 1이고, n is 0 or 1;
    L은 하기 화학식 2이고,L is Formula 2 below,
    [화학식 2][Formula 2]
    Figure PCTKR2022013646-appb-img-000211
    Figure PCTKR2022013646-appb-img-000211
    상기 화학식 2에 있어서, In Formula 2,
    A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고, 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,
    B1, B2 및 B3은 서로 독립적으로 직접 결합, 헤테로사이클, 또는 헤테로아릴이며, 여기에서 헤테로사이클, 또는 헤테로아릴 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며, 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;
    R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 또는 -OH이며, R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, or -OH;
    q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
    E는 하기 화학식 3임.E is Formula 3 below.
    [화학식 3][Formula 3]
    Figure PCTKR2022013646-appb-img-000212
    Figure PCTKR2022013646-appb-img-000212
    상기 화학식 3에 있어서, In Formula 3,
    R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-;
    R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시인, 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;
    화합물 또는 이의 약학적으로 허용 가능한 염. A compound or a pharmaceutically acceptable salt thereof.
  3. 제2항에 있어서, 상기 화학식 1에서The method of claim 2, wherein in Formula 1
    R1 및 R2는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, 히드록시C1-6알킬, C1-6알콕시알킬, C1-6알콕시, 또는 -OH이고,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,
    X는 NH이고,X is NH;
    A는 하기 치환기들 중 어느 하나이며, 여기에서 하기 치환기들은 고리 내 하나 이상의 수소가 임의로(optionally) C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시로 치환되며,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;
    Figure PCTKR2022013646-appb-img-000213
    Figure PCTKR2022013646-appb-img-000213
    n은 0, 또는 1이고, n is 0 or 1;
    L은 하기 화학식 2이고,L is Formula 2 below,
    [화학식 2][Formula 2]
    Figure PCTKR2022013646-appb-img-000214
    Figure PCTKR2022013646-appb-img-000214
    상기 화학식 2에 있어서, In Formula 2,
    A1, A2 및 A3은 서로 독립적으로 직접 결합, -O-, -N(R3)-, -C(R3)(R3')-, -C(O)-, -C(O)NH-, -NHC(O)-, -C(O)CH2NH-, -C(O)CH2O-, -NHC(O)CH2NH-, 또는 -NHC(O)CH2O-이고, 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,
    B1, B2 및 B3은 서로 독립적으로 직접 결합, 또는 하기 치환기들 중 어느 하나이며, 여기에서 하기 치환기들은 고리 내 하나 이상의 수소가 임의로 C1-6알킬, 할로겐, 할로C1-6알킬, 또는 -OH로 치환되며,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,
    Figure PCTKR2022013646-appb-img-000215
    Figure PCTKR2022013646-appb-img-000215
    R3 및 R3'는 서로 독립적으로 H, C1-6알킬, 할로겐, 또는 -OH이며, R 3 and R 3 'are independently of each other H, C 1-6 alkyl, halogen, or -OH;
    q1 내지 q5는 서로 독립적으로 0 내지 10의 정수이며, q1 to q5 are independently integers from 0 to 10;
    E는 하기 화학식 3임.E is Formula 3 below.
    [화학식 3][Formula 3]
    Figure PCTKR2022013646-appb-img-000216
    Figure PCTKR2022013646-appb-img-000216
    상기 화학식 3에 있어서, In Formula 3,
    R4는 H, C1-6알킬, 또는 할로겐이고, R 4 is H, C 1-6 alkyl, or halogen;
    Y는 -CH2-, -C(O)-, 또는 -N=N-인, Y is -CH 2 -, -C(O)-, or -N=N-;
    화합물 또는 이의 약학적으로 허용 가능한 염.A compound or a pharmaceutically acceptable salt thereof.
  4. 제1항에 있어서, 상기 E는 하기 화학식 3'이며, The method of claim 1, wherein E is Formula 3',
    [화학식 3'][Formula 3']
    Figure PCTKR2022013646-appb-img-000217
    Figure PCTKR2022013646-appb-img-000217
    상기 화학식 3'에서, In Formula 3',
    R4는 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, R 4 is H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    Y는 -C(R5)(R5')-, -C(O)-, -C(R5)(R5')-C(R5)(R5')-, -C(R5)=C(R5')-, -C(R5)=N-, -N=C(R5)-, 또는 -N=N-이고, 여기에서, R5 및 R5'는 서로 독립적으로 H, C1-6알킬, 할로겐, 할로C1-6알킬, C1-6알콕시 또는 할로C1-6알콕시이고, Y is -C(R 5 )(R 5 ')-, -C(O)-, -C(R 5 )(R 5 ')-C(R 5 )(R 5 ')-, -C(R 5 )=C(R 5 ')-, -C(R 5 )=N-, -N=C(R 5 )-, or -N=N-, wherein R 5 and R 5 'are mutually independently H, C 1-6 alkyl, halogen, haloC 1-6 alkyl, C 1-6 alkoxy or haloC 1-6 alkoxy;
    E는
    Figure PCTKR2022013646-appb-img-000218
    또는
    Figure PCTKR2022013646-appb-img-000219
    에 직접 연결되어 있는,     E is
    Figure PCTKR2022013646-appb-img-000218
    or
    Figure PCTKR2022013646-appb-img-000219
    directly connected to
    화합물 또는 이의 약학적으로 허용 가능한 염.A compound or a pharmaceutically acceptable salt thereof.
  5. 제1항에 있어서, 상기 화합물은 하기 화합물 중 어느 하나인 화합물 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 1, wherein the compound is any one of the following compounds, or a pharmaceutically acceptable salt thereof.
    Figure PCTKR2022013646-appb-img-000220
    Figure PCTKR2022013646-appb-img-000220
    Figure PCTKR2022013646-appb-img-000221
    Figure PCTKR2022013646-appb-img-000221
    Figure PCTKR2022013646-appb-img-000222
    Figure PCTKR2022013646-appb-img-000222
    Figure PCTKR2022013646-appb-img-000223
    Figure PCTKR2022013646-appb-img-000223
    Figure PCTKR2022013646-appb-img-000224
    Figure PCTKR2022013646-appb-img-000224
    Figure PCTKR2022013646-appb-img-000225
    Figure PCTKR2022013646-appb-img-000225
  6. 제5항에 있어서, 상기 화합물은 하기 화합물들 중 어느 하나인, 화합물 또는 이의 약학적으로 허용 가능한 염.The compound according to claim 5, wherein the compound is any one of the following compounds, or a pharmaceutically acceptable salt thereof.
    Figure PCTKR2022013646-appb-img-000226
    Figure PCTKR2022013646-appb-img-000226
    Figure PCTKR2022013646-appb-img-000227
    Figure PCTKR2022013646-appb-img-000227
    Figure PCTKR2022013646-appb-img-000228
    Figure PCTKR2022013646-appb-img-000228
  7. 제1항 내지 제6항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체를 포함하는 조성물.A composition comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  8. 유효 성분으로 제1항 내지 제6항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는, ENL 단백질의 분해를 위한 약학 조성물.A pharmaceutical composition for degradation of ENL protein, comprising the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 제8항에 있어서, 상기 약학 조성물은 암의 치료 또는 예방용인, 약학 조성물. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is for treatment or prevention of cancer.
  10. 제9항에 있어서, 상기 암은 백혈병 또는 신장암인, 약학 조성물. The pharmaceutical composition according to claim 9, wherein the cancer is leukemia or renal cancer.
  11. 제10항에 있어서, 상기 백혈병은 급성 림프구성 백혈병 또는 급성 골수성 백혈병인, 약학 조성물. The pharmaceutical composition according to claim 10, wherein the leukemia is acute lymphocytic leukemia or acute myelogenous leukemia.
  12. 제1항 내지 제6항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, ENL 단백질 관련 질환의 치료 또는 예방 방법. A method for treating or preventing an ENL protein-related disease, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof to a subject in need thereof.
  13. 제12항에 있어서, 상기 ENL 단백질 관련 질환은 암인 치료 또는 예방 방법. The method of claim 12, wherein the ENL protein-related disease is cancer.
  14. 제13항에 있어서, 상기 암은 백혈병 또는 신장암인 치료 또는 예방 방법. The method of claim 13, wherein the cancer is leukemia or renal cancer.
  15. 제14항에 있어서, 상기 백혈병은 급성 림프구성 백혈병 또는 급성 골수성 백혈병인, 치료 또는 예방 방법. The method of claim 14, wherein the leukemia is acute lymphocytic leukemia or acute myelogenous leukemia, treatment or prevention method.
PCT/KR2022/013646 2021-09-13 2022-09-13 Compound for degrading enl protein and medical uses thereof WO2023038500A1 (en)

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Citations (2)

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