WO2018208123A1 - Nouveau dérivé de pipéridine-2,6-dione et son utilisation - Google Patents

Nouveau dérivé de pipéridine-2,6-dione et son utilisation Download PDF

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Publication number
WO2018208123A1
WO2018208123A1 PCT/KR2018/005444 KR2018005444W WO2018208123A1 WO 2018208123 A1 WO2018208123 A1 WO 2018208123A1 KR 2018005444 W KR2018005444 W KR 2018005444W WO 2018208123 A1 WO2018208123 A1 WO 2018208123A1
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WIPO (PCT)
Prior art keywords
triazine
substituted
dione
cancer
piperidine
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PCT/KR2018/005444
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English (en)
Korean (ko)
Inventor
황종연
하재두
조성윤
김필호
윤창수
박지훈
이정옥
최상운
이주연
안선주
Original Assignee
한국화학연구원
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Priority claimed from KR1020170184761A external-priority patent/KR102014478B1/ko
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Priority to EP18798940.5A priority Critical patent/EP3623366B9/fr
Priority to JP2019561172A priority patent/JP7157764B2/ja
Priority to US16/609,805 priority patent/US11192878B2/en
Priority to CN201880031388.8A priority patent/CN110621664B/zh
Publication of WO2018208123A1 publication Critical patent/WO2018208123A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel piperidine-2,6-dione derivative and its use, more particularly to prevent or treat the effects of leprosy, chronic graft-versus-host disease, inflammatory disease or cancer.
  • Peridine-2,6-dione derivatives are particularly useful as piperidine-2,6-dione derivatives.
  • thalidomide is a trademarked thalamide (THALOMID®) and ⁇ ⁇ - ( ⁇ -phthalimido) glutarimide or
  • Dallydomide 2- (2,6-dioxo-3-piperidinyl) -1H—isoindole-1,3 (2 ⁇ ) -racemic compound sold under the chemical name Dallydomide is a morning sickness. It has been developed to treat) but has been discontinued due to teratogenic effects. Thalidomide is currently approved in the United States for the treatment of human leprosy nodules (Physician's Desk Reference, 1081-1085 (55th ed., 2001)).
  • thalidomide is also known as leprosy, chronic graft-versus-host disease, rheumatoid arthritis,
  • thalidomide has been used to treat certain types of cancer, including refractory multiple myeloma, brain, melanoma, breast, colon, mesothelioma and renal cell carcinoma.
  • Thalidomide has been reported to be used to prevent further expression of the only Heart myopathy caused by doxorubicin in rats by "(Costa, PT, et al , 92 (10:.. Suppl 1) Blood, 235b (1998)). Different reports on the use of thalidomide in the treatment of certain cancers. Combination with carboplatin in the treatment of glioblastoma
  • Thalidomide has also been reported to be used as an anti-nausea agent in the treatment of astrocytoma (Zwart, D., 16 (12) Arzneim.-Forsch. , 1688-1689 (1966)).
  • thalidomide has been widely used for the prevention or treatment of lupus nephritis, fibromyalgia, schizophrenia, central nervous system disease, diabetes, and side effects, but it is a fatal side effect of malformation in pregnant women. As a result, he had a withdrawal from the market in late 1961.
  • the present inventors have made efforts to develop new derivative compounds that retain the physiological activity of thalidomide, but do not exhibit the side effects of thalidomide, especially new thalidomide based on piperidine-2,6-dion.
  • the invention has been completed by developing derivatives and evaluating their activity.
  • X is nitrogen (N) or carbon (C),
  • hetero cycloalkenyl unsubstituted or substituted C 6 -C 14 ⁇ l aryl, unsubstituted or substituted unsubstituted or substituted, which contain at least one heteroatom selected from an aryl alkyl, or N, the group consisting of 0 and S of C 6 -C 24 C 6 - It is substituted with one or more substituents selected from the group consisting of C 14 heteroaryl,
  • R 3 is substituted with one or more substituents selected from the group consisting of hydrogen, deuterium or unsubstituted or substituted -0 straight or branched alkyl.
  • [16] 3 ⁇ 4 is hydrogen,-(CH 2 ) n OCOR 8 or unsubstituted or substituted C r C, ⁇ straight or branched chain It is substituted with one or more substituents selected from the group consisting of alkyl,
  • R 5 to 3 ⁇ 4 are each independently hydrogen, unsubstituted or substituted amino, unsubstituted or substituted d-o straight or branched chain alkyl, unsubstituted or substituted d-do straight or branched chain alkenyl, beach Unsubstituted or substituted ⁇ 10 containing one or more hetero atoms selected from the group consisting of linear or branched alkynyl, unsubstituted or substituted C 3- .
  • n 1 to 5 and an integer.
  • Another object of the present invention is to prepare a compound represented by the following formula (2) by (a) reacting a compound represented by the following formula (2) with a compound represented by the following formula (3);
  • Another object of the present invention is a compound of Formula 1 or a pharmaceutically acceptable To provide a pharmaceutical composition for the prevention or treatment of leprosy, chronic graft-versus-host disease, inflammatory disease or cancer containing possible salts as active ingredients.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • X is nitrogen (N) or carbon (C),
  • R 3 is substituted with one or more substituents selected from the group consisting of hydrogen, deuterium or unsubstituted or substituted CrC 1 ( ⁇ straight or branched chain alkyl),
  • R 4 is hydrogen, — (CH 2 ) n OCOR 8 or unsubstituted or substituted dC, ⁇ straight or branched chain
  • R 5 to silver each independently hydrogen, unsubstituted or substituted amino, unsubstituted or substituted ⁇ 10 straight or branched chain alkyl, unsubstituted or substituted C, -C 10 straight or branched chain alkenyl, beach Heterocyclic selected from the group consisting of cyclic or substituted d-Cu ⁇ straight or branched alkynyl, unsubstituted or substituted ⁇ 10 cycloalkyl, N, O and S At least one heteroatom selected from unsubstituted or substituted C 3 -C 10 heterocycloalkyl, unsubstituted or substituted C 6 -C 14 aryl, or a group consisting of N, O and S Unsubstituted or substituted C 6 -C 14 is substituted with one or more substituents selected from the group consisting of heteroaryl, and
  • n is an integer of 1 to 5.
  • Halogen in the present invention means fluoro (F), chlorine (C1), brine (Br), iodine (I).
  • substituted includes at least one substituent, e.g., a haloken atom, nitro, hydroxy, cyano, amino, thiol, carboxyl, amide, nitrile, sulfide, disulfide , Sulfenyl, Formyl, Formyloxy ,
  • alkyl used in the present invention, unless otherwise indicated, includes straight or branched carbon atoms l-UXCrdc), more preferably carbon atoms l-6 (C r ), more preferably carbon atoms 1-4 ( ⁇ ). 4 ) hydrocarbon radicals, e.g.
  • the alkyl may be substituted or unsubstituted alkyl.
  • alkenyl or “alkynyl” includes 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, including straight or branched chains each containing one or more double or triple bonds.
  • hydrocarbons Preferably 1 to 4 carbon atoms
  • Alkyl or alkynyl can be substituted or unsubstituted alkenyl or alkynyl, respectively.
  • alkoxy used in the present invention means a -0-alkyl group, and alkyl is as described above. For example, methoxy, trifluoromethoxy, epoxy, n-propoxy, Isopropoxy, n-subspecial, t-subspecial, sec-butoxy and n-pentoxy.
  • the alkoxy may be substituted or unsubstituted alkoxy.
  • cycloalkyl used in the present invention means a ring alkyl group and is formed with a single ring of 3 to 10 carbon atoms.
  • the cycloalkyl may be substituted or unsubstituted cycloalkyl.
  • cycloalkenyl used in the present invention means a ring alkenyl group and is formed with a single ring of 3 to 10 carbon atoms.
  • cyclonuxenyl cyclopentenyl
  • cyclobutenyl etc.
  • the cycloalkenyl may be substituted or unsubstituted cycloalkenyl.
  • aryl as used in the present invention means an aromatic moiety, which is a carbon ring functional group, and is a monocyclic ring (e.g., phenyl) or a polyfused ring (e.g. naphthyl, 6 to 14 carbon atoms). Anthryl, phenanthryl). The aryl may be substituted or unsubstituted aryl.
  • arylalkyl used in the present invention means an aryl group substituted with an alkyl group, and aryl and alkyl are as described above.
  • Heterocycloalkyl has single or multiple fused rings, have 3 to 12 ring atoms, and at least one ring atom is a hetero atom (for example , Nitrogen, sulfur or oxygen) means “cycloalkyl”, “cycloalkenyl” and “aryl”, each substituted with a different kind.
  • the pharmaceutically acceptable salts refer to salts or complexes of Formula 1 having a desirable biological activity.
  • examples of such salts include, but are not limited to, inorganic acids [eg, hydrochloric acid (eg, hydrochloric acid). acid),
  • salts formed with organic acids such as poly-galacturonic acid.
  • the compounds are also known pharmaceutically acceptable to those skilled in the art. It may be administered as a quaternary salt, in particular chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate Acetate, Glycolate Maleate, Malate, Fumarate, Citrate, Tartrate, Ascorbate, Cinnamoate, Mandeloate and Diphenyl Acetate)
  • the compound of 1 may contain not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates that can be prepared by conventional methods.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included in the scope of the present invention.
  • R, or 3 ⁇ 4 are each independently hydrogen, hydroxy, halogen, cyano, amino, nitro, -CH 3, -OCF 3, -OCH 3, -NHCOCH ,, -COOH, -CONH 2, -CONHCH Is substituted with one or more substituents selected from the group consisting of 3 or -NHCOC 6 H 5 ,
  • R 4 is —CH 2 OCOC (CH 3 ) 3 , -CH 2 OCOC 6 H 5 , -CH 2 COC 5 H 10 N, -CH 2 OCOC 4 H 8 N, -CH 2 OCOCH (NH 2 ) CH (CH 3 ) CH 2 CH 3 , -CH 2 OCOCH 2 CH 2 CH 3 or -CH 2 OCOC 4 H 7 It is substituted with one or more substituents selected from the group consisting of, more preferably
  • ⁇ is nitrogen ( ⁇ ).
  • ⁇ is nitrogen ( ⁇ )
  • R, or R 2 are each independently hydrogen, hydroxy, halogen, cyano, amino, nitro,
  • R4 is -CH 2 OCOC (CH 3 ) 3 , -CH 2 OCOC 6 H 5 , -CH 2 COC 5 H 10 N, -CH 2 OCOC 4 H 8 N, -CH 2
  • the present invention also provides a method for preparing a compound represented by the following Chemical Formula 4, comprising: (a) reacting a compound represented by the following Chemical Formula 2 with a compound represented by the following Chemical Formula 3; and
  • R, or 3 ⁇ 4 are each independently hydrogen, hydroxy, halogen, cyano, amino, nitro, -CH 3, -OCF 3, -OCH 3 , -NHCOCH ,, -COOH, -CONH 2, -CONHCH 3 Or one or more substituents selected from the group consisting of -NHCOC 6 3/4.
  • the solvent used in step (a) of the present invention is not particularly limited as long as the solvent dissolves starting materials and does not inhibit reaction.
  • Ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether or dioxane, aromatic hydrocarbon solvents such as benzene, toluene or xylene;
  • Amide solvents such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide or ⁇ -methylpyrrolidone; organic solvents such as dimethyl sulfoxide; methanol, ethanol, propanol, ⁇ -butanol or t-butanol Alcohol-based solvents; or combinations thereof
  • a solvent may be used as a mixture of solvent and water.
  • dimethylformamide Preferably, but not limited to, dimethylformamide.
  • an appropriate base may be used to facilitate the reaction in step (a). Examples of the base include sodium hydride and potassium.
  • t-butoxide sodium methoxide, sodium ethoxide, ⁇ , ⁇ -diisopropylamine, diisopropylethylamine 2,4-diaminobutyl acid (DBU) and the like can be used, preferably diiso Propylethylamine can be used but is not limited thereto.
  • DBU diiso Propylethylamine
  • the reaction molar ratio of the compound of Chemical Formula 2 and compound of Chemical Formula 3 may be 1: 3 to 5, and most preferably, the reaction is performed at a molar ratio of 1: 4.
  • Step (b) is a compound of Formula 4 generated in step (a)
  • sodium nitride it is preferable to add sodium nitride to react with the ring, and to react under weakly acidic and room temperature conditions.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of leprosy, chronic graft-versus-host disease, inflammatory disease or cancer comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the treatment means, unless stated otherwise, to reverse, alleviate, inhibit, or prevent the progression of a disease or disease to which the term applies, or one or more symptoms of the disease or disease.
  • treatment refers to the act of treating.
  • Ikaros / Aiolos GSPT1
  • CRBN protein is a type of E3 ubiquitin ligase, which binds to thalidomide and its analogs, pomalidomide and lenalidomide, and binds ubiquitin to proteins such as Ikaros / Aiolos protein and GSPT1 protein. It is known to have the activity of attaching.
  • the cancer may include breast cancer, colon cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, and anal muscle cancer.
  • Colon cancer breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate It may be selected from the group consisting of cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or urinary tract cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brain stem glioma and pituitary adenoma. It is not limited to this.
  • the compound of Formula 1 of the present invention may be more specifically a compound of Formula 6.
  • the compound of Formula 1 of the present invention may be selected from the following compounds.
  • the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various formulations for oral and parenteral administration during clinical administration. It can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating crabs, surfactants and the like.
  • Solid preparations for oral administration include tablets, patients, powders, granules, capsules, troches, and the like, and the solid preparations may include one or more of the compounds of Formula 1 of the present invention or ' pharmaceutically acceptable Salts may be formulated by mixing at least one excipient, for example starch, calcium carbonate, sucrose or lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc can also be used.
  • Liquid preparations for oral administration include suspensions, solvents, emulsions, or syrup braking, and may include other excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, liquid paraffin. . ,
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspension solvents, emulsions, lyophilized preparations, suppositories.
  • Non-aqueous solvents and suspension solvents include vegetable oils such as propylene glycol, polyethylene glycol and olive oil.
  • Injectable esters such as ethyl oleate may be used.
  • Suppository bases may include witepsol, macrogol, tween 61, cacao butter, laurin, glycerol and gelatin.
  • the dosage of the compound of Formula 1 or the pharmaceutically acceptable salt of the present invention may vary depending on the patient's age, weight, sex, dosage form, health condition and degree of disease. Is based on a 70 kg adult patient, typically 0.1-100 mg / day, preferably 1-500 mg / day, and divided into once daily index exponents at regular intervals as determined by the physician or pharmacist. You can also: ⁇
  • the invention and pharmaceutical composition may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy and biological response modifiers.
  • the compound may be formulated into various forms according to the purpose.
  • tablets were prepared by tableting according to the conventional method for preparing tablets.
  • the capsules were prepared by layering the gelatine capsules according to the conventional method for preparing capsules.
  • the compound of formula 1 according to the present invention specifically binds to CRBN protein and is involved in its function. May be useful for the prevention or treatment of disease or cancer.
  • FIG. 1 shows the degradation activity of Aiolos when the compound of Formula 7 was treated for 6 hours.
  • 6-Di silver (12 mg, 17%) was obtained as a white solid.
  • Triphosgene (570 mg, 1.9 mmol) was added to a 2-amino-6-chlorobenzoic acid (lg, 5.8 mmol) solution dissolved in 1,4-dioxane (10), and the solution was refluxed for 2 hours. The reaction was then cooled in ice. The solid was washed with nucleic acid and dried in l. lg (99%) of pure compound was obtained as a brown solid.
  • Hung 4 Long Rong ⁇ Yung ⁇ WZ Rong (I omui 96O ⁇ £ ⁇ ) ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the crude compound was obtained as a blue solid (80 mg) which was used for next step without further purification.
  • the solution was diluted with 100 AcOEt and diluted again with 100 of water.
  • the aqueous layers were separated and extracted with EtOAc.
  • the organic layers were combined, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • the residue was purified by chromatography on silica gel.
  • N-bromosuccinimide (16.9 g, 122.2 mmol) and benzoyl peroxide (197 mg, () .815 mmol) were added at room temperature and the mixture was stirred at reflux for 8 hours. Cool to room temperature and filter. The filtrate was concentrated. The residue was purified by silica gel column chromatography using EA / Hx (8%) as eluent to yield a pale yellow solid (15.9 g, 58.0 mmol). , 71%).
  • Lithium hydroxide monohydrate (638 mg, 15.2 mmol) was added to the solution of 1.52 mmol) at room temperature, and the reaction mixture was stirred at 70 ° C. overnight. The reaction mixture was concentrated to remove THF and methanol. (40) was added, the pH was adjusted to pH 3 with 1N HC1 (aq.) And extracted with EtOAc (40m ⁇ 2 times). The combined organic layers were concentrated under reduced pressure to give ⁇ 16-5> (332 mg, 1.49 mmol, 98%) was obtained as a yellow solid (complex of E / Z isomers of about 1.7 : 1).
  • 3-aminopiperidine-2,6-dione (0.67 g, 5.2 mmol) was dissolved in MeOH (lOmg), heated and refluxed for 5 hours, then ⁇ (1.45) was added and proceeded overnight. After dilution, extract with EA and concentrate. ⁇ The concentrate is dissolved in ruene again, PPTS (O.lg) is added, and heated to reflux. When reaction is complete, neutralize with saturated NaHC0 3 solution and EA Extracted, dried and separated by
  • Example 14 According to the preparation method of Example 14 , a compound of formula .25 was prepared.
  • Example 14 According to the preparation method of Example 14, a compound of Formula 26 was prepared.
  • N-bromosuccinimide (1.81 g, 13.12 mmol) and benzoyl peroxide (22 mg, 0.087 mmol) were added to a solution of a compound of dichloroethane (45 m £) enophenate (27 g) (2 g, 8.74 mmol). It was added at room temperature and refluxed for 7 hours. The reaction mixture was cooled to room temperature.

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Abstract

La présente invention concerne un nouveau dérivé de pipéridine-2,6-dione et son utilisation et, plus particulièrement, un composé dérivé de pipéridine-2,6-dione ayant une structure d'un analogue de thalidomide. La présente invention concerne également un composé de formule chimique 1 qui se lie de manière spécifique à la protéine CRBN, et qui est impliqué dans ses fonctions. Par conséquent, le composé de la présente invention peut être favorablement utilisé dans la prévention ou le traitement de la lèpre, d'une maladie chronique du greffon contre l'hôte, d'une maladie inflammatoire ou d'un cancer, qui sont provoqués par des actions de la protéine CRBN.
PCT/KR2018/005444 2017-05-12 2018-05-11 Nouveau dérivé de pipéridine-2,6-dione et son utilisation WO2018208123A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP18798940.5A EP3623366B9 (fr) 2017-05-12 2018-05-11 Nouveau dérivé de pipéridine-2,6-dione et son utilisation
JP2019561172A JP7157764B2 (ja) 2017-05-12 2018-05-11 新規なピペリジン－２，６－ジオン誘導体及びその用途
US16/609,805 US11192878B2 (en) 2017-05-12 2018-05-11 Piperidine-2,6-dione derivative and use thereof
CN201880031388.8A CN110621664B (zh) 2017-05-12 2018-05-11 新型哌啶-2,6-二酮衍生物及其用途

Applications Claiming Priority (4)

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KR20170059620 2017-05-12
KR10-2017-0059620 2017-05-12
KR1020170184761A KR102014478B1 (ko) 2017-05-12 2017-12-29 신규한 피페리딘-2,6-디온 유도체 및 이의 용도
KR10-2017-0184761 2017-12-29

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WO2020181232A1 (fr) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
WO2021047627A1 (fr) * 2019-09-12 2021-03-18 南京明德新药研发有限公司 Composé cyclique fusionné capable de dégrader une protéine et son utilisation
US20210269413A1 (en) * 2020-02-21 2021-09-02 Plexium, Inc. Quinazolinone compounds and related compounds

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WO2020181232A1 (fr) 2019-03-06 2020-09-10 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
EP3935050A4 (fr) * 2019-03-06 2023-01-04 C4 Therapeutics, Inc. Composés hétérocycliques pour traitement médical
WO2021047627A1 (fr) * 2019-09-12 2021-03-18 南京明德新药研发有限公司 Composé cyclique fusionné capable de dégrader une protéine et son utilisation
CN114761400A (zh) * 2019-09-12 2022-07-15 南京明德新药研发有限公司 一种可降解蛋白的并环类化合物及其应用
US20210269413A1 (en) * 2020-02-21 2021-09-02 Plexium, Inc. Quinazolinone compounds and related compounds
US11807620B2 (en) * 2020-02-21 2023-11-07 Plexium, Inc. Quinazolinone compounds and related compounds

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