WO2009053799A1 - Nouveaux ligands du récepteur cannobinoïde, compositions pharmaceutiques les contenant et leur procédé de préparation - Google Patents

Nouveaux ligands du récepteur cannobinoïde, compositions pharmaceutiques les contenant et leur procédé de préparation Download PDF

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Publication number
WO2009053799A1
WO2009053799A1 PCT/IB2008/002667 IB2008002667W WO2009053799A1 WO 2009053799 A1 WO2009053799 A1 WO 2009053799A1 IB 2008002667 W IB2008002667 W IB 2008002667W WO 2009053799 A1 WO2009053799 A1 WO 2009053799A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
disorders
formula
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PCT/IB2008/002667
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English (en)
Inventor
Meyyappan Muthupplaniappan
Sanjay Margal
Kumar Sukeerthi
Neelima Khairatkar-Joshi
Pallavi Karnik
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Glenmark Pharmaceuticals, S.A.
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Application filed by Glenmark Pharmaceuticals, S.A. filed Critical Glenmark Pharmaceuticals, S.A.
Publication of WO2009053799A1 publication Critical patent/WO2009053799A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/28—Cinnolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • R and R may be joined together with nitrogen to form an optionally substituted 3 to 7 membered saturated or unsaturated cyclic ring, which may optionally include one or more heteroatoms selected from O, NR and S; each occurrence of R x and R y is independently selected from hydrogen, halo, cyano, -OR, -SR, -NRR , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic group and heterocyclylalkyl ; each occurrence R 2 and R 3 is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, -SR 4 , -SOR 4 , -SO 2 R 4 , -SO 2 NR 4 R 5 , -CO 2 NR 4 R 5 , CO 2 R 4 , C(O)R 4 ,
  • Another embodiment is a compound of formula (II), wherein R 1 is branched or unbranched, substituted or unsubstituted alkyl.
  • Another embodiment is a compound of formula (II), wherein R 1 is substituted or unsubstituted cycloalkylalkyl.
  • the cannabinoid receptor modulator is a compound of formula (III):
  • Z is O or S
  • R 1 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, and substituted or unsubstituted heterocyclyl; each occurrence of R 2 and R 3 is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, formyl, -SR 4 , -SOR 4 , -SO 2 R 4 , -SO 2 NR 4 R 5 , - CO 2 NR 4 R 5 , CO 2 R 4 , C(O)R 4 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstiruted alkynyl, substituted or unsubstituted
  • Another embodiment is a compound of formula (III), wherein Z is O.
  • Another embodiment is a compound of formula (III), wherein R 1 is substituted or unsubstituted arylalkyl, preferably benzyl. In another embodiment, benzyl is substituted with one or more halogens, preferably fluoro.
  • R 1 is substituted or unsubstituted aryl, preferably phenyl. In another embodiment, phenyl is substituted with one or more halogens, preferably fluoro or chloro.
  • treating or “treatment” of a state, disorder or condition includes:
  • compositions of the present invention may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • the compound of formula (3) (wherein X is halogen) can be alkylated with an alkylating agent, such as an alkyl halide or an alkyl sulfonate, in the presence of a base, such as alkali metal hydrides (e.g., NaH), to afford a compound of formula (4).
  • an alkylating agent such as an alkyl halide or an alkyl sulfonate
  • a base such as alkali metal hydrides (e.g., NaH)
  • Compounds of formula 8a can be prepared according to scheme 6.
  • a compound of formula (12) (wherein X is halogen; and R is alkyl) can be treated with amide acetals of formula (a) to afford a compound of formula (15), which can be further treated with an amine of formula R 1 NH 2 to afford a compound of formula (16) (wherein X is halogen; and R is alkyl).
  • Hydrolysis of the compound of formula (17) gives the compound of formula (8a).
  • Scheme 7 depicts the synthesis of a compound of formula (HId).
  • a compound of formula (8b) is coupled with a free or salt form of R 2 C(O)CH 2 NH 2 through an amide coupling procedure well known in the art, [e.g., BOP (Benzotriazole-1-yl-oxy- tris-(dimethylamino)-phosphonium hexafluorophosphate) and DMF] to afford a compound of formula (18).
  • the compound of formula 18 can be cyclised by treating with dehydrating agents, for example POCl 3 , to give compounds of formula (HId).
  • Scheme 8 depicts the synthesis of a compound of formula (HIf) from a compound of formula (18).
  • the compound of formula (18) can be converted to a compound of formula (IHe) by reacting with a thionating reagent, such as P 2 S 5 or Lawesson's reagent.
  • a thionating reagent such as P 2 S 5 or Lawesson's reagent.
  • the compound of formula (IHe) can be reacted with a thiophilic reagent, such as a mercuric salt (e.g., Hg(OAc) 2 ), to form the compound of formula
  • 11 C and 8 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e, 2H can afford therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of formula (I), (II) or (III) and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Compounds of formula (I), (II) and (III) may be prepared in crystalline or noncrystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
  • Step 2 l-Amino-3,3-dimethyl-2-butanone hydrochloride:
  • Procedure A To a solution of a l-alkyl-3-halocinnolinone (1.0 equiv.) and a terminal alkyne (1.5 to 3 equiv.) in 1 :1 mixture of DMF and triethylamine were added catalytic amount of bis-[triphenylphosphine]palladium(II) chloride (2 mol %) and copper(I)iodide (1 mol %). After stirring the mixture at RT until TLC indicated completion of the reaction, solvent was removed and the residue subjected to silica gel column chromatography to furnish the corresponding l-alkyl-3-alkynyl cinnolinone.
  • Example 12 l-(Cvclohexylmethyl)-3-(3,3-Dimethyl-l-butvnyl)-l,4-dihvdro-4- cinnolinone:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux modulateurs du récepteur cannobinoïde, notamment des modulateurs du récepteur cannobinoïde 1 (CB1) ou cannobinoïde 2 (CB2), et leurs utilisations pour le traitement de maladies, d'états et/ou de troubles modulés par un récepteur cannobinoïde (tels que la douleur, les troubles neurodégénératifs, les troubles de l'alimentation, la perte de poids ou le contrôle du poids et l'obésité).
PCT/IB2008/002667 2007-10-24 2008-10-08 Nouveaux ligands du récepteur cannobinoïde, compositions pharmaceutiques les contenant et leur procédé de préparation WO2009053799A1 (fr)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
IN2111MU2007 2007-10-24
IN2111/MUM/2007 2007-10-24
US1532507P 2007-12-20 2007-12-20
US61/015,325 2007-12-20
IN2566/MUM/2007 2007-12-26
IN2566MU2007 2007-12-26
US2355108P 2008-01-25 2008-01-25
US61/023,551 2008-01-25
IN492MU2008 2008-03-11
IN492/MUM/2008 2008-03-11
US5115708P 2008-05-07 2008-05-07
US61/051,157 2008-05-07

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WO2009053799A1 true WO2009053799A1 (fr) 2009-04-30

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Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010064701A1 (fr) * 2008-12-05 2010-06-10 大塚製薬株式会社 Agent pharmaceutique comprenant un composé de quinolone
WO2010063610A1 (fr) * 2008-12-04 2010-06-10 F. Hoffmann-La Roche Ag Dérivés de pyridazinone
WO2010116084A1 (fr) * 2009-04-07 2010-10-14 Sanofi-Aventis Derives de 1-alkyl-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
FR2950055A1 (fr) * 2009-09-17 2011-03-18 Sanofi Aventis Derives de 3-amino-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
JP2011168586A (ja) * 2010-01-22 2011-09-01 Toyama Chem Co Ltd アリール基を有する複素環化合物
ITNA20100030A1 (it) * 2010-06-23 2011-12-24 Seconda Univ Di Napoli Sostituzione bioisosterica del gruppo ammidico di 4-chinolon-3-carbossammidi 6-sostituite: ligandi cb2 potenti e selettivi di miglior profilo chimico-fisico
WO2012066330A1 (fr) 2010-11-17 2012-05-24 Heptares Therapeutics Limited Composés utiles en tant qu'inhibiteurs du récepteur a2a
WO2012090177A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Modulateurs des récepteurs cannabinoïdes
WO2012090179A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Dérivés d'isoquinoline en tant que modulateurs des récepteurs cannabinoïdes
US8269011B2 (en) 2007-06-06 2012-09-18 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
US8304546B2 (en) 2008-12-05 2012-11-06 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
EP2524915A1 (fr) * 2011-05-20 2012-11-21 Sanofi Dérivés de 2-amino-3-(imidazol-2-yl)-pyridin-4-one et leur utilisation en tant qu'inhibiteurs de kinase du récepteur VEGF
WO2013005168A2 (fr) 2011-07-05 2013-01-10 Lupin Limited Modulateurs des récepteurs de cannabinoïdes
WO2013129622A1 (fr) 2012-03-02 2013-09-06 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
JP2015522598A (ja) * 2012-07-17 2015-08-06 サノフイ 肝細胞癌を処置するためのｖｅｇｆｒ−３阻害剤の使用
US9328119B2 (en) 2013-09-12 2016-05-03 Alios Biopharma, Inc. AZA-pyridone compounds and uses thereof
WO2016115013A1 (fr) * 2015-01-12 2016-07-21 Janssen Pharmaceutica Nv Dérivés de cinnoline utiles en tant qu'agonistes inverses de récepteurs cb-1
US9777005B2 (en) 2012-11-19 2017-10-03 Takeda Pharmaceutical Company Limited Bicyclic heterocyclic compound containing a substituted pyrrole ring
US10208045B2 (en) 2015-03-11 2019-02-19 Alios Biopharma, Inc. Aza-pyridone compounds and uses thereof
WO2020055164A1 (fr) * 2018-09-12 2020-03-19 크리스탈지노믹스(주) Dérivé de 7-hydroxy-4h-thiéno[3,2-b]pyridin-5-one et son utilisation
WO2023072273A1 (fr) * 2021-10-29 2023-05-04 先声再明医药有限公司 Composé polycyclique utilisé comme inhibiteur de cbl-b

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Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9403773B2 (en) 2007-06-06 2016-08-02 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
US8269011B2 (en) 2007-06-06 2012-09-18 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
US8642619B2 (en) 2007-06-06 2014-02-04 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
US9045464B2 (en) 2007-06-06 2015-06-02 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
WO2010063610A1 (fr) * 2008-12-04 2010-06-10 F. Hoffmann-La Roche Ag Dérivés de pyridazinone
US8178538B2 (en) 2008-12-04 2012-05-15 Hoffmann-La Roche Inc. Pyridazinones
US8592593B2 (en) 2008-12-05 2013-11-26 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
USRE45108E1 (en) 2008-12-05 2014-09-02 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
WO2010064701A1 (fr) * 2008-12-05 2010-06-10 大塚製薬株式会社 Agent pharmaceutique comprenant un composé de quinolone
US9018229B2 (en) 2008-12-05 2015-04-28 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
JP2014001227A (ja) * 2008-12-05 2014-01-09 Otsuka Pharmaceut Co Ltd キノロン化合物及び医薬組成物
US8304546B2 (en) 2008-12-05 2012-11-06 Otsuka Pharmaceutical Co., Ltd. Quinolone compound and pharmaceutical composition
US8420651B2 (en) 2009-04-07 2013-04-16 Sanofi Substituted 1-alkylcinnolin-4(1H)-one derivatives, preparation thereof and therapeutic application of same
WO2010116084A1 (fr) * 2009-04-07 2010-10-14 Sanofi-Aventis Derives de 1-alkyl-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
WO2011033225A3 (fr) * 2009-09-17 2011-06-03 Sanofi-Aventis Derives de 3-amino-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
WO2011033225A2 (fr) 2009-09-17 2011-03-24 Sanofi-Aventis Derives de 3-amino-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
FR2950055A1 (fr) * 2009-09-17 2011-03-18 Sanofi Aventis Derives de 3-amino-cinnolin-4(1h)-one substitues, leur preparation et leur application en therapeutique
JP2011168586A (ja) * 2010-01-22 2011-09-01 Toyama Chem Co Ltd アリール基を有する複素環化合物
ITNA20100030A1 (it) * 2010-06-23 2011-12-24 Seconda Univ Di Napoli Sostituzione bioisosterica del gruppo ammidico di 4-chinolon-3-carbossammidi 6-sostituite: ligandi cb2 potenti e selettivi di miglior profilo chimico-fisico
WO2012066330A1 (fr) 2010-11-17 2012-05-24 Heptares Therapeutics Limited Composés utiles en tant qu'inhibiteurs du récepteur a2a
WO2012090179A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Dérivés d'isoquinoline en tant que modulateurs des récepteurs cannabinoïdes
WO2012090177A2 (fr) 2010-12-30 2012-07-05 Lupin Limited Modulateurs des récepteurs cannabinoïdes
KR20140025465A (ko) * 2011-05-20 2014-03-04 사노피 2-아미노-3-(이미다졸-2-일)-피리딘-4-온 유도체 및 vegf 수용체 키나제 억제제로서의 그의 용도
AU2012261077B2 (en) * 2011-05-20 2016-05-05 Sanofi 2-amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors
JP2014513707A (ja) * 2011-05-20 2014-06-05 サノフイ ２−アミノ−３−（イミダゾール−２−イル）ピリジン−４−オン誘導体及びｖｅｇｆ受容体キナーゼ阻害剤としてのその使用
US9675606B2 (en) 2011-05-20 2017-06-13 Sanofi 2-amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors
EA023580B1 (ru) * 2011-05-20 2016-06-30 Санофи Производные 2-амино-3-(имидазол-2-ил)пиридин-4-она и их применение в качестве ингибиторов киназы рецептора vegf
EP2524915A1 (fr) * 2011-05-20 2012-11-21 Sanofi Dérivés de 2-amino-3-(imidazol-2-yl)-pyridin-4-one et leur utilisation en tant qu'inhibiteurs de kinase du récepteur VEGF
WO2012159959A1 (fr) * 2011-05-20 2012-11-29 Sanofi Dérivés de 2-amino-3-(inidazol-2-yl)-pyridine-4-one et utilisation de ceux-ci comme inhibiteurs de kinases associées au récepteur du vegf
CN103687852A (zh) * 2011-05-20 2014-03-26 赛诺菲 2-氨基-3-(咪唑-2-基)-吡啶-4-酮衍生物及其作为vegf受体激酶抑制剂的用途
US9126972B2 (en) 2011-05-20 2015-09-08 Sanofi 2-amino-3-(imidazol-2-yl)-pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors
KR102005121B1 (ko) 2011-05-20 2019-07-29 사노피 2-아미노-3-(이미다졸-2-일)-피리딘-4-온 유도체 및 vegf 수용체 키나제 억제제로서의 그의 용도
WO2013005168A2 (fr) 2011-07-05 2013-01-10 Lupin Limited Modulateurs des récepteurs de cannabinoïdes
US9006442B2 (en) 2011-07-05 2015-04-14 Lupin Limited Cannabinoid receptor modulators
WO2013129622A1 (fr) 2012-03-02 2013-09-06 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
US9403802B2 (en) 2012-03-02 2016-08-02 Takeda Pharmaceutical Company Limited Heterocyclic compound and use therefor
JP2015522598A (ja) * 2012-07-17 2015-08-06 サノフイ 肝細胞癌を処置するためのｖｅｇｆｒ−３阻害剤の使用
US9777005B2 (en) 2012-11-19 2017-10-03 Takeda Pharmaceutical Company Limited Bicyclic heterocyclic compound containing a substituted pyrrole ring
US10251882B2 (en) 2013-09-12 2019-04-09 Alios Biopharma, Inc. Aza-pyridone compounds and uses thereof
US9328119B2 (en) 2013-09-12 2016-05-03 Alios Biopharma, Inc. AZA-pyridone compounds and uses thereof
US10702523B2 (en) 2013-09-12 2020-07-07 Janssen Biopharma, Inc. AZA-pyridone compounds and uses thereof
US10980805B2 (en) 2013-09-12 2021-04-20 Janssen Biopharma, Inc. Aza-pyridone compounds and uses thereof
WO2016115013A1 (fr) * 2015-01-12 2016-07-21 Janssen Pharmaceutica Nv Dérivés de cinnoline utiles en tant qu'agonistes inverses de récepteurs cb-1
US9732061B2 (en) 2015-01-12 2017-08-15 Janssen Pharmaceutica Nv Cinnoline derivatives useful as CB-1 receptor inverse agonists
US10208045B2 (en) 2015-03-11 2019-02-19 Alios Biopharma, Inc. Aza-pyridone compounds and uses thereof
WO2020055164A1 (fr) * 2018-09-12 2020-03-19 크리스탈지노믹스(주) Dérivé de 7-hydroxy-4h-thiéno[3,2-b]pyridin-5-one et son utilisation
WO2023072273A1 (fr) * 2021-10-29 2023-05-04 先声再明医药有限公司 Composé polycyclique utilisé comme inhibiteur de cbl-b

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