WO2021051827A1 - Inhibiteur de protéine d'apoptose, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de protéine d'apoptose, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021051827A1
WO2021051827A1 PCT/CN2020/089459 CN2020089459W WO2021051827A1 WO 2021051827 A1 WO2021051827 A1 WO 2021051827A1 CN 2020089459 W CN2020089459 W CN 2020089459W WO 2021051827 A1 WO2021051827 A1 WO 2021051827A1
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cancer
group
formula
methyl
bis
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PCT/CN2020/089459
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English (en)
Chinese (zh)
Inventor
宋志春
张崇光
包金远
黄辉
张孝清
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南京华威医药科技集团有限公司
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Publication of WO2021051827A1 publication Critical patent/WO2021051827A1/fr

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    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a cell apoptosis protein inhibitor and a preparation method and application thereof.
  • Apoptosis refers to the orderly and autonomous death of cells controlled by genes in order to maintain the stability of the internal environment. It plays an important role in the evolution of organisms, the stability of the internal environment, and the development of multiple systems. Apoptosis signal transduction is divided into intrinsic (mediated by death receptor-ligand interaction) and extrinsic (mediated by cell stress and mitochondrial permeability). The two pathways finally converge in Caspase. Once the apoptotic signal is activated, caspase will cleave a large number of substrates related to cell death, causing cell death.
  • Inhibitor of apoptosis is a family of highly conserved endogenous anti-apoptotic factors, which inhibit cells mainly by inhibiting the activity of Caspase and participating in the mediation of nuclear factor NF- ⁇ B. Apoptosis.
  • SMAC mimics also known as IAP antagonists
  • IAP antagonists are synthetic small molecules that mimic the structure of the four N-terminal amino acids of SMAC and IAP antagonist activity. When administered to animals suffering from proliferative diseases, the SMAC mimics antagonize IAP, leading to an increase in apoptosis in abnormally proliferating cells. There is a need to develop new IAP antagonists with better activity, selectivity and safety.
  • the present invention provides a compound represented by formula I and its racemates, stereoisomers, tautomers, isotopic labels, nitrogen oxides, solvates, poly Crystal form, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are independently selected from;
  • R 3 , R 4 and R 5 are each independently selected from H or optionally substituted by 1, 2 or 3 R: (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one, two or more Heteroatomic (C 1 -C 12 ) aliphatic hydrocarbon group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-20 aryl group or 5-14 membered heteroaryl group;
  • Ring A and Ring B are each independently selected from: C 6-20 aryl or 5-14 membered heteroaryl;
  • R 6 and R 7 are each independently selected from halogen, hydroxyl, or selected from optionally substituted by 1, 2 or 3 R: (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one, two or more A heteroatom (C 1 -C 12 ) aliphatic hydrocarbon group, a C 3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C 6-20 aryl group or a 5-14 membered heteroaryl group;
  • n and n are independently selected from: 0, 1, 2 or 3;
  • R is selected from halogen, CN, OH, SH, NH 2 , COOH, or selected from optionally substituted by 1, 2 or 3 R': (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one or two (C 1 -C 12 ) aliphatic hydrocarbon group with one or more heteroatoms , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-20 aryl group or 5-14 membered heteroaryl group;
  • R' is selected from halogen, CN, OH, SH, NH 2 , COOH;
  • P 1 and P 2 are independently selected from halogen, OH, CN, NH 2 , COOH, (C 1 -C 12 ) aliphatic hydrocarbon group, optionally A (C 1 -C 12 ) aliphatic hydrocarbon group containing one, two or more heteroatoms.
  • W is selected from a single bond, -O-, -S-, -NH- or optionally substituted by 1, 2 or 3 R: (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one, two or (C 1 -C 12 ) aliphatic hydrocarbon groups with more heteroatoms, C 3-12 cycloalkyl groups, 3-12 membered heterocyclic groups, C 6-20 aryl groups or 5-14 membered heteroaryl groups.
  • the heteroatom may be selected from sulfur, nitrogen, oxygen, phosphorus and silicon, optionally ,
  • the heteroatom is inserted into the aliphatic hydrocarbon group, optionally CC bond and CH bond.
  • it can be selected from (C 1 -C 12 ) aliphatic hydrocarbyloxy group, (C 1 -C 12 ) aliphatic hydrocarbyl mercapto group, (C 1 -C 6 ) aliphatic hydrocarbyloxy group, (C 1 -C 6 ) aliphatic hydrocarbyl mercapto group , (C 1 -C 6 ) aliphatic hydrocarbyloxy group (C 1 -C 6 ) aliphatic hydrocarbyl group, (C 1 -C 6 ) aliphatic hydrocarbyl mercapto group (C 1 -C 6 ) aliphatic hydrocarbyl group, N-(C 1 -C 3) ) Aliphatic hydrocarbon group (C 1 -C 6 ) aliphatic hydrocarbon group, N,N-bis-(C 1 -C 3 ) aliphatic hydrocarbon group (C 1 -C 6 ) aliphatic hydrocarbon group;
  • the (C 1 -C 12 ) aliphatic hydrocarbon group may be selected from (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, and in some embodiments, Can be selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl;
  • the R 3 , R 4 and R 5 may be independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1 -Pentenyl, 1-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1 -Pentynyl, 1-hexenyl, ethynyl
  • halogen is selected from F, Cl, Br, I;
  • the structure of formula I is further selected from the following formula II, formula III, formula IV, and formula V:
  • R 1 , R 2 , R 6 , R 7 , P 1 , P 2 , W, n, m, ring A, and ring B are as defined in the above formula I .
  • R 1 and R 2 are independently selected from;
  • R 3 , R 4 and R 5 are each independently selected from H or the following groups optionally substituted by 1, 2 or 3 R: (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one, two or (C 1 -C 12 ) aliphatic hydrocarbon groups with more heteroatoms, C 3-12 cycloalkyl groups, 3-12 membered heterocyclic groups;
  • Ring A and Ring B are each independently selected from: C 6-20 aryl or 5-14 membered heteroaryl;
  • R 6 and R 7 are each independently selected from halogen or hydroxyl
  • n and n are independently selected from: 0, 1, 2 or 3;
  • R is selected from halogen, CN, OH, SH, NH 2 , COOH, or selected from optionally substituted by 1, 2 or 3 R': (C 1 -C 12 ) aliphatic hydrocarbon group, optionally including one or two (C 1 -C 12 ) aliphatic hydrocarbon group with one or more heteroatoms , C 3-12 cycloalkyl, 3-12 membered heterocyclic group, C 6-20 aryl group or 5-14 membered heteroaryl group;
  • R' is selected from halogen, CN, OH, SH, NH 2 , COOH;
  • P 1 and P 2 are each independently selected from halogen, OH, NH 2 , and (C 1 -C 12 ) aliphatic hydrocarbon groups.
  • W is selected from a single bond, -O-, -S-, -NH-.
  • the present invention also provides the compound represented by formula I (including the compound of formula II-form V) and its racemates, stereoisomers, tautomers, isotope markers, nitrogen oxides, solvates, poly
  • the preparation methods of crystalline forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof are not limited to the methods described below. All raw materials are prepared according to the group characteristics of the target molecule in accordance with the general formula, and are prepared through the schemes in these routes and methods well known to those of ordinary skill in the organic chemistry field or directly purchased.
  • the compounds of the present invention can be synthesized by combining the following methods with synthetic methods known in the field of synthetic organic chemistry or related modification methods recognized by those skilled in the art.
  • the preparation of the compound of the present invention includes the following steps:
  • the preparation of the compound of the present invention includes the following steps:
  • M-9 can be obtained by using the preparation steps in the first scheme (M-9 is prepared from M-1 as a starting material).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , P 1 , P 2 , and W are as defined in formula I;
  • R 3 ′ is selected from groups within the range defined by R 3 , and independently selected from groups different from R 3;
  • PG 1 and PG 2 represent different amino protecting groups, which can be selected from the group consisting of tert-butoxycarbonyl (N-boc), benzyloxycarbonyl protecting group (N-cbz), fluorene methoxycarbonyl protecting group (N-Fmoc ), preferably, PG 1 is selected from tert-butoxycarbonyl, and PG 2 is selected from benzyloxycarbonyl protecting groups.
  • M-1 can be used as a starting material to prepare M-9, and the preparation of M-9 includes the following steps:
  • N-PG 1 protected prolinol M-1 as the starting material, it reacts with phthalimide under the action of triphenylphosphine and diisopropyl azodicarboxylate to form M- 2;
  • the reaction temperature can be selected from 0°C to 25°C
  • the reaction solvent can be selected from inert aprotic solvents, for example, selected from tetrahydrofuran, toluene, dichloromethane, etc.;
  • the reaction temperature can be selected from 25°C to 80°C
  • the reaction solvent can be selected from methanol, ethanol, tetrahydrofuran, etc.
  • the reaction temperature can be selected from 70°C to 90°C
  • the reaction solvent can be selected from acetonitrile, DMF, tetrahydrofuran, etc.
  • the alkaline conditions can be selected from alkali metal or alkaline earth metal carbonates, such as Potassium carbonate, sodium carbonate, etc.;
  • the reaction temperature can be selected from room temperature, for example, 25°C, and the reaction solvent can be selected from acetic acid;
  • hydrochloric acid can be added to the acidic system, for example, a 4N hydrochloric acid aqueous solution can be added;
  • the oxidizing agent used is Des Martin reagent
  • the reaction temperature can be selected from 0°C to 25°C
  • the reaction solvent can be selected from inert aprotic solvents, such as tetrahydrofuran, dichloromethane, toluene, etc.;
  • the process of preparing Formula I from M-9 includes the following steps:
  • the catalyst can be selected from Oxone, sodium metabisulfite, etc.
  • the reaction temperature can be selected from 25°C to 140°C
  • the reaction solvent can be selected from inert high boiling point solvents, such as DMSO, DMF, etc.;
  • the reaction solvent can be selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.
  • the conditions for removing the protective group can be selected from acidic conditions.
  • the protective group is selected from N-boc
  • you can select In the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected from the presence of piperidine, for example, when the protecting group is selected from N-fmoc;
  • the inert organic solvent can be selected from acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • the temperature can be selected from 25°C to 120°C
  • the condensing agent can be selected from N, N '-Diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, etc.;
  • the conditions for removing the protecting group can be selected from acidic conditions, for example, when the protecting group is selected from N-boc, it can be selected from the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected.
  • the reaction solvent is selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.;
  • the inert organic solvent can be selected from acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • the temperature can be selected from 25°C to 120°C
  • the condensing agent can be selected from N, N '-Diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, etc.;
  • the reaction solvent in the reaction is tetrahydrofuran, dichloromethane, methanol, toluene and the like.
  • the process of preparing Formula I from M-9 includes the following steps:
  • the catalyst can be selected from Oxone, sodium metabisulfite, etc.
  • the reaction temperature can be selected from 25°C to 140°C
  • the reaction solvent can be selected from inert high boiling point solvents, such as DMSO, DMF, etc.;
  • the reaction solvent can be selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.
  • the conditions for removing the protective group can be selected from acidic conditions.
  • the protective group is selected from N-boc
  • you can select In the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected from the presence of piperidine, for example, when the protecting group is selected from N-fmoc;
  • N-3 undergoes condensation reaction with N-4 in an inert organic solvent under the action of a condensing agent to obtain N-5;
  • the inert organic solvent can be selected from acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • the temperature can be selected from 25°C to 120°C
  • the condensing agent can be selected from N, N' -Diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, etc.;
  • the reaction solvent can be selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.
  • the conditions for removing the protective group can be selected from acidic conditions.
  • the protective group is selected from N-boc
  • you can select In the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected from the presence of piperidine, for example, when the protecting group is selected from N-fmoc;
  • N-6 undergoes condensation reaction with N-7 in an inert organic solvent under the action of a condensing agent to obtain N-8;
  • the inert organic solvent can be selected from acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • the temperature can be selected from 25°C to 120°C
  • the condensing agent can be selected from N, N '-Diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, etc.;
  • the reaction solvent can be selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.
  • the conditions for removing the protective group can be selected from acidic conditions.
  • the protective group is selected from N-boc
  • you can select In the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected from the presence of piperidine, for example, when the protecting group is selected from N-fmoc;
  • the inert organic solvent can be selected from acetonitrile, toluene, chloroform, dichloromethane, tetrahydrofuran, dimethyl sulfoxide
  • the temperature can be selected from 25°C to 120°C
  • the condensing agent can be selected from N, N '-Diisopropylcarbodiimide, benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate, 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate, etc.;
  • the reaction solvent can be selected from tetrahydrofuran, dichloromethane, methanol, toluene, etc.
  • the conditions for removing the protective group can be selected from acidic conditions.
  • the protective group is selected from N-boc
  • you can select In the presence of palladium on carbon, for example, when the protecting group is selected from N-cbz, it can be selected from the presence of piperidine, for example, when the protecting group is selected from N-fmoc.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I of the present invention and its racemates, stereoisomers, tautomers, isotope markers, nitrogen oxides, solvates, and polymorphs. Forms, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention and its racemates, stereoisomers, tautomers, isotope markers, nitroxides Substances, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
  • the carrier in the pharmaceutical composition is "acceptable", which is compatible with the active ingredient of the composition (and preferably capable of stabilizing the active ingredient) and is not harmful to the subject being treated.
  • One or more solubilizers can be used as pharmaceutical excipients for the delivery of active compounds.
  • the present invention further provides the compound of formula I and its racemates, stereoisomers, tautomers, isotope markers, nitrogen oxides, solvates, polymorphs, metabolites, esters, pro
  • the present invention further provides the compound of formula I and its racemates, stereoisomers, tautomers, isotope markers, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or Use of its pharmaceutically acceptable salt in medicine for treating diseases or disorders caused by IAP disorders.
  • the compounds of the present invention can be used to treat proliferative diseases, such as a variety of benign tumors or malignant tumors (cancer), benign proliferative diseases (such as psoriasis, benign prostatic hypertrophy and restenosis), or autoimmune diseases ( For example, autoimmune proliferative glomerulonephritis, lymphoid tissue proliferative autoimmune response).
  • proliferative diseases such as a variety of benign tumors or malignant tumors (cancer), benign proliferative diseases (such as psoriasis, benign prostatic hypertrophy and restenosis), or autoimmune diseases ( For example, autoimmune proliferative glomerulonephritis, lymphoid tissue proliferative autoimmune response).
  • Cancers that can be treated with IAP antagonists include but are not limited to one or more of the following cancers: lung adenocarcinoma, pancreatic cancer, colon cancer, ovarian cancer, breast cancer, mesothelioma, peripheral neuroma, bladder cancer , Glioblastoma, melanoma, adrenal cortical carcinoma, AIDS-related lymphoma, anal cancer, bladder cancer, meningioma, glioma, astrocytoma, breast cancer, cervical cancer, Chronic myelodysplastic disorders (e.g., chronic lymphocytic leukemia, chronic myelogenous leukemia), colon cancer, endocrine adenocarcinoma, endometrial cancer, ependymoma, esophageal cancer, Ewing’s sarcoma, extracranial germ cell tumor, Extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, gallbladder cancer, gastric cancer
  • the present invention further provides the compound of formula I and its racemates, stereoisomers, tautomers, isotope markers, nitrogen oxides, solvates, polymorphs, metabolites, esters, pro
  • the use of the drug or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of a medicament for preventing and/or treating tumors or tumor-related disorders, the tumors or tumor-related disorders are as described above.
  • the method of the present invention may include administering the compound of the present invention alone, as well as administering the compound of the present invention in combination with one or more other chemotherapeutic agents.
  • the administration of multiple drugs can be performed simultaneously or sequentially.
  • halogen refers to F, Cl, Br, and I. In other words, F, Cl, Br, and I can be described as “halogen" in this specification.
  • aliphatic hydrocarbon group includes saturated or unsaturated, linear or branched chain or cyclic hydrocarbon groups.
  • the type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc.
  • the carbon atoms of the aliphatic hydrocarbon group The number is preferably 1-12, and can also be 1-10, and a further preferred range is 1-6, which can specifically include but not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl , Isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl
  • the "aliphatic hydrocarbon group” may optionally include one, two or more heteroatoms (or construed as optional heteroatoms inserted into the aliphatic hydrocarbon group, optionally CC bonds and CH bonds).
  • Suitable heteroatoms are obvious to those skilled in the art and include, for example, sulfur, nitrogen, oxygen, phosphorus, and silicon.
  • the heteroatom-containing aliphatic hydrocarbon group can be selected from the following groups: (C 1 -C 6 ) aliphatic hydrocarbon group oxy group, (C 1 -C 6 ) aliphatic hydrocarbon group mercapto group, (C 1 -C 6 ) aliphatic hydrocarbon group oxygen Group (C 1 -C 6 ) aliphatic hydrocarbon group, (C 1 -C 6 ) aliphatic hydrocarbon group mercapto group (C 1 -C 6 ) aliphatic hydrocarbon group, N-(C 1 -C 3 ) aliphatic hydrocarbon group amine group (C 1 -C 6) ) Aliphatic hydrocarbon group, N,N-bis-(C 1 -C 3 ) aliphatic hydrocarbon amino (C 1 -C 6 ) aliphatic hydrocarbon group, such as methoxy, ethoxy, propoxy, butoxy, Pentyloxy, methoxymethyl, ethoxymethyl, propoxymethyl, methoxye
  • C 3-12 cycloalkyl should be understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring, which has 3-12 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl should be understood to mean a saturated or unsaturated monovalent monocyclic or bicyclic ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic group. Hydrocarbon groups such as tetralin or decalin.
  • 3-12 membered heterocyclic group means a saturated or unsaturated monovalent monocyclic or bicyclic ring, which contains 1-5 heteroatoms independently selected from N, O and S, and heteroatom-containing groups do not have Aromatic, the 3-12 membered heterocyclic group is preferably "3-10 membered heterocyclic group".
  • 3-10 membered heterocyclic group means a saturated monovalent monocyclic or bicyclic ring, which contains 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may be connected to the rest of the molecule through any of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholine Group, piperazinyl, or trithiaalkyl; or 7-membered ring, such as diazacycloheptanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, tetrahydrothienyl, dioxane Pen
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the 3-12 membered heterocyclic group may be further selected from the following groups:
  • C 6-20 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring with 6-20 carbon atoms, preferably “C 6-14 aryl” .
  • the term “C 6-14 aryl” should be understood as preferably meaning a monocyclic, bicyclic or partially aromatic monocyclic or partially aromatic monocyclic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms
  • a tricyclic hydrocarbon ring (“C 6-14 aryl"), especially a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one having 9 carbon atoms Ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring having 13 carbon
  • 5-14 membered heteroaryl should be understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S, and, in addition, in each In the case it can be benzo-fused.
  • the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, thio-4H-pyrazolyl, etc.
  • heterocyclic groups or heteroaryl groups include all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl; thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl, and thiophen-3-yl.
  • the compound of the present invention may be chiral, and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemate form or optically active form.
  • the compounds of the present invention or intermediates thereof can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in synthesis in this form. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with optically active resolving reagents.
  • Suitable resolution reagents are optically active acids such as R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, appropriate N-protected amino acids (e.g., N- Benzoyl proline or N-benzenesulfonyl proline) or various optically active camphor sulfonic acids.
  • optically active resolving reagents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers
  • Suitable eluents for this purpose are aqueous or alcohol-containing solvent mixtures, for example, hexane/isopropanol/acetonitrile.
  • N-oxides since nitrogen needs to have available lone pairs of electrons for being oxidized to nitrogen oxides, not all nitrogen-containing heterocycles can form N-oxides; those skilled in the art will recognize that N-oxides can be formed. -Nitrogen-containing heterocycles of oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides.
  • the synthetic methods for preparing heterocyclic and tertiary amine N-oxides are well known to those skilled in the art, and the synthetic methods include the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), peroxy Hydrogen oxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane (dioxirane) such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • MCPBA peroxyacids
  • alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane (dioxirane) such as dimethyldioxirane oxidize heterocycles and tertiary amines.
  • the pharmaceutically acceptable salt may be, for example, an acid addition salt of the compound of the present invention that has a nitrogen atom in the chain or ring and is sufficiently basic, for example, an acid addition salt formed with the following inorganic acids: for example, hydrochloric acid, hydrofluorine Acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or hydrogen sulfate, or acid addition salts formed with the following organic acids: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid , Propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphor acid, cinnamic acid, cyclopentane Propionic acid, digluconic acid, 3-hydroxy-2-nap
  • an alkali metal salt such as a sodium salt or potassium salt
  • an alkaline earth metal salt such as a calcium salt or a magnesium salt
  • an ammonium salt or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with sodium ions, potassium ions, N-methylglucamine, dimethylglucamine, ethylglucosamine, Lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trihydroxymethylaminomethane, aminopropanediol, 1-amino-2 ,3,4-Butanetriol.
  • an alkali metal salt such as a sodium salt or potassium salt
  • an alkaline earth metal salt such as a calcium salt or a magnesium salt
  • an ammonium salt or salts formed with organic bases that provide physiologically acceptable cations, such as salts formed with sodium ions, potassium ions, N-methyl
  • the pharmaceutically acceptable salt includes the salt formed by the group -COOH with the following substances: sodium ion, potassium ion, calcium ion, magnesium ion, N-methylglucamine, dimethylglucamine, Ethyl glucosamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, meglumine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol , 1-Amino-2,3,4-butanetriol.
  • basic nitrogen-containing groups can be quaternized with the following reagents: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as sulfuric acid Dimethyl, diethyl sulfate, dibutyl sulfate and dipentyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl Halides such as benzyl and phenethyl bromide.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • dialkyl sulfates such as sulfuric acid Dimethyl, diethyl sulfate, dibutyl sulfate and dipentyl
  • pharmaceutically acceptable salts include hydrochloride, sulfate, nitrate, bisulfate, hydrobromide, acetate, oxalate, citrate, methanesulfonate, formate, or Meglumine salt and so on.
  • the "pharmaceutically acceptable salt” includes not only the salt formed at one salt-forming site of the compound of the present invention, but also 2, 3 or all of them.
  • the salt formed at the salt-forming site can be varied within a relatively large range, for example, it can be 4 :1 ⁇ 1:4, such as 3:1, 2:1, 1:1, 1:2, 1:3, etc.
  • pharmaceutically acceptable anions include anions selected from the ionization of inorganic acids or organic acids.
  • the "inorganic acid” includes, but is not limited to, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid.
  • the "organic acid” includes but is not limited to formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid , 2-(4-Hydroxybenzoyl)benzoic acid, camphor acid, cinnamic acid, cyclopentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, hexanoic acid, pectinic acid , Persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfuric acid, ethanesulfonic acid, benz
  • the compounds of the present invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms can exist in the (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is produced, and when multiple asymmetric centers are contained, a diastereomeric mixture is obtained. In some cases, there may be asymmetry due to hindered rotation around a specific bond, for example, the central bond connects two substituted aromatic rings of a specific compound.
  • the substituent may also exist in a cis- or trans-isomeric form.
  • the compounds of the present invention also include all possible stereoisomers of each, which is a single stereoisomer or the stereoisomer (for example, R-isomer or S-isomer, or E-isomer or Z-isomer) in the form of any mixture in any ratio.
  • a single stereoisomer (e.g., single enantiomer or single diastereomer) of the compound of the present invention can be achieved by any suitable prior art method (e.g., chromatography, especially, e.g., chiral chromatography) Separation.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more mutually convertible species.
  • Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in an equilibrium form. An attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule.
  • the ketone type is dominant; in phenol, the enol type is dominant.
  • the present invention encompasses all tautomeric forms of the compound.
  • the involved compounds also include isotopically-labeled compounds.
  • the isotopically-labeled compounds are the same as those shown in Formula I, but one or more of the atoms are different from the usual atomic mass or mass number. Naturally occurring atomic mass or mass number atomic substitution.
  • isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively. , 17 O, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention.
  • the replacement of heavier isotopes can provide certain therapeutic advantages derived from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore can be used in certain Some cases are preferred.
  • the compounds of the present invention as claimed in the claims can be specifically limited to be substituted with deuterium or tritium.
  • the absence of the term deuterium or tritium in the hydrogen appearing in the substituent does not mean that deuterium or tritium is excluded, but deuterium or tritium may also be included in the same way.
  • the term "effective amount” or “therapeutically effective amount” refers to the amount of the compound of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below).
  • the therapeutically effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject to be treated and the disease condition such as the weight and age of the subject, the severity of the disease condition and the mode of administration, etc. It can be easily determined by a person of ordinary skill in the art.
  • the specific dosage will vary depending on the following factors: the particular compound selected, the dosing regimen on which it is based, whether it is administered in combination with other compounds, the timing of administration, the tissue to be administered, and the physical delivery system carried.
  • solvate refers to those forms of the compound of the present invention, which form a complex by coordination with solvent molecules in a solid or liquid state. Hydrates are a specific form of solvates in which the coordination is carried out with water. In the present invention, the preferred solvate is a hydrate. Further, the pharmaceutically acceptable solvate (hydrate) of the compound of the general formula I of the present invention refers to the co-crystal and clathrate formed by the compound I and one or more stoichiometric molecules of water or other solvents. Solvents that can be used for solvates include, but are not limited to: water, methanol, ethanol, ethylene glycol, and acetic acid.
  • prodrug represents the conversion of a compound into a compound represented by the aforementioned general formula or specific compound in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissues.
  • the prodrugs of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acids. Esters.
  • a compound in the present invention contains a hydroxyl/carboxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, for example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • the compound of the present invention adopts a novel structure of general formula I, has good binding affinity to XIAP, cIAP1, and cIAP2 protein, has good IAP inhibitory activity, and the inhibitory effect of some compounds is significantly better than the positive control drug;
  • the compound of the present invention has a good inhibitory effect on cell growth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines, and the inhibitory effect of some compounds is significantly better than the positive control drug.
  • the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods.
  • the acquisition process involving chiral compounds all include the steps of preparation, separation and purification using a chiral column.
  • Example 9 Di-tert-butyl ((2R,2'R)-((2S,2'S)-2,2'-((5,5'-difluoro-1H,1'H-[2,2' -Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane) Alkyl-2,1-diyl)) Preparation of Dicarbamate
  • Example 11 Di-tert-butyl ((2R,2'R)-((2R,2'R)-((2S,2'S)-2,2'-((5,5'-difluoro-1H, 1'H-[2,2'-Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(pyrrolidine-2,1-diyl))bis(3 -Methyl-1-oxobutane-2,1-diyl))bis(azadiyl))bis(1-oxopropane-2,1-diyl))bis(methylcarbamate) )
  • Example 12 (2R,2'R)-N,N'-((2R,2'R)-((2S,2'S)-2,2'-((5,5'-difluoro-1H, 1'H-[2,2'-Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(pyrrolidine-2,1-diyl))bis(3 -Methyl-1-oxobutane-2,1-diyl)) bis(2-(methylamino)propionamide) preparation
  • Example 30 Di-tert-butyl((2R,2'R)-2-amino-1-((S)-2-((1'-((S)-1-((R)-2-amino (Propanol group)pyrrolidin-2-yl)methyl)-5,5'-difluoro-1H,1'H-[2,2'-dibenzo[d]imidazol]-1-yl)methyl )Pyrrolidin-1-yl)-3-methylbutan-1-one-bis(methylcarbamate) preparation
  • Example 32 Di-tert-butyl ((2R,2'R)-(R)-N-((R)-1-((S)-2-((5,5'-difluoro-1'- ((S)-1-((R)-2-((R)-2-(methylamino)alanyl)pyrrolidin-2-yl)methyl)-1H,1'H-[2, 2'-Bibenzo[D]imidazole]-1-yl)methyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)-2-(methylamino) ) Preparation of propionamide-bis(methylcarbamate)
  • Example 50 Di-tert-butyl ((2R,2'R)-((5S,5'S)-5,5'-((5,5'-difluoro-1H,1'H-[2,2' -Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(3-hydroxypyrrolidine-5,1-diyl))bis(3-methyl-1- Preparation of oxobutane-2,1-diyl)) dicarbamate
  • Example 52 Di-tert-butyl ((2R,2'R)-((2R,2'R)-((5S,5'S)-5,5'-((5,5'-difluoro-1H, 1'H-[2,2'-Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(3-hydroxypyrrolidine-5,1-diyl)) Bis(3-methyl-1-oxobutane-2,1-diyl))bis(azadiyl))bis(1-oxopropane-2,1-diyl))bis(methylamino) Preparation of methyl formate)
  • Example 77 Di-tert-butyl ((2R,2'R)-((5S,5'S)-5,5'-((5,5'-difluoro-1H,1'H-[2,2' -Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(3-methyl-1- Preparation of oxobutane-2,1-diyl)) dicarbamate
  • Example 78 (2R,2'R)-1,1'-((5S,5'S)-5,5'-((5,5'-difluoro-1H,1'H-[2,2' -Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl))bis(2-amino-3-methyl Butan-1-one) preparation
  • Example 79 Di-tert-butyl ((2R,2'R)-((2R,2'R)-((5S,5'S)-5,5'-((5,5'-difluoro-1H, 1'H-[2,2'-Dibenzo[d]imidazole]-1,1'-diyl)bis(methylene))bis(3-fluoropyrrolidine-5,1-diyl)) Bis(3-methyl-1-oxobutane-2,1-diyl))bis(azadiyl))bis(1-oxopropane-2,1-diyl))bis(methylamino) Preparation of methyl formate)
  • Embodiment 104
  • Example 107 Test of the binding affinity of the compound to XIAP, cIAP1, and cIAP2
  • the Bir3 structure region (10 nM) and Smac polypeptide (10 nM) were incubated in the test buffer (50 mM Tris, 120 mM Nacl, 0.1% BSA, 1 mM DTT, 0.05% TritonX100) in the presence of the test compound for 1 h at room temperature.
  • the mixture is transferred to a streptavidin-coated plate, and then incubated at room temperature for 1 hour to allow the biotin-linked peptide and the Bir3 structure region to bind to the plate.
  • Example 108 Cell growth inhibition test in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines
  • the compound of the present invention has a good inhibitory effect on cell growth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines. It can be seen from Table 4 that some compounds have significantly better inhibitory effects on MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines than the control drugs.

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Abstract

La présente invention concerne un composé représenté par la formule I, et un racémate, un stéréoisomère, un tautomère, un marqueur isotopique, un solvate, un polymorphe, un métabolite, un ester, un promédicament ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le comprenant, son procédé de préparation et son utilisation pharmaceutique. La structure de formule I est la suivante.
PCT/CN2020/089459 2019-09-18 2020-05-09 Inhibiteur de protéine d'apoptose, son procédé de préparation et son utilisation WO2021051827A1 (fr)

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Citations (6)

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WO2008014252A2 (fr) * 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Inhibiteurs des iap
CN101516904A (zh) * 2006-07-24 2009-08-26 泰特拉洛吉克药业公司 二聚的iap拮抗剂
CN102471275A (zh) * 2009-07-02 2012-05-23 泰特拉洛吉克药业公司 Smac模拟物
US20140303090A1 (en) * 2013-04-08 2014-10-09 Tetralogic Pharmaceuticals Corporation Smac Mimetic Therapy
WO2017186147A1 (fr) * 2016-04-27 2017-11-02 南京明德新药研发股份有限公司 Composé indole lié au benzimidazole agissant comme nouvel antagoniste d'iap divalent
WO2019080928A1 (fr) * 2017-10-27 2019-05-02 南京明德新药研发股份有限公司 Forme cristalline d'un antagoniste d'iap et procédé de préparation correspondant

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MX2009003834A (es) * 2006-10-12 2009-04-22 Novartis Ag Derivados de pirrolidina como inhibidores de iap.
CN108440507B (zh) * 2017-02-16 2022-10-18 南京圣和药物研发有限公司 作为细胞凋亡蛋白抑制剂的化合物及其应用

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Publication number Priority date Publication date Assignee Title
WO2008014252A2 (fr) * 2006-07-24 2008-01-31 Tetralogic Pharmaceuticals Corporation Inhibiteurs des iap
CN101516904A (zh) * 2006-07-24 2009-08-26 泰特拉洛吉克药业公司 二聚的iap拮抗剂
CN102471275A (zh) * 2009-07-02 2012-05-23 泰特拉洛吉克药业公司 Smac模拟物
US20140303090A1 (en) * 2013-04-08 2014-10-09 Tetralogic Pharmaceuticals Corporation Smac Mimetic Therapy
WO2017186147A1 (fr) * 2016-04-27 2017-11-02 南京明德新药研发股份有限公司 Composé indole lié au benzimidazole agissant comme nouvel antagoniste d'iap divalent
WO2019080928A1 (fr) * 2017-10-27 2019-05-02 南京明德新药研发股份有限公司 Forme cristalline d'un antagoniste d'iap et procédé de préparation correspondant

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