WO2024051668A1 - Spiro compound and use thereof - Google Patents

Spiro compound and use thereof Download PDF

Info

Publication number
WO2024051668A1
WO2024051668A1 PCT/CN2023/116903 CN2023116903W WO2024051668A1 WO 2024051668 A1 WO2024051668 A1 WO 2024051668A1 CN 2023116903 W CN2023116903 W CN 2023116903W WO 2024051668 A1 WO2024051668 A1 WO 2024051668A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkylene
halogen
substituted
alkyl
membered
Prior art date
Application number
PCT/CN2023/116903
Other languages
French (fr)
Chinese (zh)
Inventor
李进
刘川
夏帅
窦登峰
向四川
涂凯鑫
陈秋霞
Original Assignee
成都先导药物开发股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 成都先导药物开发股份有限公司 filed Critical 成都先导药物开发股份有限公司
Publication of WO2024051668A1 publication Critical patent/WO2024051668A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a novel spirocyclic cereblon E3 ubiquitin ligase protein-binding ligand compound.
  • Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP).
  • UPP ubiquitin-proteasome pathway
  • UPP is responsible for clearing residual proteins and is ATP-dependent, efficient, and highly selective. Its catalytic part is a ubiquitination E3 ligase, but it needs to recruit proteins that need to be degraded first.
  • PROTACs technology is designed based on the UPP principle. It connects the target protein ligand and the E3 ligase ligand with appropriate chemical bonds, thereby identifying the target protein and enhancing the binding ability of the ligase E3 to the target protein, thereby targeting ubiquitin. Chemically forced degradation of target proteins, and has the characteristics of catalyst quantity, high efficiency, and high selectivity.
  • Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags the protein for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, Amino acids serve as the building blocks of new proteins.
  • Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.
  • Cereblon is a thalidomide-binding protein that is part of the E3 ubiquitin ligase protein complex and acts as a substrate receptor to selectively act on ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene. Cereblon, damaged DNA binding protein 1 (DDBl), Cullin-4A (CUL4A) and Cullin-1 regulator (ROCI) form an E3 ubiquitin ligase complex, which can ubiquitin oxidizes a series of proteins, but the specific mechanism remains unclear. Cereblon is a commonly used E3 ligase known to be used in PROTACs technology.
  • the invention discloses a new type of spirocyclic compounds, which can be used as effective CRBN ligands, and can further synthesize corresponding PROTACs bifunctional compounds that can target protein degradation chimeras, which can be used to treat various medical diseases, especially It is abnormal cell proliferation.
  • the invention provides a compound represented by formula I, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from 3-12-membered cycloalkyl, 4-12-membered heterocycloalkyl, 6-10-membered aromatic ring, 5-10-membered heteroaromatic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring,
  • the heteroaromatic ring may be further optionally substituted with one, two, three or four independent R A1 ;
  • R A2 and R A3 are independently selected from hydrogen, -C 1-6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl;
  • R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1 ⁇ 4 -alkylene-SR 24 , -C 1 to 4 alkylene-S(O) 2 R 24 , -C 1 to 4 alkylene-S(O)R 24 , -C 1 to 4 alkylene- S(O) 2 NR 24 R 25 , -C 1 ⁇ 4 alkylene group -S(O)NR 24 R 25 , -C 1 ⁇ 4 alkylene group -S(O)NR 24 R
  • R 24 and R 25 are independently selected from hydrogen, -C 1-6 alkyl, -C 2 ⁇ 6 alkenyl, -C 2 ⁇ 6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2 ⁇ 6 alkenyl, halogen-substituted -C 2 ⁇ 6 alkynyl;
  • the A ring is selected from 10-membered nitrogen-containing aromatic heterocycles.
  • the A ring is selected from The B ring is a 6-membered nitrogen-containing aromatic heterocyclic ring.
  • the R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned A ring; preferably, the R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned B ring. replace position.
  • the A ring is selected from Among them, the ring selected from ring A can be further optionally substituted by one, two, three or four independent R A1 .
  • the R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned A ring;
  • Each R A1 is independently selected from hydrogen, halogen, -NR A2 R A3 , -OR A2 , -C 1 ⁇ 3 alkyl, and halogen-substituted -C 1 ⁇ 3 alkyl;
  • RA2 and RA3 are each independently selected from hydrogen, methyl, ethyl, and propyl.
  • the A ring is selected from
  • R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1 ⁇ 4- alkylene-C(O)R 24 , -C 1 ⁇ 4 alkylene-C(O)OR 24 ,-C 1 ⁇ 4 alkylene-C(O)NR 24 R 25 ,-C 1 ⁇ 4- alkylene-NR 24 R 25 , -C 1 ⁇ 4- alkylene-NR 24 R 25 , -C 1 to 4 alkylene-NR 24 C(O)R 25 , -C 0 to 4- alkylene
  • R 24 and R 25 are each independently selected from hydrogen, -C 1-3 alkyl group, and halogen-substituted -C 1-3 alkyl group.
  • the R 2 is selected from hydrogen, -C(O)NR 21 R 22 , -C(O)R 21 , -C 0 ⁇ 2 alkylene -NR 21 R 22 , -C(O)OR 21 , -OR twenty one ;
  • R 21 and R 22 are independently selected from hydrogen, -C 1 ⁇ 3 alkyl, -C 0 ⁇ 1 alkylene-(6-membered aromatic ring), -C 0 ⁇ 1 alkylene-(10-membered heteroaromatic ring) ), -(4 to 6-membered heterocycloalkyl), -(3 to 6-membered cycloalkyl), wherein the aromatic ring, heteroaromatic ring, heterocycloalkyl, and cycloalkyl can be further optionally substituted by one or two One, three or four independent R 26 substitutions;
  • Each R 26 is independently selected from hydrogen, -C 1 to 3 alkyl, -(4 to 6 membered heterocycloalkyl), -C(O)R 24 , -C(O)OR 24 , -OC(O )R 24 ;
  • R 24 is selected from hydrogen, methyl, ethyl, propyl.
  • the R 2 is selected from hydrogen, hydroxyl,
  • the compound represented by Formula I of the present invention is specifically:
  • the present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the preparation and treatment of diseases related to abnormal cell proliferation.
  • the disease is cancer.
  • the present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of targeted protein degradation drugs.
  • the present invention also provides the use of the above compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of targeted protein degradation drugs.
  • C a to b alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms.
  • C 1 -6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms.
  • Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl). base) and hexyl base. Alkyl groups may also be part of other groups, such as C 1 -6 alkoxy groups.
  • alkylene group refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms.
  • C a - b alkylene refers to an alkylene group having a to b carbon atoms.
  • Alkylene groups include branched and straight chain hydrocarbyl groups.
  • C 1-6 alkylene is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like.
  • the term "propylene” can be exemplified by the following structure:
  • the term "dimethylbutylene” may be exemplified, for example, by any of the following structures:
  • the term "(C 1 -6 )alkylene” is intended to include such branched hydrocarbyl groups, such as cyclopropylmethylene, which can be exemplified by the following structures:
  • -C 0 ⁇ 4 alkylene can be C 0 alkylene, C 1 alkylene (for example -CH 2 -), C 2 alkylene (for example -CH 2 CH 2 -, etc.), C 3 alkylene Alkyl or C 4 alkylene;
  • C 0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as AC 0 alkylene-B refers to AB, that is, the A group and B The groups are connected directly by chemical bonds.
  • C ab alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadiene Key et al.
  • Alkenylene refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond and two unsaturated chemical valences.
  • Alkynyl refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group containing at least one triple bond.
  • alkynyl is also intended to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkynyl is intended to include ethynyl, propynyl, and the like.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Haloalkyl and halogen-substituted alkyl mean that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms.
  • C 1-4 halogen alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms.
  • the oxygen atom in "-C(O)R", “-S(O) 2 R”, etc. mentioned in the present invention is double-bonded to the carbon atom or sulfur atom, and the R group is connected to the oxygen atom or sulfur atom. Connected by a single key.
  • cycloalkyl and “cycloalkane” mentioned in the present invention refer to those having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro ring and adamantane systems). ) of a saturated or partially saturated cyclic group.
  • cycloalkyl applies when the point of attachment is at a nonaromatic carbon atom (e.g., 5,6,7,8,-tetra Hydronaphthalene-5-yl).
  • cycloalkyl includes cycloalkenyl groups such as cyclohexenyl.
  • cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl.
  • cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like.
  • Adamantyl groups include, but are not limited to, the following structures:
  • heterocycle refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, oxygen atom atoms, sulfur atoms, etc.
  • the heteroatom refers to a nitrogen atom, oxygen atom atoms, sulfur atoms, etc.
  • Bicyclic refers to two rings that share two ring atoms.
  • the bridge that separates the two rings is a single bond or a chain of one or two ring atoms.
  • monocyclic saturated heterocycloalkyl groups are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuryl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, Tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl.
  • bicyclic saturated heterocycloalkyl examples include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
  • Spiroheterocyclyl and “spiroheterocycle” are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system with two single rings sharing one carbon atom, which consists of carbon atoms and selected Made from heteroatoms of nitrogen, oxygen, sulfur and phosphorus.
  • “5- to 12-membered spiroheterocycle” refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.
  • Bridged ring or bridged cyclic group refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples thereof include but are not limited to:
  • Bridged heterocyclyl and “bridged heterocyclyl” are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. Specific examples include but are not limited to:
  • aromatic ring and aryl group refer to aromatic hydrocarbon groups having multiple carbon atoms.
  • Aryl groups are usually monocyclic, bicyclic or tricyclic aryl groups having 5 to 20 carbon atoms.
  • aryl refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • heteroaryl ring and “heteroaryl ring group” mentioned in the present invention refer to an aromatic unsaturated ring containing at least one heteroatom; the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc.
  • Aromatic monocyclic or bicyclic hydrocarbons that generally contain multiple ring atoms, one or more of which are heteroatoms selected from O, N, and S. Preferably there are one to three heteroatoms.
  • Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzene Thiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole base, benzothiazolyl, benzoxazolyl.
  • Steps include enantiomers and diastereomers
  • the "deuterated compound” of the present invention means that one or more hydrogen atoms in the molecule or group are replaced by deuterium atoms, wherein The proportion of deuterium atoms is greater than the abundance of deuterium in nature.
  • pharmaceutically acceptable means a carrier, carrier, diluent, excipient, and/or salt formed that is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and is physiologically compatible Compatible with receptors.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or their stereoisomers, acidic and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts ( Internal salts), also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the above compound, or its stereoisomer, with a certain amount of acid or base (for example, equivalent amounts).
  • salts may form a precipitate in the solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by reacting in an aqueous medium and then freeze-drying.
  • the salt mentioned in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butylene salt of the compound. salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc.
  • the reaction was carried out under a nitrogen atmosphere.
  • the solution refers to an aqueous solution.
  • the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C ⁇ ⁇ 30°C ⁇ .
  • M is mol per liter.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10-6 (ppm). NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 600) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (Methol-d 4 ), the internal standard is tetramethylsilane (TMS). LC-MS was measured using a Shimadzu liquid mass spectrometer.
  • Pd 2 (dba) 3 dipalladium tribenzylideneacetone
  • DIPEA N, N-diisopropylethylamine
  • DMSO dimethyl sulfoxide
  • AcOH acetic acid
  • Sphos 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl
  • LC-MS liquid mass spectrometry
  • NaCl sodium chloride
  • MPLC medium pressure liquid phase preparation
  • TMEDA tetramethylethylenediamine.
  • compound A2 can be obtained.
  • compound A4 can be obtained.
  • compound A10 can be obtained.
  • Microplate reader BMG PHERAstar FSX
  • ECHO LABCYTE Echo 665
  • microplate constant temperature oscillator Hangzhou Ruicheng Instrument Co., Ltd.
  • disodium hydrogen phosphate Sigma
  • sodium dihydrogen phosphate Sigma
  • bovine serum Protein Sigma
  • Anti-6His-Tb crypate Gold CISBIO
  • CRBN/DDB1 protein HitGen
  • 384-well plate Grenier Bio-one
  • the vehicle group (containing 5.0nM CRBN/DDB1, 0.2nM Anti-6His-Tb crypate Gold, 50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) was used as the negative control and the reaction buffer group (containing 0.2nM Anti -6His-Tb crypate Gold, 50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) is the blank control;
  • Remaining activity (%) 100% ⁇ (Flu compound group -Flu blank control )/(Flu negative control -Flu blank control )
  • Table 1 Compounds and CRBN/DDB1 protein inhibition table Among them, + represents 200 ⁇ M>IC 50 >100 ⁇ M, ++ represents 100 ⁇ M>IC 50 >10 ⁇ M, +++ represents 10 ⁇ M>IC 50 >1 ⁇ M, ++++ represents IC 50 ⁇ 1 ⁇ M.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Provided are a compound having a binding effect with an E3 ligase protein (CRBN) as represented by formula I and a use of the compound in the preparation of a drug for treating abnormal cell proliferation diseases.

Description

螺环化合物及其用途Spirocyclic compounds and their uses 技术领域Technical field
本发明属于医药领域，具体涉及一种新型螺环类小脑蛋白(cereblon)E3泛素连接酶蛋白质结合的配体化合物。The invention belongs to the field of medicine, and specifically relates to a novel spirocyclic cereblon E3 ubiquitin ligase protein-binding ligand compound.
背景技术Background technique
蛋白质降解是一种高度受调的和维持细胞稳态所必需的过程。通过泛素-蛋白酶体途径(Ubiquitin-proteasome pathway，UPP)实现对受损的、错误折叠的或过量蛋白质的选择性鉴别和去除。UPP负责清除残次蛋白，具有依赖ATP、高效、高度选择性的特点，其催化部分是泛素化E3连接酶，但需要首先募集到需要降解的蛋白。PROTACs技术基于UPP原理设计而成，把目标蛋白配体和E3连接酶的配体用合适的化学键连接起来，从而可以识别靶蛋白且增强连接酶E3与靶蛋白的结合能力，进而靶向泛素化强迫降解靶蛋白，且具有催化剂量、高效、高度选择性等特点。Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is responsible for clearing residual proteins and is ATP-dependent, efficient, and highly selective. Its catalytic part is a ubiquitination E3 ligase, but it needs to recruit proteins that need to be degraded first. PROTACs technology is designed based on the UPP principle. It connects the target protein ligand and the E3 ligase ligand with appropriate chemical bonds, thereby identifying the target protein and enhancing the binding ability of the ligase E3 to the target protein, thereby targeting ubiquitin. Chemically forced degradation of target proteins, and has the characteristics of catalyst quantity, high efficiency, and high selectivity.
多个泛素分子通过E3泛素连接酶与末端赖氨酸残基的共价连接对蛋白质进行标记以进行蛋白酶体降解，其中该蛋白质被消化成小肽并最终消化成其组成氨基酸，所述氨基酸用作新蛋白质的构建模块。有缺陷的蛋白酶体降解与多种临床病症有关，所述病症包括阿尔茨海默病、帕金森病、亨廷顿病、肌营养不良、心血管疾病和癌症等。Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags the protein for proteasomal degradation, where the protein is digested into small peptides and ultimately into its constituent amino acids, Amino acids serve as the building blocks of new proteins. Defective proteasomal degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer, among others.
小脑蛋白(Cereblon)是一种沙利度胺的结合蛋白，是E3泛素连接酶蛋白复合物的一部分，它作为底物受体选择作用于泛素化的蛋白质。Cereblon是由人类CRBN基因编码的蛋白，Cereblon与损伤DNA结合蛋白1(DDBl)、Cullin-4A(CUL4A)以及Cullin-1调节器(ROCI)组成E3泛素连接酶复合体，该复合体能泛素化一系列蛋白，但具体机制尚不清楚。Cereblon是目前已知应用于PROTACs技术常用的一种E3连接酶。Cereblon is a thalidomide-binding protein that is part of the E3 ubiquitin ligase protein complex and acts as a substrate receptor to selectively act on ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene. Cereblon, damaged DNA binding protein 1 (DDBl), Cullin-4A (CUL4A) and Cullin-1 regulator (ROCI) form an E3 ubiquitin ligase complex, which can ubiquitin oxidizes a series of proteins, but the specific mechanism remains unclear. Cereblon is a commonly used E3 ligase known to be used in PROTACs technology.
本发明公开了一类新型的螺环化合物，它们可以作为有效的CRBN配体，进一步可以合成相应的能使蛋白降解靶向嵌合体的PROTACs双功能化合物，其可用于治疗各种医学病症，特别是异常细胞增殖。The invention discloses a new type of spirocyclic compounds, which can be used as effective CRBN ligands, and can further synthesize corresponding PROTACs bifunctional compounds that can target protein degradation chimeras, which can be used to treat various medical diseases, especially It is abnormal cell proliferation.
发明内容Contents of the invention
本发明提供了一种式I所示的化合物，或其立体异构体、或其氘代化合物，或其药学上可接受的盐：
The invention provides a compound represented by formula I, or a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:
其中，in,
A环选自3～12元环烷基、4～12元杂环烷基、6～10元芳环、5～10元杂芳环；其中，环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的RA1取代；Ring A is selected from 3-12-membered cycloalkyl, 4-12-membered heterocycloalkyl, 6-10-membered aromatic ring, 5-10-membered heteroaromatic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring, The heteroaromatic ring may be further optionally substituted with one, two, three or four independent R A1 ;
每个RA1分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CRA2RA3、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-ORA2、-C0～4亚烷基-OC(O)RA2、-C0～4亚烷基-SRA2、-C0～4亚烷基-S(O)2RA2、-C0～4亚烷基-S(O)RA2、-C0～4亚烷基-S(O)2NRA2RA3、-C0～4亚烷基-S(O)NRA2RA3、-C0～4亚烷基-C(O)RA2、-C0～4亚烷基-C(O)ORA2、-C0～4亚烷基-C(O)NRA2RA3、-C0～4亚烷基-NRA2RA3、-C0～4亚烷基-NRA2C(O)RA3、-C0～4亚烷基-NRA2S(O)2RA3、-C0～4亚烷基-NRA2S(O)RA3、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的RA4取代；Each R A1 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR A2 , - C 0～4 alkylene -OC(O)R A2 , -C 0～4 alkylene -SR A2 , -C 0～4 alkylene -S(O) 2 R A2 , -C 0～4 alkylene Alkyl-S(O) RA2 , -C 0～4 alkylene-S(O) 2 NR A2 R A3 , -C 0～4 alkylene-S(O)NR A2 R A3 , -C 0 ～4 alkylene-C(O) RA2 , -C 0～4 alkylene-C(O)OR A2 , -C 0～4 alkylene-C(O)NR A2 R A3 , -C 0 ~4 alkylene-NR A2 R A3 , -C 0 ~ 4 alkylene -NR A2 C(O)R A3 , -C 0 ~ 4 alkylene -NR A2 S(O) 2 R A3 , -C 0～4 alkylene-NR A2 S(O)R A3 , -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(4～10 membered hetero Cycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered heteroaromatic ring); among them, alkylene, cycloalkyl The base, heterocycloalkyl, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R A4 ;
每个RA4分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CRA2RA3、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-ORA2、-C0～4亚烷基-OC(O)RA2、-C0～4亚烷基-SRA2、-C0～4亚烷基-S(O)2RA2、-C0～4亚烷基-S(O)RA2、-C0～4亚烷基-S(O)2NRA2RA3、-C0～4亚烷基-S(O)NRA2RA3、-C0～4亚烷基-C(O)RA2、-C0～4亚烷基-C(O)ORA2、-C0～4亚烷基-C(O)NRA2RA3、-C0～4亚烷基-NRA2RA3、-C0～4亚烷基-NRA2C(O)RA3、-C0～4亚烷基-NRA2S(O)2RA3、-C0～4亚烷基-NRA2S(O)RA3；Each R A4 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR A2 , - C 0～4 alkylene -OC(O)R A2 , -C 0～4 alkylene -SR A2 , -C 0～4 alkylene -S(O) 2 R A2 , -C 0～4 alkylene Alkyl-S(O) RA2 , -C 0～4 alkylene-S(O) 2 NR A2 R A3 , -C 0～4 alkylene-S(O)NR A2 R A3 , -C 0 ～4 alkylene-C(O) RA2 , -C 0～4 alkylene-C(O)OR A2 , -C 0～4 alkylene-C(O)NR A2 R A3 , -C 0 ~4 alkylene-NR A2 R A3 , -C 0 ~ 4 alkylene -NR A2 C(O)R A3 , -C 0 ~ 4 alkylene -NR A2 S(O) 2 R A3 , -C 0～4 alkylene-NR A2 S(O)R A3 ;
RA2、RA3分别独立选自氢、-C1-6的烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基；R A2 and R A3 are independently selected from hydrogen, -C 1-6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl;
R2独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR21R22、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-SR21、-C0～4亚烷基-S(O)2R21、-C0～4亚烷基-S(O)R21、-C0～4亚烷基-S(O)2NR21R22、-C0～4亚烷基-S(O)NR21R22、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22、 -C0～4亚烷基-NR21C(O)R22、-C0～4亚烷基-NR21S(O)2R22、-C0～4亚烷基-NR21S(O)R22、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R23取代；R 2 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl , halogen-substituted -C 1 to 6 alkyl group, halogen-substituted -C 2 to 6 alkenyl group, halogen-substituted -C 2 to 6 alkynyl group, -C 0 to 4 alkylene group -OR 21 , -C 0～ 4- alkylene group -OC(O)R 21 , -C 0～4 alkylene group-SR 21 , -C 0～4 alkylene group-S(O) 2 R 21 , -C 0～4 alkylene group- S(O)R 21 , -C 0～4 alkylene -S(O) 2 NR 21 R 22 , -C 0～4 alkylene -S(O)NR 21 R 22 , -C 0～4 alkylene Alkyl-C(O)R 21 , -C 0～ 4alkylene-C(O)OR 21 , -C 0～ 4alkylene-C(O)NR 21 R 22 , -C 0～4alkylene Alkyl-NR 21 R 22 , -C 0～4 alkylene-NR 21 C(O)R 22 , -C 0～4 alkylene-NR 21 S(O) 2 R 22 , -C 0～4 alkylene-NR 21 S( O)R 22 , -C 0～4 alkylene-(3-10 membered cycloalkyl), -C 0～4 alkylene-(4-10 membered heterocycloalkyl), -C 0～4 sub Alkyl-(6-10 membered aromatic ring), -C 0-4 alkylene-(5-10 membered heteroaromatic ring); among them, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, hetero The aromatic ring may be further optionally substituted by one, two, three or four independent R 23 ;
每个R23分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR21R22、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-SR21、-C0～4亚烷基-S(O)2R21、-C0～4亚烷基-S(O)R21、-C0～4亚烷基-S(O)2NR21R22、-C0～4亚烷基-S(O)NR21R22、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22、-C0～4亚烷基-NR21C(O)R22、-C0～4亚烷基-NR21S(O)2R22、-C0～4亚烷基-NR21S(O)R22、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；Each R 23 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 21 , - C 0～4 alkylene -OC(O)R 21 , -C 0～4 alkylene -SR 21 , -C 0～4 alkylene -S(O) 2 R 21 , -C 0～4 alkylene Alkyl-S(O)R 21 , -C 0 to 4 alkylene -S(O) 2 NR 21 R 22 , -C 0 to 4 alkylene -S(O)NR 21 R 22 , -C 0 ~4 alkylene-C(O)R 21 , -C 0 ~ 4 alkylene -C(O)OR 21 , -C 0 ~ 4 alkylene -C(O)NR 21 R 22 , -C 0 ~4 alkylene-NR 21 R 22 , -C 0 ~ 4 alkylene -NR 21 C(O)R 22 , -C 0 ~ 4 alkylene -NR 21 S(O) 2 R 22 , -C 0～4 alkylene-NR 21 S(O)R 22 , -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(4～10 membered hetero Cycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered heteroaromatic ring); among them, alkylene, cycloalkyl The base, heterocycloalkyl, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 26 ;
R21、R22分别独立选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C1～4亚烷基-OR24、-C1～4亚烷基-OC(O)R24、-C1～4亚烷基-SR24、-C1～4亚烷基-S(O)2R24、-C1～4亚烷基-S(O)R24、-C1～4亚烷基-S(O)2NR24R25、-C1～4亚烷基-S(O)NR24R25、-C1～4亚烷基-C(O)R24、-C1～4亚烷基-C(O)OR24、-C1～4亚烷基-C(O)NR24R25、-C1～4亚烷基-NR24R25、-C1～4亚烷基-NR24C(O)R25、-C1～4亚烷基-NR24S(O)2R25、-C1～4亚烷基-NR24S(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1～ 4 -alkylene-SR 24 , -C 1 to 4 alkylene-S(O) 2 R 24 , -C 1 to 4 alkylene-S(O)R 24 , -C 1 to 4 alkylene- S(O) 2 NR 24 R 25 , -C 1～4 alkylene group -S(O)NR 24 R 25 , -C 1～4 alkylene group -C(O)R 24 , -C 1～4 sub Alkyl-C(O)OR 24 , -C 1 to 4 alkylene -C(O)NR 24 R 25 , -C 1 to 4 alkylene -NR 24 R 25 , -C 1 to 4 alkylene -NR 24 C(O)R 25 , -C 1～4 alkylene group -NR 24 S(O) 2 R 25 , -C 1～4 alkylene group -NR 24 S(O)R 25 , -C 0 ~4 alkylene-(3~10 membered cycloalkyl), -C 0~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6~10 membered Aromatic ring), -C 0 ~ 4 alkylene - (5 ~ 10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally replaced by a , two, three or four independent R 26 substitutions;
每个R26分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR24R25、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR24、-C0～4亚烷基-OC(O)R24、-C0～4亚烷基-SR24、-C0～4亚烷基-S(O)2R24、-C0～4亚烷基-S(O)R24、-C0～4亚烷基-S(O)2NR24R25、-C0～4亚烷基-S(O)NR24R25、-C0～4亚烷基-C(O)R24、-C0～4亚烷基-C(O)OR24、-C0～4亚烷基-C(O)NR24R25、-C0～4亚烷基-NR24R25、-C0～4亚烷基-NR24C(O)R25、-C0～4亚烷基-NR24S(O)2R25、-C0～4亚烷基-NR24S(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、 芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R27取代；Each R 26 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 24 , - C 0～4 alkylene -OC(O)R 24 , -C 0～4 alkylene -SR 24 , -C 0～4 alkylene -S(O) 2 R 24 , -C 0～4 alkylene Alkyl-S(O)R 24 , -C 0 to 4 alkylene -S(O) 2 NR 24 R 25 , -C 0 to 4 alkylene -S(O)NR 24 R 25 , -C 0 ~4 alkylene-C(O)R 24 , -C 0 ~ 4 alkylene -C(O)OR 24 , -C 0 ~ 4 alkylene -C(O)NR 24 R 25 , -C 0 ~4 alkylene-NR 24 R 25 , -C 0 ~ 4 alkylene -NR 24 C(O)R 25 , -C 0 ~ 4 alkylene -NR 24 S(O) 2 R 25 , -C 0～4 alkylene-NR 24 S(O)R 25 , -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(4～10 membered hetero Cycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered heteroaromatic ring); among them, alkylene, cycloalkyl base, heterocycloalkyl, The aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 27 ;
R24、R25分别独立选自氢、-C1-6的烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基；R 24 and R 25 are independently selected from hydrogen, -C 1-6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl;
每个R27分别独立选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基。Each R 27 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen substitution -C 1 to 6 alkyl group, halogen-substituted -C 2 to 6 alkenyl group, and halogen-substituted -C 2 to 6 alkynyl group.
作为优选，所述A环选自10元含氮芳杂环。Preferably, the A ring is selected from 10-membered nitrogen-containing aromatic heterocycles.
进一步地，further,
所述A环选自所述B环为6元含氮芳杂环。式I中与A环相连的R2和N原子可连接在上述A环的任何可取代位置；优选地，式I中与A环相连的R2和N原子可连接在上述B环的任何可取代位置。The A ring is selected from The B ring is a 6-membered nitrogen-containing aromatic heterocyclic ring. The R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned A ring; preferably, the R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned B ring. replace position.
优选地，Preferably,
所述A环选自 其中，A环选自的环可进一步任选被一个、两个、三个或四个独立的RA1取代。式I中与A环相连的R2和N原子可连接在上述A环的任何可取代位置； The A ring is selected from Among them, the ring selected from ring A can be further optionally substituted by one, two, three or four independent R A1 . The R 2 and N atoms connected to the A ring in formula I can be connected to any substitutable position of the above-mentioned A ring;
作为优选，As a preference,
每个RA1分别独立选自氢、卤素、-NRA2RA3、-ORA2、-C1～3烷基、卤素取代的-C1～3烷基；Each R A1 is independently selected from hydrogen, halogen, -NR A2 R A3 , -OR A2 , -C 1～3 alkyl, and halogen-substituted -C 1～3 alkyl;
RA2、RA3分别独立选自氢、甲基、乙基、丙基。 RA2 and RA3 are each independently selected from hydrogen, methyl, ethyl, and propyl.
作为优选，As a preference,
所述A环选自 The A ring is selected from
作为优选，As a preference,
R2选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22；-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R23取代；R 2 is selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen substituted -C 1 ~6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl, -C 0~4 alkylene-OR 21 , -C 0~4 alkylene-OC( O)R 21 , -C 0～4 alkylene-C(O)R 21 , -C 0～4 alkylene-C(O)OR 21 , -C 0～4 alkylene-C(O) NR 21 R 22 , -C 0～4 alkylene group-NR 21 R 22 ; -C 0～4 alkylene group-(3～10 membered cycloalkyl group), -C 0～4 alkylene group-(4～ 10-membered heterocycloalkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5-10 membered heteroaromatic ring); among which, alkylene , cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally substituted by one, two, three or four independent R 23 ;
每个R23分别独立选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-C(O)R21；-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；Each R 23 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen substitution -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 21 , -C 0 to 4 alkylene -OC(O)R 21 , -C 0～4 alkylene-C(O)R 21 ; -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 cycloalkyl Alkyl-(4-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring), -C 0-4 alkylene-(5-10 membered heteroaromatic ring) ; Wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally substituted by one, two, three or four independent R 26 ;
R21、R22分别独立选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C1～4亚烷基-OR24、-C1～4亚烷基-OC(O)R24、-C1～4亚烷基-C(O)R24、-C1～4亚烷基-C(O)OR24、-C1～4亚烷基-C(O)NR24R25、-C1～4亚烷基-NR24R25、-C1～4亚烷基-NR24C(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1～ 4- alkylene-C(O)R 24 , -C 1～4 alkylene-C(O)OR 24 ,-C 1～4 alkylene-C(O)NR 24 R 25 ,-C 1～ 4- alkylene-NR 24 R 25 , -C 1 to 4 alkylene-NR 24 C(O)R 25 , -C 0 to 4- alkylene-(3-10 membered cycloalkyl), -C 0 ~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered hetero Aromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 26 ;
每个R26分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR24R25、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR24、-C0～4亚烷基-OC(O)R24、-C0～4亚烷基-C(O)R24、-C0～4亚烷基-C(O)OR24、 -C0～4亚烷基-C(O)NR24R25、-C0～4亚烷基-NR24R25、-C0～4亚烷基-NR24C(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；Each R 26 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 24 , - C 0～4 alkylene-OC(O)R 24 , -C 0～4 alkylene-C(O)R 24 , -C 0～4 alkylene-C(O)OR 24 , -C 0～4 alkylene-C(O)NR 24 R 25 , -C 0～4 alkylene-NR 24 R 25 , -C 0～4 alkylene-NR 24 C(O)R 25 , -C 0~4 alkylene-(3~10 membered cycloalkyl), -C 0~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6 ~10-membered aromatic ring), -C 0~4 alkylene-(5~10-membered heteroaromatic ring);
R24、R25分别独立选自氢、-C1-3的烷基、卤素取代的-C1～3烷基。R 24 and R 25 are each independently selected from hydrogen, -C 1-3 alkyl group, and halogen-substituted -C 1-3 alkyl group.
作为优选，As a preference,
所述R2选自氢、-C(O)NR21R22、-C(O)R21、-C0～2亚烷基-NR21R22、-C(O)OR21、-OR21；The R 2 is selected from hydrogen, -C(O)NR 21 R 22 , -C(O)R 21 , -C 0～2 alkylene -NR 21 R 22 , -C(O)OR 21 , -OR twenty one ;
R21、R22分别独立选自氢、-C1～3烷基、-C0～1亚烷基-(6元芳环)、-C0～1亚烷基-(10元杂芳环)、-(4～6元杂环烷基)、-(3～6元环烷基)，其中，芳环、杂芳环、杂环烷基、环烷基可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1～3 alkyl, -C 0～1 alkylene-(6-membered aromatic ring), -C 0～1 alkylene-(10-membered heteroaromatic ring) ), -(4 to 6-membered heterocycloalkyl), -(3 to 6-membered cycloalkyl), wherein the aromatic ring, heteroaromatic ring, heterocycloalkyl, and cycloalkyl can be further optionally substituted by one or two One, three or four independent R 26 substitutions;
每个R26分别独立选自氢、-C1～3烷基、-(4～6元杂环烷基)、-C(O)R24、-C(O)OR24、-OC(O)R24；Each R 26 is independently selected from hydrogen, -C 1 to 3 alkyl, -(4 to 6 membered heterocycloalkyl), -C(O)R 24 , -C(O)OR 24 , -OC(O )R 24 ;
R24选自氢、甲基、乙基、丙基。R 24 is selected from hydrogen, methyl, ethyl, propyl.
进一步地，further,
所述R2选自氢、羟基、 The R 2 is selected from hydrogen, hydroxyl,
在发明的一些具体实施方案中，本发明式I所示的化合物具体为：

In some specific embodiments of the invention, the compound represented by Formula I of the present invention is specifically:

本发明还提供了上述的化合物，或其立体异构体、或其氘代化合物，或其药学上可接受的盐制备治疗细胞异常增殖相关疾病中的用途。The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the preparation and treatment of diseases related to abnormal cell proliferation.
进一步地，所述疾病为癌症。Further, the disease is cancer.
本发明还提供了上述化合物、或其立体异构体、或其氘代化合物，或其药学上可接受的盐在制备靶向蛋白降解药物中的用途。The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of targeted protein degradation drugs.
本发明还提供了上述化合物、或其立体异构体、或其氘代化合物，或其药学上可接受的盐作为中间体在制备靶向蛋白降解药物中的用途。The present invention also provides the use of the above compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of targeted protein degradation drugs.
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。 Compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature systems.
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definitions of terms used in the present invention: Unless otherwise stated, the initial definition provided for a group or term in this article applies to the group or term in the entire specification; for terms that are not specifically defined in this article, it should be based on the disclosure content and context. , giving the meanings that those skilled in the art can give them.
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。“取代”也可指分子中原子的孤对电子被“＝O”、“＝S”等替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule. "Substitution" can also mean that the lone pair of electrons of an atom in a molecule is replaced by "=O", "=S", etc.
“可进一步任选被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。"Can be further optionally substituted" means that "substitution" may but does not necessarily occur, and this description includes the occurrence or non-occurrence.
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀Ca～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，“C1～4烷基”是指包含1～4个碳原子的烷基。The minimum and maximum content of carbon atoms in a hydrocarbon group is indicated by a prefix, for example, the prefix C a to b alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C 1-4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.
“烷基”是指具有指定数目的成员原子的饱和烃链。例如，C1～6烷基是指具有1至6个成员原子，例如1至4个成员原子的烷基基团。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如C1～6烷氧基。"Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C 1 -6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl). base) and hexyl base. Alkyl groups may also be part of other groups, such as C 1 -6 alkoxy groups.
本发明中所述的“亚烷基”是指具有指定数目个碳原子的二价饱和脂族烃基。“Ca～b亚烷基”是指具有a至b个碳原子的亚烷基基团。亚烷基基团包括支链和直链烃基基团。例如，“C1～6亚烷基”意在包括亚甲基、亚乙基、亚丙基、2-甲基亚丙基、二甲基亚乙基、亚戊基等等。因此，术语“亚丙基”可以通过下列结构例举：同样地，术语“二甲基亚丁基”可以例如通过下列结构的任一种例举：此外，术语“(C1～6)亚烷基”意在包括此类支链烃基基团，诸如环丙基亚甲基，其可以通过下列结构例举：还例如-C0～4亚烷基可以为C0亚烷基、C1亚烷基(例如-CH2-)、C2亚烷基(例如-CH2CH2-等)、C3亚烷基或C4亚烷基；C0亚烷基指的是此处的基团不存在，以化学键的形式连接，如A-C0亚烷基-B指的是A-B，即A基团与B基团直接通过化学键连接。The "alkylene group" mentioned in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. "C a - b alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, "C 1-6 alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Therefore, the term "propylene" can be exemplified by the following structure: Likewise, the term "dimethylbutylene" may be exemplified, for example, by any of the following structures: Furthermore, the term "(C 1 -6 )alkylene" is intended to include such branched hydrocarbyl groups, such as cyclopropylmethylene, which can be exemplified by the following structures: For example, -C 0 ~ 4 alkylene can be C 0 alkylene, C 1 alkylene (for example -CH 2 -), C 2 alkylene (for example -CH 2 CH 2 -, etc.), C 3 alkylene Alkyl or C 4 alkylene; C 0 alkylene means that the group here does not exist and is connected in the form of a chemical bond, such as AC 0 alkylene-B refers to AB, that is, the A group and B The groups are connected directly by chemical bonds.
“烯基”是指具有指定数目个碳原子和在一些实施方案中2至6个碳原子或2至4个碳原子且具有至少1个乙烯基不饱和位点(>C＝C<)的直链或支链烃基基团。例如，Ca-b烯基是指具有a至b个碳原子的烯基基团并且意在包括例如乙烯基、丙烯基、异丙烯基、1,3-丁二烯 基等。"Alkenyl" means having the specified number of carbon atoms and in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of ethylenically unsaturated (>C=C<) Straight or branched chain hydrocarbyl groups. For example, C ab alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadiene Key et al.
本发明中所述的“亚烯基”是指具有2至10个碳原子、至少一个双键和两个不饱和化学价的烃链。例如，(C3-C6)亚烯基包括>C＝CH-CH2-、-CH-CH＝CH-CH2-等。"Alkenylene" as used in the present invention refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond and two unsaturated chemical valences. For example, (C 3 -C 6 ) alkenylene includes >C=CH-CH 2 -, -CH-CH=CH-CH 2 -, etc.
“炔基”是指含有至少一个三键的直链一价烃基或支链一价烃基。术语“炔基”还意在包括具有一个三键和一个双键的那些烃基基团。例如，(C2-C6)炔基意在包括乙炔基、丙炔基等。"Alkynyl" refers to a straight chain monovalent hydrocarbon group or a branched chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C 2 -C 6 )alkynyl is intended to include ethynyl, propynyl, and the like.
“卤素”为氟、氯、溴或碘。"Halogen" is fluorine, chlorine, bromine or iodine.
“卤素烷基”、“卤素取代的烷基”指烷基中的氢原子可被一个或多个卤素原子取代。例如C1～4卤素烷基指氢原子被一个或多个卤素原子取代的包含1～4个碳原子的烷基。"Haloalkyl" and "halogen-substituted alkyl" mean that the hydrogen atoms in the alkyl group may be replaced by one or more halogen atoms. For example, C 1-4 halogen alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are replaced by one or more halogen atoms.
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。"-OR", "-NRR", etc. mentioned in the present invention mean that the R group is connected to an oxygen atom or a nitrogen atom by a single bond.
本发明中所述的“-C(O)R”、“-S(O)2R”等中的氧原子是与碳原子或硫原子以双键相连，R基团与氧原子或硫原子以单键相连。The oxygen atom in "-C(O)R", "-S(O) 2 R", etc. mentioned in the present invention is double-bonded to the carbon atom or sulfur atom, and the R group is connected to the oxygen atom or sulfur atom. Connected by a single key.
本发明中所述的“环烷基”、“环烷烃”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(包括稠合、桥连、螺环和金刚烷体系)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系，当连接点位于非芳族碳原子时，适用术语“环烷基”(例如5,6,7,8,-四氢化萘-5-基)。术语“环烷基”包括环烯基基团，诸如环己烯基。环烷基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的环烷基基团的实例是双环己基、双环戊基、双环辛基等。例如金刚烷基包括但不限于以下结构： The "cycloalkyl" and "cycloalkane" mentioned in the present invention refer to those having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro ring and adamantane systems). ) of a saturated or partially saturated cyclic group. For polycyclic systems with aromatic and nonaromatic rings containing no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a nonaromatic carbon atom (e.g., 5,6,7,8,-tetra Hydronaphthalene-5-yl). The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl and the like. For example Adamantyl groups include, but are not limited to, the following structures:
本发明中所述的“杂环”、“杂环烷基”、“杂环烷烃”是指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环环系统、优选3至9个环原子的一价饱和或部分不饱和单环或二环环系统，其包含1、2或3个选自N、O和S的环杂原子，其余的环原子是碳。二环表示由共有两个环原子的两个环组成的，即将两个环分开的桥是单键或是一个或两个环原子的链。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、 四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1，1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。The "heterocycle", "heterocycloalkyl" and "heterocycloalkane" mentioned in the present invention refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, oxygen atom atoms, sulfur atoms, etc. Usually represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with 3 to 9 ring atoms, which contains 1, 2 Or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms are carbon. Bicyclic refers to two rings that share two ring atoms. The bridge that separates the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuryl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, Tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
“螺杂环基”和“螺杂环”可互换使用，是指具有两个单环共用一个碳原子的非芳香族饱和环或非芳香性的不饱和环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成。例如“5至12元螺杂环”是指具有5至12个环原子，其中1、2或3个环原子为杂原子的螺杂环。"Spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system with two single rings sharing one carbon atom, which consists of carbon atoms and selected Made from heteroatoms of nitrogen, oxygen, sulfur and phosphorus. For example, "5- to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.
“桥环或桥环基”是指两个或两个以上环状结构彼此共用两个不相邻的原子所形成的饱和或不饱和环状基团，其具体实施例包括但不限于： "Bridged ring or bridged cyclic group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples thereof include but are not limited to:
“桥杂环基”和“桥杂环”可互换使用，是指两个或两个以上环状结构彼此共用两个不相邻的原子所形成的饱和或不饱和环状基团，其由碳原子及选自氮、氧、硫和磷的杂原子构成。其具体实施例包括但不限于： "Bridged heterocyclyl" and "bridged heterocyclyl" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. Specific examples include but are not limited to:
本发明中所述的“芳环”、“芳基”是指具有多个碳原子的芳烃基团。芳基通常是具有5-20个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。The "aromatic ring" and "aryl group" mentioned in the present invention refer to aromatic hydrocarbon groups having multiple carbon atoms. Aryl groups are usually monocyclic, bicyclic or tricyclic aryl groups having 5 to 20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
本发明中所述的“杂芳环”、“杂芳环基”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。The "heteroaryl ring" and "heteroaryl ring group" mentioned in the present invention refer to an aromatic unsaturated ring containing at least one heteroatom; the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Aromatic monocyclic or bicyclic hydrocarbons that generally contain multiple ring atoms, one or more of which are heteroatoms selected from O, N, and S. Preferably there are one to three heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzene Thiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole base, benzothiazolyl, benzoxazolyl.
“立体异构体”包括对映异构体和非对映异构体；"Stereoisomers" include enantiomers and diastereomers;
本发明的“氘代化合物”是指分子或基团中的1个或多个氢原子被氘原子取代，其中 氘原子的占比大于氘在自然界中的丰度。The "deuterated compound" of the present invention means that one or more hydrogen atoms in the molecule or group are replaced by deuterium atoms, wherein The proportion of deuterium atoms is greater than the abundance of deuterium in nature.
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。The term "pharmaceutically acceptable" means a carrier, carrier, diluent, excipient, and/or salt formed that is generally chemically or physically compatible with the other ingredients constituting a pharmaceutical dosage form and is physiologically compatible Compatible with receptors.
术语“盐”和“药学上可接受的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or their stereoisomers, acidic and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts ( Internal salts), also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compounds. It can also be obtained by appropriately mixing the above compound, or its stereoisomer, with a certain amount of acid or base (for example, equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by reacting in an aqueous medium and then freeze-drying. The salt mentioned in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butylene salt of the compound. salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above content of the present invention, according to the common technical knowledge and common means in the field, without departing from the above basic technical idea of the present invention, various other forms of modifications, replacements or changes can also be made.
具体实施方式Detailed ways
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above contents of the present invention will be further described in detail below through specific implementation methods in the form of examples. However, this should not be understood to mean that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology, etc.
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。室温为最适宜的反应温度，为20℃□～30℃□。实施例中无特殊说明，M是摩尔每升。There are no special instructions in the examples, and the reaction was carried out under a nitrogen atmosphere. There is no special explanation in the examples, and the solution refers to an aqueous solution. There are no special instructions in the examples, and the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20℃ □ ~ 30℃ □ . There is no special explanation in the examples, M is mol per liter.
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 600)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3),氘代甲醇(Methol-d4)，内标为四甲基硅烷(TMS)。LC-MS的测定使用岛津液质联用仪The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 600) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (Methol-d 4 ), the internal standard is tetramethylsilane (TMS). LC-MS was measured using a Shimadzu liquid mass spectrometer.
(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。 (Shimadzu LC-MS 2020(ESI)). HPLC measurement used a Shimadzu high-pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai Silica Gel 200~300 mesh silica gel as the carrier.
实施例中所述试剂缩写如下：Pd2(dba)3:三二亚苄基丙酮二钯；DIPEA:N,N-二异丙基乙胺；DMSO:二甲基亚砜；AcOH:醋酸；Sphos：2-双环己基膦-2',6'-二甲氧基-1,1'-二联苯；LC-MS：液质联用；NaCl：氯化钠；MPLC：中压液相制备；TMEDA：四甲基乙二胺。The abbreviations of the reagents described in the examples are as follows: Pd 2 (dba) 3 : dipalladium tribenzylideneacetone; DIPEA: N, N-diisopropylethylamine; DMSO: dimethyl sulfoxide; AcOH: acetic acid; Sphos: 2-bicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl; LC-MS: liquid mass spectrometry; NaCl: sodium chloride; MPLC: medium pressure liquid phase preparation ; TMEDA: tetramethylethylenediamine.
实施例1、化合物A1的制备
Example 1, Preparation of Compound A1
步骤一、化合物A-3的制备
Step 1. Preparation of compound A-3
50mL反应瓶中依次加入化合物A-1(100.00mg,502.42μmol)，A-2(22.65mg,502.42μmol),DIPEA(194.80mg,1.51mmol,262.53μL)溶于5mL四氢呋喃中，反应体在室温下反应15个小时(LC-MS监测)，然后反应液用饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩除去溶剂后得到化合物A-3(粗品)，然后用MPLC纯化得到化合物A-3(86.00mg,414.14μmol,82.43％产率)。Add compounds A-1 (100.00 mg, 502.42 μmol), A-2 (22.65 mg, 502.42 μmol), and DIPEA (194.80 mg, 1.51 mmol, 262.53 μL) in sequence into a 50 mL reaction bottle and dissolve them in 5 mL of tetrahydrofuran. The reaction mixture is at room temperature. The reaction was carried out for 15 hours (LC-MS monitoring), and then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. , concentrated under reduced pressure to remove the solvent to obtain compound A-3 (crude product), which was then purified by MPLC to obtain compound A-3 (86.00 mg, 414.14 μmol, 82.43% yield).
步骤二、化合物A1的合成
Step 2. Synthesis of Compound A1
50mL反应瓶中依次加入化合物A-3(28.00mg,134.84μmol)，A-4(18.90mg,134.84μmol),AcOH(2mL)与DMSO(2mL)，100℃加热条件下搅拌反应2小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用MPLC化合物A1化合物(4.00mg,12.85μmol,9.53％产率,纯度99.9％)。LC-MS:C16H18N6O2,[M+H]+:312.1,found 312.2。 1H NMR(600MHz,DMSO-d6)δ7.95(dd,J＝8.5,1.4Hz,1H),7.53(ddd,J＝8.5,6.8,1.4Hz,1H),7.37(dd,J＝8.4,1.2Hz,1H),7.09(ddd,J＝8.4,6.8,1.2Hz,1H),4.23(d,J＝8.6Hz,2H),4.02(d,J＝8.6Hz,2H),3.24(s,6H),3.04(s,2H)。Add compound A-3 (28.00 mg, 134.84 μmol), A-4 (18.90 mg, 134.84 μmol), AcOH (2 mL) and DMSO (2 mL) in sequence to a 50 mL reaction bottle, stir and react under heating conditions at 100°C for 2 hours and then quench. Kill the reaction (LC-MS monitoring), complete the extraction with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent to dryness, concentrate under reduced pressure and use MPLC Compound A1 compound (4.00 mg, 12.85 μmol, 9.53% yield, purity 99.9%). LC-MS: C 16 H 18 N 6 O 2 ,[M+H] + :312.1, found 312.2. 1 H NMR (600MHz, DMSO-d6) δ7.95 (dd, J＝8.5, 1.4Hz, 1H), 7.53 (ddd, J＝8.5, 6.8, 1.4Hz, 1H), 7.37 (dd, J＝8.4, 1.2Hz,1H),7.09(ddd,J＝8.4,6.8,1.2Hz,1H),4.23(d,J＝8.6Hz,2H),4.02(d,J＝8.6Hz,2H),3.24(s, 6H),3.04(s,2H).
参照化合物A1的合成方法，用下表的原料1替代化合物A-2，其它原料和操作方法不变，可得到化合物A2。
Referring to the synthesis method of compound A1, using raw material 1 in the table below to replace compound A-2, and keeping other raw materials and operating methods unchanged, compound A2 can be obtained.
实施例2、化合物A3的制备
Example 2, Preparation of Compound A3
步骤一、化合物A3的合成
Step 1. Synthesis of Compound A3
50mL反应瓶中依次加入化合物A-6(20.00mg,110.75μmol)，A-4(15.52mg,110.75μmol),DIPEA(42.94mg,332.24μmol,57.87μL)与DMSO(2mL)，150℃加热条件下搅拌反应15小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用MPLC化合物A3化合物(8.00mg,28.14μmol,25.14％产率,纯度99.1％)。LC-MS:C14H13N4O3,[M+H]+:285.1,found 285.2。1H NMR(400MHz,Methanol-d4)δ8.02(d,J＝8.0Hz,1H),7.69(t,J＝8.0Hz,1H),7.49-7.23(m,2H),4.54(d,J＝9.5Hz,2H),4.33(d,J＝9.5Hz,2H),3.02(s,2H)。Compound A-6 (20.00 mg, 110.75 μmol), A-4 (15.52 mg, 110.75 μmol), DIPEA (42.94 mg, 332.24 μmol, 57.87 μL) and DMSO (2 mL) were added in sequence to the 50 mL reaction bottle, and the heating conditions were 150°C. After stirring for 15 hours, the reaction was quenched (LC-MS monitoring). The extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. , concentrated under reduced pressure and used MPLC compound A3 (8.00 mg, 28.14 μmol, 25.14% yield, purity 99.1%). LC-MS: C 14 H 13 N 4 O 3 ,[M+H] + :285.1, found 285.2. 1 H NMR (400MHz, Methanol-d4) δ8.02(d,J＝8.0Hz,1H),7.69(t,J＝8.0Hz,1H),7.49-7.23(m,2H),4.54(d,J =9.5Hz, 2H), 4.33 (d, J = 9.5Hz, 2H), 3.02 (s, 2H).
参照化合物A3的合成方法，用下表的原料1替代化合物A-6，其它原料和操作方法不变，可得到化合物A4。
Referring to the synthesis method of compound A3, using raw material 1 in the table below to replace compound A-6, and keeping other raw materials and operating methods unchanged, compound A4 can be obtained.
实施例3、化合物A5的制备
Example 3, Preparation of Compound A5
步骤一、化合物A-9的制备
Step 1. Preparation of Compound A-9
50mL反应瓶中依次加入化合物A-8(150.00mg,753.63μmol)，A-4(34.95mg,753.63μmol),DIPEA(292.20mg,1.51mmol,262.53μL)溶于8mL四氢呋喃中，反应体系温度在室温下反应12个小时(LC-MS监测)，然后反应液用饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩除去溶剂后得到化合物A-9(粗品)，然后用MPLC纯化得到化合物A-9(100.00mg,481.40μmol,63.90％产率)。Compound A-8 (150.00 mg, 753.63 μmol), A-4 (34.95 mg, 753.63 μmol), and DIPEA (292.20 mg, 1.51 mmol, 262.53 μL) were sequentially added to the 50 mL reaction bottle and dissolved in 8 mL of tetrahydrofuran. The reaction system temperature was at React at room temperature for 12 hours (LC-MS monitoring). Then the reaction solution is extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases are combined, dried over anhydrous sodium sulfate, and evaporated to dryness. The solvent was concentrated under reduced pressure to remove the solvent to obtain compound A-9 (crude product), which was then purified by MPLC to obtain compound A-9 (100.00 mg, 481.40 μmol, 63.90% yield).
步骤二、化合物A5的合成
Step 2. Synthesis of Compound A5
50mL反应瓶中依次加入化合物A-9(20.00mg,66.07μmol)，A-2(2.98mg,66.07μmol),AcOH(2mL)与DMSO(2mL)，100℃加热条件下搅拌反应15小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用MPLC化合物A5化合物(2.20mg,7.07μmol,10.70％产率,纯度99.9％)。LC-MS:C16H18N5O2,[M+H]+:312.1,found 312.2.1H NMR(400MHz,DMSO-d6)δ11.65and 11.37(s,2H),8.16-7.68(m,3H),7.45-7.40(m,1H),5.08-4.88(m,2H),4.61-4.26(m,2H),3.25(s,6H),3.08(s,2H). Add compounds A-9 (20.00 mg, 66.07 μmol), A-2 (2.98 mg, 66.07 μmol), AcOH (2 mL) and DMSO (2 mL) in sequence to a 50 mL reaction bottle, stir and react under heating conditions at 100°C for 15 hours and then quench. Kill the reaction (LC-MS monitoring), complete the extraction with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent to dryness, concentrate under reduced pressure and use MPLC Compound A5 (2.20 mg, 7.07 μmol, 10.70% yield, purity 99.9%). LC-MS:C 16 H 18 N 5 O 2 ,[M+H] + :312.1,found 312.2. 1 H NMR(400MHz,DMSO-d6)δ11.65and 11.37(s,2H),8.16-7.68(m ,3H),7.45-7.40(m,1H),5.08-4.88(m,2H),4.61-4.26(m,2H),3.25(s,6H),3.08(s,2H).
参照化合物A5的合成方法，用下表的原料1替代化合物A-2，其它原料和操作方法不变，可得到化合物A6和A7。
Referring to the synthesis method of compound A5, using raw material 1 in the table below to replace compound A-2, and keeping other raw materials and operating methods unchanged, compounds A6 and A7 can be obtained.
实施例4、化合物A8的制备
Example 4, Preparation of Compound A8
步骤一、化合物A-13的制备
Step 1. Preparation of compound A-13
50mL反应瓶中依次加入化合物A-12(300.00mg,1.51mmol)，A-2(271.91mg,6.03mmol),碳酸钾(1.25g,9.04mmol)溶于10mL N-甲基吡咯烷酮中，反应体系在180℃加热条件反应4个小时(LC-MS监测)，然后反应液用饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩除去溶剂后得到化合物A-13(粗品)，然后用MPLC纯化得到化合物A-13(170.00mg,818.65μmol,54.31％产率)。Compound A-12 (300.00mg, 1.51mmol), A-2 (271.91mg, 6.03mmol), potassium carbonate (1.25g, 9.04mmol) were added in sequence to the 50mL reaction bottle and dissolved in 10mL N-methylpyrrolidone. The reaction system React under heating conditions at 180°C for 4 hours (LC-MS monitoring). Then the reaction solution is extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases are combined and dried with anhydrous sodium sulfate. , evaporate the solvent to dryness, and concentrate under reduced pressure to remove the solvent to obtain compound A-13 (crude product), which is then purified by MPLC to obtain compound A-13 (170.00 mg, 818.65 μmol, 54.31% yield).
步骤二、化合物A8的合成
Step 2. Synthesis of Compound A8
50mL反应瓶中依次加入化合物A-13(100.00mg,481.56μmol)，A-4(80.98mg,577.87μmol),碳酸铯(313.98mg,963.12μmol)，Sphos(19.74mg,48.16μmol)和Pd2(dba)3(22.03mg,24.08μmol)溶解在1，4-二氧六环(5mL)，120℃加热条件下隔绝空气搅拌反应2小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用制备MPLC化合物A8化合物(1.50mg,4.82μmol,1.00％产率,纯度92.0％)。LC-MS:C16H18N5O2,[M+H]+:312.1,found 312.2.1H NMR(400MHz,DMSO-d6)δ8.17-8.03(m, 1H),7.97-7.79(m,3H),4.51(d,J＝8.4Hz,2H),4.33(d,J＝8.4Hz,2H),3.11(s,2H),2.92(s,6H)。Compound A-13 (100.00 mg, 481.56 μmol), A-4 (80.98 mg, 577.87 μmol), cesium carbonate (313.98 mg, 963.12 μmol), Sphos (19.74 mg, 48.16 μmol) and Pd 2 were added in sequence to the 50 mL reaction bottle. (dba) 3 (22.03 mg, 24.08 μmol) was dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 120°C without air for 2 hours and then the reaction was quenched (LC-MS monitoring), saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL) to complete the extraction, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent to dryness, concentrate under reduced pressure and use to prepare MPLC compound A8 compound (1.50 mg, 4.82 μmol, 1.00 % yield, purity 92.0%). LC-MS:C 16 H 18 N 5 O 2 ,[M+H] + :312.1, found 312.2. 1 H NMR (400MHz, DMSO-d6) δ8.17-8.03 (m, 1H),7.97-7.79(m,3H),4.51(d,J＝8.4Hz,2H),4.33(d,J＝8.4Hz,2H),3.11(s,2H),2.92(s,6H).
实施例5、化合物A9的制备
Example 5, Preparation of Compound A9
步骤一、化合物A-15的制备
Step 1. Preparation of Compound A-15
50mL反应瓶中依次加入化合物A-14(398.00mg,2.00mmol)，A-2(90.15mg,2.00mmol),DIPEA(516.88mg,4.00mmol,696.60μL)溶于8mL DMSO中，反应体系在80℃加热条件反应10个小时(LC-MS监测)，然后反应液用饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩除去溶剂后得到化合物A-15(粗品)，然后用MPLC纯化得到化合物A-15(300.00mg,1.44mmol,72.25％产率)。Compound A-14 (398.00mg, 2.00mmol), A-2 (90.15mg, 2.00mmol), DIPEA (516.88mg, 4.00mmol, 696.60μL) were added in sequence to the 50mL reaction bottle and dissolved in 8mL DMSO. The reaction system was at 80 The reaction was carried out under heating conditions at ℃ for 10 hours (LC-MS monitoring), and then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and evaporated. The solvent was dried and concentrated under reduced pressure to remove the solvent to obtain compound A-15 (crude product), which was then purified by MPLC to obtain compound A-15 (300.00 mg, 1.44 mmol, 72.25% yield).
步骤二、化合物A9的合成
Step 2. Synthesis of Compound A9
50mL反应瓶中依次加入化合物A-15(120.00mg,577.87μmol)，A-4(121.47mg,866.81μmol),碳酸铯(379.08mg,1.16mmol)，Sphos(23.69mg,57.79μmol)和Pd2(dba)3(26.44mg,28.89μmol)溶解在1，4-二氧六环(3mL)，140℃加热条件下隔绝空气搅拌反应4小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用制备MPLC 化合物A9化合物(19.50mg,59.00μmol,10.21％产率,纯度94.2％)。LC-MS:C16H18N5O2,[M+H]+:312.1,found 312.1.1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),7.86-7.50(m,2H),7.45-7.11(m,2H),4.30(d,J＝9.0Hz,2H),4.14(d,J＝9.0Hz,2H),3.02(s,2H),2.50(s,6H).Compound A-15 (120.00 mg, 577.87 μmol), A-4 (121.47 mg, 866.81 μmol), cesium carbonate (379.08 mg, 1.16 mmol), Sphos (23.69 mg, 57.79 μmol) and Pd 2 were added in sequence to the 50 mL reaction bottle. (dba) 3 (26.44 mg, 28.89 μmol) was dissolved in 1,4-dioxane (3 mL), and the reaction was stirred at 140°C without air for 4 hours and then the reaction was quenched (LC-MS monitoring), saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL) to complete the extraction, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent to dryness, concentrate under reduced pressure and use for preparative MPLC Compound A9 (19.50 mg, 59.00 μmol, 10.21% yield, purity 94.2%). LC-MS:C 16 H 18 N 5 O 2 ,[M+H] + :312.1,found 312.1. 1 H NMR(400MHz,DMSO-d6)δ11.22(s,1H),7.86-7.50(m, 2H),7.45-7.11(m,2H),4.30(d,J＝9.0Hz,2H),4.14(d,J＝9.0Hz,2H),3.02(s,2H),2.50(s,6H).
参照化合物A9的合成方法，用下表的原料1替代化合物A-2，其它原料和操作方法不变，可得到化合物A10。
Referring to the synthesis method of compound A9, using raw material 1 in the table below instead of compound A-2, and keeping other raw materials and operating methods unchanged, compound A10 can be obtained.
实施例6、化合物A11和A12的制备
Example 6, Preparation of Compounds A11 and A12
步骤一、化合物A-16的制备
Step 1. Preparation of compound A-16
50mL反应瓶中依次加入化合物A-14(100.00mg,2.00mmol)，A-4(70.41mg,502.42μmol),DIPEA(194.80mg,1.51mmol,262.54μL)溶于5mL乙腈中，反应体系在80℃加热条件反应15个小时(LC-MS监测)，然后反应液用饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩除去溶剂后得到化合物A-16(粗品)，然后用MPLC纯化得到化合物A-16(120.00mg,396.41μmol,78.90％产率)。Compound A-14 (100.00 mg, 2.00 mmol), A-4 (70.41 mg, 502.42 μmol), and DIPEA (194.80 mg, 1.51 mmol, 262.54 μL) were added in sequence to the 50 mL reaction bottle and dissolved in 5 mL acetonitrile. The reaction system was at 80 °C heating conditions for 15 hours (LC-MS monitoring), then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), the organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate and evaporated. The solvent was dried and concentrated under reduced pressure to remove the solvent to obtain compound A-16 (crude product), which was then purified by MPLC to obtain compound A-16 (120.00 mg, 396.41 μmol, 78.90% yield).
步骤二、化合物A11的合成
Step 2. Synthesis of Compound A11
50mL反应瓶中依次加入化合物A-16(20.00mg,66.07μmol),6M HCl(66.07μmol)，溶解在水中(2mL)，100℃加热条件下隔绝空气搅拌反应2小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用制备MPLC化合物A11化合物(8.00mg,28.14μmol,42.60％产率,纯度90.0％)。LC-MS:C14H13N4O3,[M+H]+:285.1,found 285.2。1H NMR(400MHz,Methanol-d4)δ7.59-7.38(m,1H),7.35-7.06(m,3H),4.60-4.40(m,4H),3.12(s,2H).Compound A-16 (20.00mg, 66.07μmol) and 6M HCl (66.07μmol) were added in sequence to a 50mL reaction bottle, dissolved in water (2mL), heated at 100°C and isolated from the air, stirred for 2 hours and then quenched the reaction (LC- MS monitoring), complete the extraction with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent to dryness, concentrate under reduced pressure and use to prepare MPLC compound A11 compound ( 8.00mg, 28.14μmol, 42.60% yield, purity 90.0%). LC-MS: C 14 H 13 N 4 O 3 ,[M+H] + :285.1, found 285.2. 1 H NMR (400MHz, Methanol-d4) δ7.59-7.38(m,1H),7.35-7.06(m,3H),4.60-4.40(m,4H),3.12(s,2H).
步骤三、化合物A12的合成
Step 3. Synthesis of Compound A12
50mL反应瓶中依次加入化合物A-16(20.00mg,66.07μmol)，AcOH(660.69μmol)，Zn(660.69μmol)和TMEDA(76.77mg,660.69μmol)溶解在乙醇中(3mL)，45℃加热条件下隔绝空气搅拌反应15小时后淬灭反应(LC-MS监测)，饱和NaCl溶液(10mL)与乙酸乙酯(3×20mL)完成萃取，合并有机相，有机相用无水硫酸钠干燥，蒸干溶剂，减压浓缩后用制备MPLC化合物A12化合物(2.00mg,7.46μmol,11.28％产率,纯度91.2％)。LC-MS:C14H13N4O2,[M+H]+:269.1,found 269.1。1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.37(s,1H),8.00-7.30(m,4H),4.40(d,J＝8.8Hz,2H),4.24(d,J＝8.8Hz,2H),3.07(s,2H)。Compound A-16 (20.00 mg, 66.07 μmol), AcOH (660.69 μmol), Zn (660.69 μmol) and TMEDA (76.77 mg, 660.69 μmol) were sequentially added to the 50 mL reaction bottle and dissolved in ethanol (3 mL). Heating conditions at 45°C The reaction was stirred for 15 hours without air, and then the reaction was quenched (LC-MS monitoring). The extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate and evaporated. The solvent was dried, concentrated under reduced pressure and used to prepare MPLC compound A12 (2.00 mg, 7.46 μmol, 11.28% yield, purity 91.2%). LC-MS: C 14 H 13 N 4 O 2 ,[M+H] + :269.1, found 269.1. 1 H NMR (400MHz, DMSO-d6) δ11.27 (s, 1H), 8.37 (s, 1H), 8.00-7.30 (m, 4H), 4.40 (d, J = 8.8Hz, 2H), 4.24 (d ,J＝8.8Hz,2H),3.07(s,2H).
本发明通过以下试验例说明本发明技术效果：The present invention illustrates the technical effects of the present invention through the following test examples:
试验例1、化合物对CRBN/DDB1活性抑制的检测(FRET)Test Example 1, Detection of Inhibition of CRBN/DDB1 Activity by Compounds (FRET)
1、实验材料与试剂1. Experimental materials and reagents
酶标仪(BMG PHERAstar FSX)、ECHO(LABCYTE Echo 665)、微孔板恒温振荡器(杭州瑞诚仪器股份有限公司)、磷酸氢二钠(Sigma)、磷酸二氢钠(Sigma)、牛血清蛋白(Sigma)、Anti-6His-Tb crypate Gold(CISBIO)、CRBN/DDB1蛋白(HitGen)、384孔板(Grenier Bio-one)。Microplate reader (BMG PHERAstar FSX), ECHO (LABCYTE Echo 665), microplate constant temperature oscillator (Hangzhou Ruicheng Instrument Co., Ltd.), disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), bovine serum Protein (Sigma), Anti-6His-Tb crypate Gold (CISBIO), CRBN/DDB1 protein (HitGen), 384-well plate (Grenier Bio-one).
2、实验方法2. Experimental methods
用DMSO将化合物干粉溶解，使用ECHO对化合物进行梯度稀释，并加入384孔反应板中，使DMSO在整个反应体系(10.0μL)中的终浓度为1.0％，并加入等量的DMSO作为对照。Dissolve the compound dry powder with DMSO, use ECHO to perform gradient dilution of the compound, and add it to the 384-well reaction plate so that the final concentration of DMSO in the entire reaction system (10.0 μL) is 1.0%, and add an equal amount of DMSO as a control.
使用20mM磷酸氢二钠，20mM磷酸二氢钠，0.08％牛血清蛋白，pH7.0缓冲液将CRBN/DDB1蛋白稀释至所需终浓度(5.0nM)的2倍，吸取5.0μL稀释好的CRBN/DDB1蛋白加入已经加好化合物的384孔反应板中，1000rpm离心1分钟，然后放置于微孔板恒温振荡器上，25℃，250rpm，预孵15分钟。用20mM磷酸氢二钠，20mM磷酸二氢钠，0.08％牛血清蛋白，pH7.0缓冲液将Anti-6His-Tb crypate Gold和FITC标记的沙利度胺类似物稀释至所需终浓度的2倍，Anti-6His-Tb crypate Gold的终浓度为0.2nM，FITC标记的沙利度胺类似物的终浓度为50.0nM，得到Anti-6His-Tb crypate Gold/FITC标记的沙利度胺类似物混合液，吸取5.0μL Anti-6His-Tb crypate Gold/FITC标记的沙利度胺类似物混合液加入384孔反应板中，1000rpm离心1分钟，然后放置于微孔板恒温振荡器上，25℃，250rpm，孵育30分钟。反应结束后，酶标仪读取384孔反应板中的荧光信号值(Ex＝337 nm Em＝520/490nm)。Use 20mM sodium hydrogen phosphate, 20mM sodium hydrogen phosphate, 0.08% bovine serum albumin, pH7.0 buffer to dilute the CRBN/DDB1 protein to 2 times the required final concentration (5.0nM), and pipette 5.0μL of diluted CRBN. /DDB1 protein was added to the 384-well reaction plate with added compounds, centrifuged at 1000 rpm for 1 minute, then placed on a microplate thermostatic oscillator at 25°C, 250 rpm, and pre-incubated for 15 minutes. Dilute Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analog to 2 of the desired final concentration with 20mM sodium phosphate disodium, 0.08% bovine serum albumin, pH7.0 buffer times, the final concentration of Anti-6His-Tb crypate Gold is 0.2nM, and the final concentration of FITC-labeled thalidomide analogue is 50.0nM, to obtain Anti-6His-Tb crypate Gold/FITC-labeled thalidomide analogue Mixed solution, add 5.0 μL Anti-6His-Tb crypate Gold/FITC-labeled thalidomide analogue mixed solution into a 384-well reaction plate, centrifuge at 1000 rpm for 1 minute, then place on a microplate constant-temperature oscillator, 25°C , 250rpm, incubate for 30 minutes. After the reaction, the microplate reader reads the fluorescence signal value in the 384-well reaction plate (Ex=337 nm Em=520/490nm).
3、数据分析3. Data analysis
以溶媒组(含5.0nM CRBN/DDB1，0.2nM Anti-6His-Tb crypate Gold，50.0nM FITC标记的沙利度胺类似物及1.0％DMSO)为阴性对照、反应缓冲液组(含0.2nM Anti-6His-Tb crypate Gold，50.0nM FITC标记的沙利度胺类似物及1.0％DMSO)为空白对照；The vehicle group (containing 5.0nM CRBN/DDB1, 0.2nM Anti-6His-Tb crypate Gold, 50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) was used as the negative control and the reaction buffer group (containing 0.2nM Anti -6His-Tb crypate Gold, 50.0nM FITC-labeled thalidomide analog and 1.0% DMSO) is the blank control;
计算各浓度剩余活力百分比，公式如下：Calculate the remaining activity percentage of each concentration, the formula is as follows:
剩余活力(％)＝100％×(Flu化合物组-Flu空白对照)/(Flu阴性对照-Flu空白对照)Remaining activity (%) = 100% × (Flu compound group -Flu blank control )/(Flu negative control -Flu blank control )
然后用GraphPad 6.0拟合剂效曲线计算IC50值。Then GraphPad 6.0 was used to fit the dose-effect curve and calculate the IC 50 value.
表1：化合物与CRBN/DDB1蛋白抑制表

其中，+代表200μM>IC50>100μM，++代表100μM>IC50>10μM，+++代表10
μM>IC50>1μM，++++代表IC50<1μM。 Table 1: Compounds and CRBN/DDB1 protein inhibition table

Among them, + represents 200μM>IC 50 >100μM, ++ represents 100μM>IC 50 >10μM, +++ represents 10
μM>IC 50 >1μM, ++++ represents IC 50 <1μM.

Claims (14)

  1. 式I所示的化合物，或其立体异构体、或其氘代化合物，或其药学上可接受的盐：
    The compound represented by formula I, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt:
    其中，in,
    A环选自3～12元环烷基、4～12元杂环烷基、6～10元芳环、5～10元杂芳环；其中，环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的RA1取代；Ring A is selected from 3-12-membered cycloalkyl, 4-12-membered heterocycloalkyl, 6-10-membered aromatic ring, 5-10-membered heteroaromatic ring; among them, cycloalkyl, heterocycloalkyl, aromatic ring, The heteroaromatic ring may be further optionally substituted by one, two, three or four independent R A1 ;
    每个RA1分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CRA2RA3、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-ORA2、-C0～4亚烷基-OC(O)RA2、-C0～4亚烷基-SRA2、-C0～4亚烷基-S(O)2RA2、-C0～4亚烷基-S(O)RA2、-C0～4亚烷基-S(O)2NRA2RA3、-C0～4亚烷基-S(O)NRA2RA3、-C0～4亚烷基-C(O)RA2、-C0～4亚烷基-C(O)ORA2、-C0～4亚烷基-C(O)NRA2RA3、-C0～4亚烷基-NRA2RA3、-C0～4亚烷基-NRA2C(O)RA3、-C0～4亚烷基-NRA2S(O)2RA3、-C0～4亚烷基-NRA2S(O)RA3、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的RA4取代；Each R A1 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR A2 , - C 0～4 alkylene -OC(O)R A2 , -C 0～4 alkylene -SR A2 , -C 0～4 alkylene -S(O) 2 R A2 , -C 0～4 alkylene Alkyl-S(O) RA2 , -C 0～4 alkylene-S(O) 2 NR A2 R A3 , -C 0～4 alkylene-S(O)NR A2 R A3 , -C 0 ～4 alkylene-C(O) RA2 , -C 0～4 alkylene-C(O)OR A2 , -C 0～4 alkylene-C(O)NR A2 R A3 , -C 0 ~4 alkylene-NR A2 R A3 , -C 0 ~ 4 alkylene -NR A2 C(O)R A3 , -C 0 ~ 4 alkylene -NR A2 S(O) 2 R A3 , -C 0～4 alkylene-NR A2 S(O)R A3 , -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(4～10 membered hetero Cycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered heteroaromatic ring); among them, alkylene, cycloalkyl The base, heterocycloalkyl, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R A4 ;
    每个RA4分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CRA2RA3、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-ORA2、-C0～4亚烷基-OC(O)RA2、-C0～4亚烷基-SRA2、-C0～4亚烷基-S(O)2RA2、-C0～4亚烷基-S(O)RA2、-C0～4亚烷基-S(O)2NRA2RA3、-C0～4亚烷基-S(O)NRA2RA3、-C0～4亚烷基-C(O)RA2、-C0～4亚烷基-C(O)ORA2、-C0～4亚烷基-C(O)NRA2RA3、-C0～4亚烷基-NRA2RA3、-C0～4亚烷基-NRA2C(O)RA3、-C0～4亚烷基-NRA2S(O)2RA3、-C0～4亚烷基-NRA2S(O)RA3；Each R A4 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR A2 , - C 0～4 alkylene -OC(O)R A2 , -C 0～4 alkylene -SR A2 , -C 0～4 alkylene -S(O) 2 R A2 , -C 0～4 alkylene Alkyl-S(O) RA2 , -C 0～4 alkylene-S(O) 2 NR A2 R A3 , -C 0～4 alkylene-S(O)NR A2 R A3 , -C 0 ～4 alkylene-C(O) RA2 , -C 0～4 alkylene-C(O)OR A2 , -C 0～4 alkylene-C(O)NR A2 R A3 , -C 0 ~4 alkylene-NR A2 R A3 , -C 0 ~ 4 alkylene -NR A2 C(O)R A3 , -C 0 ~ 4 alkylene -NR A2 S(O) 2 R A3 , -C 0～4 alkylene-NR A2 S(O)R A3 ;
    RA2、RA3分别独立选自氢、-C1-6的烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基；R A2 and R A3 are independently selected from hydrogen, -C 1-6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl;
    R2独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR21R22、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基- OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-SR21、-C0～4亚烷基-S(O)2R21、-C0～4亚烷基-S(O)R21、-C0～4亚烷基-S(O)2NR21R22、-C0～4亚烷基-S(O)NR21R22、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22、-C0～4亚烷基-NR21C(O)R22、-C0～4亚烷基-NR21S(O)2R22、-C0～4亚烷基-NR21S(O)R22、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R23取代；R 2 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl , halogen-substituted -C 1 to 6 alkyl group, halogen-substituted -C 2 to 6 alkenyl group, halogen-substituted -C 2 to 6 alkynyl group, -C 0 to 4 alkylene group- OR 21 , -C 0～4 alkylene -OC(O)R 21 , -C 0～4 alkylene -SR 21 , -C 0～4 alkylene -S(O) 2 R 21 , -C 0～4 alkylene-S(O)R 21 , -C 0～4 alkylene -S(O) 2 NR 21 R 22 , -C 0～4 alkylene -S(O)NR 21 R 22 , -C 0～4 alkylene-C(O)R 21 , -C 0～4 alkylene-C(O)OR 21 , -C 0～4 alkylene-C(O)NR 21 R 22 , -C 0～4 alkylene-NR 21 R 22 , -C 0～4 alkylene-NR 21 C(O)R 22 , -C 0～4 alkylene-NR 21 S(O) 2 R 22 , -C 0~4 alkylene-NR 21 S(O)R 22 , -C 0~4 alkylene-(3~10 membered cycloalkyl), -C 0~4 alkylene-(4 ~10-membered heterocycloalkyl), -C 0~4 -alkylene-(6-10-membered aromatic ring), -C 0~4- alkylene-(5-10-membered heteroaromatic ring); among which, alkylene The base, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 23 ;
    每个R23分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR21R22、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-SR21、-C0～4亚烷基-S(O)2R21、-C0～4亚烷基-S(O)R21、-C0～4亚烷基-S(O)2NR21R22、-C0～4亚烷基-S(O)NR21R22、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22、-C0～4亚烷基-NR21C(O)R22、-C0～4亚烷基-NR21S(O)2R22、-C0～4亚烷基-NR21S(O)R22、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；Each R 23 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 21 , - C 0～4 alkylene -OC(O)R 21 , -C 0～4 alkylene -SR 21 , -C 0～4 alkylene -S(O) 2 R 21 , -C 0～4 alkylene Alkyl-S(O)R 21 , -C 0 to 4 alkylene -S(O) 2 NR 21 R 22 , -C 0 to 4 alkylene -S(O)NR 21 R 22 , -C 0 ~4 alkylene-C(O)R 21 , -C 0 ~ 4 alkylene -C(O)OR 21 , -C 0 ~ 4 alkylene -C(O)NR 21 R 22 , -C 0 ~4 alkylene-NR 21 R 22 , -C 0 ~ 4 alkylene -NR 21 C(O)R 22 , -C 0 ~ 4 alkylene -NR 21 S(O) 2 R 22 , -C 0～4 alkylene-NR 21 S(O)R 22 , -C 0～4 alkylene-(3～10 membered cycloalkyl), -C 0～4 alkylene-(4～10 membered hetero Cycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered heteroaromatic ring); among them, alkylene, cycloalkyl The base, heterocycloalkyl, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 26 ;
    R21、R22分别独立选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C1～4亚烷基-OR24、-C1～4亚烷基-OC(O)R24、-C1～4亚烷基-SR24、-C1～4亚烷基-S(O)2R24、-C1～4亚烷基-S(O)R24、-C1～4亚烷基-S(O)2NR24R25、-C1～4亚烷基-S(O)NR24R25、-C1～4亚烷基-C(O)R24、-C1～4亚烷基-C(O)OR24、-C1～4亚烷基-C(O)NR24R25、-C1～4亚烷基-NR24R25、-C1～4亚烷基-NR24C(O)R25、-C1～4亚烷基-NR24S(O)2R25、-C1～4亚烷基-NR24S(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1～ 4 -alkylene-SR 24 , -C 1 to 4 alkylene-S(O) 2 R 24 , -C 1 to 4 alkylene-S(O)R 24 , -C 1 to 4 alkylene- S(O) 2 NR 24 R 25 , -C 1～4 alkylene group -S(O)NR 24 R 25 , -C 1～4 alkylene group -C(O)R 24 , -C 1～4 sub Alkyl-C(O)OR 24 , -C 1 to 4 alkylene -C(O)NR 24 R 25 , -C 1 to 4 alkylene -NR 24 R 25 , -C 1 to 4 alkylene -NR 24 C(O)R 25 , -C 1～4 alkylene group -NR 24 S(O) 2 R 25 , -C 1～4 alkylene group -NR 24 S(O)R 25 , -C 0 ~4 alkylene-(3~10 membered cycloalkyl), -C 0~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6~10 membered Aromatic ring), -C 0 ~ 4 alkylene - (5 ~ 10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally replaced by a , two, three or four independent R 26 substitutions;
    每个R26分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR24R25、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR24、-C0～4亚烷基-OC(O)R24、-C0～4亚烷基-SR24、-C0～4亚烷基-S(O)2R24、-C0～4亚烷基-S(O)R24、-C0～4亚烷基-S(O)2NR24R25、-C0～4亚烷基-S(O)NR24R25、-C0～4亚烷基-C(O)R24、-C0～4亚烷基-C(O)OR24、-C0～4亚烷基-C(O)NR24R25、-C0～4亚烷基 -NR24R25、-C0～4亚烷基-NR24C(O)R25、-C0～4亚烷基-NR24S(O)2R25、-C0～4亚烷基-NR24S(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R27取代；Each R 26 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 24 , - C 0～4 alkylene -OC(O)R 24 , -C 0～4 alkylene -SR 24 , -C 0～4 alkylene -S(O) 2 R 24 , -C 0～4 alkylene Alkyl-S(O)R 24 , -C 0 to 4 alkylene -S(O) 2 NR 24 R 25 , -C 0 to 4 alkylene -S(O)NR 24 R 25 , -C 0 ~4 alkylene-C(O)R 24 , -C 0 ~ 4 alkylene -C(O)OR 24 , -C 0 ~ 4 alkylene -C(O)NR 24 R 25 , -C 0 ~4 alkylene -NR 24 R 25 , -C 0～4 alkylene -NR 24 C(O)R 25 , -C 0～4 alkylene -NR 24 S(O) 2 R 25 , -C 0～4 alkylene Base -NR 24 S(O)R 25 , -C 0～4 alkylene-(3-10 membered cycloalkyl), -C 0～4 alkylene-(4-10 membered heterocycloalkyl), -C 0～4 alkylene-(6-10 membered aromatic ring), -C 0～4 alkylene-(5-10 membered heteroaromatic ring); among them, alkylene, cycloalkyl, heterocycloalkyl The base, aromatic ring and heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 27 ;
    R24、R25分别独立选自氢、-C1-6的烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基；R 24 and R 25 are independently selected from hydrogen, -C 1-6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen-substituted -C 1-6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl;
    每个R27分别独立选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基。Each R 27 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen substitution -C 1 to 6 alkyl group, halogen-substituted -C 2 to 6 alkenyl group, and halogen-substituted -C 2 to 6 alkynyl group.
  2. 根据权利要求1所述的化合物，其特征在于：所述A环选自10元含氮芳杂环。The compound according to claim 1, characterized in that: the A ring is selected from a 10-membered nitrogen-containing aromatic heterocycle.
  3. 根据权利要求2所述的化合物，其特征在于：The compound according to claim 2, characterized in that:
    所述A环选自所述B环为6元含氮芳杂环。The A ring is selected from The B ring is a 6-membered nitrogen-containing aromatic heterocyclic ring.
  4. 根据权利要求1任一所述的化合物，其特征在于：The compound according to any one of claims 1, characterized in that:
    所述A环选自 其中，A环选自的环可进一步任选被一个、两个、三个或四个独立的RA1取代。 The A ring is selected from Among them, the ring selected from ring A can be further optionally substituted by one, two, three or four independent R A1 .
  5. 根据权利要求4所述的化合物，其特征在于：The compound according to claim 4, characterized in that:
    每个RA1分别独立选自氢、卤素、-NRA2RA3、-ORA2、-C1～3烷基、卤素取代的-C1～3烷基；Each R A1 is independently selected from hydrogen, halogen, -NR A2 R A3 , -OR A2 , -C 1～3 alkyl, and halogen-substituted -C 1～3 alkyl;
    RA2、RA3分别独立选自氢、甲基、乙基、丙基。 RA2 and RA3 are each independently selected from hydrogen, methyl, ethyl, and propyl.
  6. 根据权利要求1～5任一所述的化合物，其特征在于：The compound according to any one of claims 1 to 5, characterized in that:
    所述A环选自 The A ring is selected from
  7. 根据权利要求1所述的化合物，其特征在于：The compound according to claim 1, characterized in that:
    R2选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-C(O)R21、-C0～4亚烷基-C(O)OR21、-C0～4亚烷基-C(O)NR21R22、-C0～4亚烷基-NR21R22；-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R23取代；R 2 is selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～6 alkynyl, halogen substituted -C 1 ~6 alkyl, halogen-substituted -C 2~6 alkenyl, halogen-substituted -C 2~6 alkynyl, -C 0~4 alkylene-OR 21 , -C 0~4 alkylene-OC( O)R 21 , -C 0～4 alkylene-C(O)R 21 , -C 0～4 alkylene-C(O)OR 21 , -C 0～4 alkylene-C(O) NR 21 R 22 , -C 0～4 alkylene group-NR 21 R 22 ; -C 0～4 alkylene group-(3～10 membered cycloalkyl group), -C 0～4 alkylene group-(4～ 10-membered heterocycloalkyl), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 alkylene-(5-10 membered heteroaromatic ring); among which, alkylene , cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally substituted by one, two, three or four independent R 23 ;
    每个R23分别独立选自氢、卤素、氰基、硝基、＝O、＝S、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR21、-C0～4亚烷基-OC(O)R21、-C0～4亚烷基-C(O)R21；-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；Each R 23 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1~6 alkyl, -C 2~6 alkenyl, -C 2~6 alkynyl, halogen substitution -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 21 , -C 0 to 4 alkylene Base -OC(O)R 21 , -C 0～4 alkylene group-C(O)R 21 ; -C 0～4 alkylene group-(3～10 membered cycloalkyl group), -C 0～4 cycloalkyl group Alkyl-(4-10 membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring), -C 0-4 alkylene-(5-10 membered heteroaromatic ring) ; Wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally substituted by one, two, three or four independent R 26 ;
    R21、R22分别独立选自氢、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C1～4亚烷基-OR24、-C1～4亚烷基-OC(O)R24、-C1～4亚烷基-C(O)R24、-C1～4亚烷基-C(O)OR24、-C1～4亚烷基-C(O)NR24R25、-C1～4亚烷基-NR24R25、-C1～4亚烷基-NR24C(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；其中，亚烷基、环烷基、杂环烷基、芳环、杂芳环可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1 to 6 alkyl, -C 2 to 6 alkenyl, -C 2 to 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted - C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 1 to 4 alkylene -OR 24 , -C 1 to 4 alkylene -OC(O)R 24 , -C 1～ 4- alkylene-C(O)R 24 , -C 1～4 alkylene-C(O)OR 24 ,-C 1～4 alkylene-C(O)NR 24 R 25 ,-C 1～ 4- alkylene-NR 24 R 25 , -C 1 to 4 alkylene-NR 24 C(O)R 25 , -C 0 to 4- alkylene-(3-10 membered cycloalkyl), -C 0 ~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6~10 membered aromatic ring), -C 0~4 alkylene-(5~10 membered hetero Aromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally substituted by one, two, three or four independent R 26 ;
    每个R26分别独立选自氢、卤素、氰基、硝基、＝O、＝S、＝CR24R25、-C1～6烷基、-C2～6烯基、-C2～6炔基、卤素取代的-C1～6烷基、卤素取代的-C2～6烯基、卤素取代的-C2～6炔基、-C0～4亚烷基-OR24、-C0～4亚烷基-OC(O)R24、-C0～4亚烷基-C(O)R24、-C0～4亚烷基-C(O)OR24、 -C0～4亚烷基-C(O)NR24R25、-C0～4亚烷基-NR24R25、-C0～4亚烷基-NR24C(O)R25、-C0～4亚烷基-(3～10元环烷基)、-C0～4亚烷基-(4～10元杂环烷基)、-C0～4亚烷基-(6～10元芳环)、-C0～4亚烷基-(5～10元杂芳环)；Each R 26 is independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 , -C 1～6 alkyl, -C 2～6 alkenyl, -C 2～ 6 alkynyl, halogen-substituted -C 1 to 6 alkyl, halogen-substituted -C 2 to 6 alkenyl, halogen-substituted -C 2 to 6 alkynyl, -C 0 to 4 alkylene -OR 24 , - C 0～4 alkylene-OC(O)R 24 , -C 0～4 alkylene-C(O)R 24 , -C 0～4 alkylene-C(O)OR 24 , -C 0～4 alkylene-C(O)NR 24 R 25 , -C 0～4 alkylene-NR 24 R 25 , -C 0～4 alkylene-NR 24 C(O)R 25 , -C 0~4 alkylene-(3~10 membered cycloalkyl), -C 0~4 alkylene-(4~10 membered heterocycloalkyl), -C 0~4 alkylene-(6 ~10-membered aromatic ring), -C 0~4 alkylene-(5~10-membered heteroaromatic ring);
    R24、R25分别独立选自氢、-C1-3的烷基、卤素取代的-C1～3烷基。R 24 and R 25 are each independently selected from hydrogen, -C 1-3 alkyl group, and halogen-substituted -C 1-3 alkyl group.
  8. 根据权利要求7所述的化合物，其特征在于：The compound according to claim 7, characterized in that:
    R2选自氢、-C(O)NR21R22、-C(O)R21、-C0～2亚烷基-NR21R22、-C(O)OR21、-OR21；R 2 is selected from hydrogen, -C(O)NR 21 R 22 , -C(O)R 21 , -C 0～2 alkylene -NR 21 R 22 , -C(O)OR 21 , -OR 21 ;
    R21、R22分别独立选自氢、-C1～3烷基、-C0～1亚烷基-(6元芳环)、-C0～1亚烷基-(10元杂芳环)、-(4～6元杂环烷基)、-(3～6元环烷基)，其中，芳环、杂芳环、杂环烷基、环烷基可进一步任选被一个、两个、三个或四个独立的R26取代；R 21 and R 22 are independently selected from hydrogen, -C 1～3 alkyl, -C 0～1 alkylene-(6-membered aromatic ring), -C 0～1 alkylene-(10-membered heteroaromatic ring) ), -(4 to 6-membered heterocycloalkyl), -(3 to 6-membered cycloalkyl), wherein the aromatic ring, heteroaromatic ring, heterocycloalkyl, and cycloalkyl can be further optionally substituted by one or two One, three or four independent R 26 substitutions;
    每个R26分别独立选自氢、-C1～3烷基、-(4～6元杂环烷基)、-C(O)R24、-C(O)OR24、-OC(O)R24；Each R 26 is independently selected from hydrogen, -C 1 to 3 alkyl, -(4 to 6 membered heterocycloalkyl), -C(O)R 24 , -C(O)OR 24 , -OC(O )R 24 ;
    R24选自氢、甲基、乙基、丙基。R 24 is selected from hydrogen, methyl, ethyl, propyl.
  9. 根据权利要求8所述的化合物，其特征在于：The compound according to claim 8, characterized in that:
    所述R2选自氢、羟基、 The R 2 is selected from hydrogen, hydroxyl,
  10. 根据权利要求1～9任一所述的化合物，其特征在于：所述化合物具体为：

    The compound according to any one of claims 1 to 9, characterized in that: the compound is specifically:

  11. 根据权利要求1～10任一所述的化合物，或其立体异构体、或其氘代化合物，或其药学上可接受的盐制备治疗细胞异常增殖相关疾病中的用途。Use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the treatment of diseases related to abnormal cell proliferation.
  12. 根据权利要求11所述的用途，其特征在于：所述疾病为癌症。The use according to claim 11, characterized in that: the disease is cancer.
  13. 权利要求1～10任一所述的化合物、或其立体异构体、或其氘代化合物，或其药学上可接受的盐在制备靶向蛋白降解药物中的用途。The use of the compound described in any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, in the preparation of targeted protein degradation drugs.
  14. 权利要求1～10任一所述的化合物、或其立体异构体、或其氘代化合物，或其药学上可接受的盐作为中间体在制备靶向蛋白降解药物中的用途。 The use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt, as an intermediate in the preparation of targeted protein degradation drugs.
PCT/CN2023/116903 2022-09-08 2023-09-05 Spiro compound and use thereof WO2024051668A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211094656.5 2022-09-08
CN202211094656 2022-09-08

Publications (1)

Publication Number Publication Date
WO2024051668A1 true WO2024051668A1 (en) 2024-03-14

Family

ID=90192048

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/116903 WO2024051668A1 (en) 2022-09-08 2023-09-05 Spiro compound and use thereof

Country Status (1)

Country Link
WO (1) WO2024051668A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112312904A (en) * 2018-04-16 2021-02-02 C4医药公司 Spiro compounds
CN112566886A (en) * 2018-06-04 2021-03-26 C4医药公司 Spiro compounds
CN112969696A (en) * 2018-11-02 2021-06-15 达纳-法伯癌症研究公司 Development and use of acetylated writer inhibitors
CN114057770A (en) * 2020-08-06 2022-02-18 成都先导药物开发股份有限公司 Bifunctional compounds targeting EGFR protein degradation
CN116375717A (en) * 2021-12-30 2023-07-04 成都先导药物开发股份有限公司 Spiro compounds and their bifunctional compounds and uses

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112312904A (en) * 2018-04-16 2021-02-02 C4医药公司 Spiro compounds
CN112566886A (en) * 2018-06-04 2021-03-26 C4医药公司 Spiro compounds
CN112969696A (en) * 2018-11-02 2021-06-15 达纳-法伯癌症研究公司 Development and use of acetylated writer inhibitors
CN114057770A (en) * 2020-08-06 2022-02-18 成都先导药物开发股份有限公司 Bifunctional compounds targeting EGFR protein degradation
CN116375717A (en) * 2021-12-30 2023-07-04 成都先导药物开发股份有限公司 Spiro compounds and their bifunctional compounds and uses

Similar Documents

Publication Publication Date Title
RU2706007C2 (en) Condensed bicyclic compounds for treating disease
US11208383B2 (en) KCNQ potentiators
MX2014014582A (en) Pyrazolopyrimidone and pyrazolopyridone inhibitors of tankyrase.
TW200406412A (en) N-substituted piperidinyl-imidazopyridine compounds as 5-HT4 receptor modulators
MX2015002602A (en) Imidazoline derivatives, preparation methods thereof, and their applications in medicine.
WO2018219281A1 (en) 4-pyrimidinediamine small molecular organic compounds and derivatives thereof and use thereof
WO2023125476A1 (en) Spiro compound, and bifunctional compound and use thereof
BR112014019402B1 (en) 2-ARIL-BENZOFURAN-7-CARBOXAMIDE COMPOUND, OR PHARMACOLOGICALLY ACCEPTABLE SALT OF THE SAME AND METHOD FOR PREPARING THE COMPOUND
AU2020232205A1 (en) Novel thyromimetics
CN102066322A (en) Compound having NPY Y5 receptor antagonist activity
ES2702524T3 (en) Compounds such as hypoxia mimetics, and compositions, and uses of these
EP4046686B1 (en) Salt types, crystal forms, and preparation methods for benzopyrazole compounds as rho kinase inhibitors
Wessig et al. Photochemical Synthesis of Both Strained and Macrocyclic (1, 7) Naphthalenophanes
Böck et al. N‐Substituted Nipecotic Acids as (S)‐SNAP‐5114 Analogues with Modified Lipophilic Domains
WO2024051668A1 (en) Spiro compound and use thereof
CN111943889A (en) Bis-aryl amine compound and preparation method and application thereof
EP4306528A1 (en) Hemtac small molecule degradation agent and use thereof
CN101253146A (en) Novel amino acid derivatives for the treatment of obesity and related disorders
WO2021179884A1 (en) Oleanolic acid derivative having conjugated diene structure c ring, and preparation method therefor and use thereof
WO2024169788A1 (en) Fused ring compound and use thereof
CN111454250B (en) Multi-target active compound and application thereof
WO2024051664A1 (en) Spiro compound and use
CN108017639B (en) IDO inhibitor and preparation method and application thereof
CN104744451A (en) 1-(3-amino propyl) substituted cyclic amine compound as well as preparation method, pharmaceutical composition and use thereof
CN106608824B (en) Aromatic acid ester compound and preparation method and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23862362

Country of ref document: EP

Kind code of ref document: A1