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WO2024149349A1 - COMPOSÉ CIBLANT POLθ ET SON UTILISATION - Google Patents

COMPOSÉ CIBLANT POLθ ET SON UTILISATION Download PDF

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Publication number
WO2024149349A1
WO2024149349A1 PCT/CN2024/071923 CN2024071923W WO2024149349A1 WO 2024149349 A1 WO2024149349 A1 WO 2024149349A1 CN 2024071923 W CN2024071923 W CN 2024071923W WO 2024149349 A1 WO2024149349 A1 WO 2024149349A1
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Prior art keywords
alkyl
alkoxy
compound
mmol
cycloalkyl
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Chinese (zh)
Inventor
李瑶
张国彪
张晓波
张亚明
颜林杰
黄世林
张晨
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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Priority to CN202480005443.1A priority Critical patent/CN120457125A/zh
Publication of WO2024149349A1 publication Critical patent/WO2024149349A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a compound having the ability to target Pol ⁇ , its stereoisomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated compounds, and use thereof in preparing medicines for treating related diseases.
  • DNA polymerase ⁇ is a unique and multifunctional DNA polymerase. Mammalian cells have evolved multiple pathways to repair DNA double-strand breaks (DSBs) to ensure genome stability.
  • DNA polymerase theta is a key component of the alternative end joining (alt-EJ) pathway, also known as the microhomology-mediated end joining (MMEJ) pathway, which is involved in DNA double-strand break repair.
  • MMEJ is an alternative repair pathway in cells in addition to non-homologous end joining (NHEJ) and homologous recombination (HR).
  • DNA polymerase ⁇ (Pol ⁇ ) is important for repairing DNA breaks, especially in homologous recombination-deficient (HRD) cells.
  • HRD including defects in the BRCA1 and BRCA2 genes, is a clinically important feature of many important types of tumors, including breast, ovarian, prostate, and pancreatic cancers.
  • Pol ⁇ is highly expressed and directs DSB repair toward alt-EJ, initiating the DNA repair process of microhomology-mediated end joining (MMEJ).
  • MMEJ microhomology-mediated end joining
  • inhibition of Pol ⁇ leads to cell death through the accumulation of toxic RAD51 intermediates and inhibition of the alt-EJ repair pathway.
  • Pol ⁇ also has the function of reverse transcribing RNA and promoting DNA repair with RNA as a template.
  • Pol ⁇ is hardly expressed in normal tissues, but is highly expressed in many tumor types (such as breast cancer, ovarian cancer, HNSCC, and lung cancer). At the same time, homologous recombination repair deficiency (HRD) is common in these tumors; therefore, there is a theoretical basis for the application of Pol ⁇ inhibitors in these tumors.
  • HRD homologous recombination repair deficiency
  • Protein degradation technology has developed rapidly in recent years because it can induce the degradation of pathogenic target proteins. It provides a new idea for new drug research and development and continues to become a powerful tool in new drug research and development. Compared with small molecule inhibitors that usually inhibit protease activity, the mechanism of protein degradation provides many advantages that are conducive to drug development. First, it has a wider range of action, higher activity, and can target "undruggable" targets. Protein degraders do not need to bind to the active site of the target protein, so they can be used to target proteins that traditional small molecule inhibitors cannot target. Secondly, traditional small molecule inhibitors need to rely on binding to the target protein to work, so the drug needs to maintain a sufficient concentration to maintain the inhibitory effect.
  • Protein degraders achieve the inhibitory effect by completing the catalytic reaction of protein degradation. After completing the degradation of a protein target, it can bind to the next protein. Moreover, the inhibitory effect on protein function will not disappear before the new protein is synthesized. Another advantage of protein degraders is that they can be used to target some targets that cause diseases as structural proteins. Generally, the functions of structural proteins are difficult to target with small molecule inhibitors because they do not involve enzyme activity, while protein degraders can destroy their structural functions by degrading target proteins.
  • HRD tumors can be treated with poly (ADP ribose) polymerase (PARP) inhibitors, which represent a rapidly growing, multi-billion dollar global market.
  • PARP poly (ADP ribose) polymerase
  • Pol ⁇ inhibitors have the potential to treat multiple types of tumors both as monotherapy and in combination with PARP inhibitors, and their unique mechanism of action may help address both types of PARP resistance.
  • druggable drugs targeting Pol ⁇ may be a means to address PARP inhibitor resistance to meet corresponding clinical needs.
  • the present invention aims to provide a compound targeting Pol ⁇ with high anti-tumor activity against Pol ⁇ and its use.
  • the present invention provides a novel Pol ⁇ -targeting compound for treating tumor-related diseases, which has excellent activity, excellent physicochemical properties, excellent pharmacokinetic properties, high bioavailability, low toxicity and side effects, and other excellent effects.
  • the PTM is a Pol ⁇ targeting binding moiety
  • the PTM has a structure of formula (I-1),
  • n, p are each independently selected from 0, 1, 2, 3, 4 or 5; in some embodiments, n is selected from 2, 3, 4 or 5; in some embodiments, n is selected from 2 or 3; in some embodiments, n is selected from 2; in some embodiments, m is selected from 0, 1, 2 or 3; in some embodiments, m is selected from 0, 1 or 2; in some embodiments, m is selected from 0 or 1; in some embodiments, p is selected from 1, 2 or 3; in some embodiments, p is selected from 1;
  • X1 is selected from N or CR x1 ; in some embodiments, X1 is selected from N; in some embodiments, X1 is selected from CR x1 ;
  • R x1 is selected from H, D, halogen, OH, CN, NH 2 , C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy or deuterated C 1-4 alkoxy; in some embodiments, R x1 is selected from H, D, C 1-4 alkyl or halogenated C 1-4 alkyl; in some embodiments, R x1 is selected from H, D, methyl, difluoromethyl, trifluoromethyl; in some embodiments, R x1 is selected from H;
  • the A ring is selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-12 membered aryl or 5-12 membered heteroaryl, the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, S, O, and the cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted with 1-5 RA ; in some specific embodiments, A is selected from 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl, the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, S, O, and the heterocycloalkyl and heteroaryl are optionally substituted with 1-5 RA ; in some specific embodiments, A is selected from one of the subunits formed by the following structures optionally substituted with 1-5 RA : In some embodiments, A is selected from one of the subunits formed by the following structures optionally substituted with 1-5 RA :
  • a 1 and A 2 are each independently selected from In some embodiments, A1 is selected from In some embodiments, A1 is selected from In some embodiments, A2 is selected from
  • R 1 and R 2 are each independently selected from H, D, halogen, OH, CN, NH 2 , —SF 5 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —OC 3-6 cycloalkyl, —C 0-4 alkyl-C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, —O-heterocycloalkyl, —C 0-4 alkyl-heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, S and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by 1-5 members selected from D
  • R 3 and R 4 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, S and O, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1-5 groups selected from D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, halogenated C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy and deuterated C 1-4 alkoxy groups; in some specific embodiments, R 3 and R 4 are each
  • R 3 , R 4 and the atoms to which they are attached together form a C 3-6 cycloalkyl group optionally substituted with halogen; in some embodiments, or R 3 , R 4 and the atoms to which they are attached together form a C 3-6 cycloalkyl group; in some embodiments, or R 3 , R 4 and the atoms to which they are attached together form a cyclopropyl group;
  • L is a bond or chemical linking moiety that covalently couples the PTM and ULM; in some embodiments, L is selected from a bond, -(L 1 ) a -(Q 1 ) b -(L 2 ) a -(Q 2 ) b -(L 3 ) a -(Q 3 ) b -(L 4 ) a -(Q 4 ) b -, and the left side of L is linked to the PTM;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NR L , C 1-4 alkyl, CO, O, S, C 2-6 alkenyl, C 2-6 alkynyl, and the alkyl, alkenyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, CN, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy and halogenated C 1-4 alkoxy; in some specific embodiments, L 1 , L 2 , L 3 , L 4 are each independently selected from NH, C 1-3 alkyl, O, C 2-4 alkynyl, and the alkyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, C 1-4 alkyl, C 1-4 alkoxy; in some specific embodiments, L 1 , L 2 , L 3 , L 4 are each independently selected from NH, C 1-3 alkyl, O, CO, C
  • RL is selected from H or C1-4 alkyl; in some embodiments, RL is selected from H, methyl or ethyl; in some embodiments, RL is selected from H;
  • the substituent of 1-3 alkoxy is substituted by one of the following groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, azohexyl, piperidinyl, pyrazolyl, thiazolyl, isopyrazolyl, pyridinyl, phenyl, azetidinyl spiroazetidinyl, azetidinyl spiroazepentyl, azetidinyl spiroazepentyl, azetidinyl spiroazepentyl, azetidinyl spiroazepentyl, azetidinyl spiroazepentyl, azetidinyl spiroazepentyl, cyclobutyl spiroazepentyl, cycl
  • a and b are each independently selected from 0, 1, 2 or 3; in some embodiments, a and b are each independently selected from 0 or 1; in some embodiments, a and b are each independently selected from 0, 1 or 2;
  • L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O, CONH, CH 2 CH 2 , In some embodiments, L is selected from one of the following structures: acetylene, propyne, O, In some embodiments, L is selected from one of the following structures: acetylene, propyne, O, In some embodiments, L is selected from one of the following structures: acetylene, propyne, O, In some embodiments, L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O, CONH, CH 2 CH 2 , In some embodiments, L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O, CONH, CH 2 CH 2 , In some embodiments, L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O, CONH, CH
  • ULM is an E3 ubiquitin ligase binding moiety; in some embodiments, ULM is selected from: In some embodiments, the ULM is selected from: In some embodiments, ULM is selected from U1, U2, U3, U4, U5, U6, U7, U8, U9, U10, U11, U12, U13, U14;
  • ULM is selected from U1, U2, U3, U4, U5, U6, U7, U8, U9, U10, U11, U12;
  • ULM is selected from U1, U2, U3, U4, U5, U6, U7, U8, U9, U10, U11;
  • ULM is selected from U1, U2, U3, U4, U5, U6;
  • R 8 and R 9 are selected from H or together form ⁇ O;
  • ULM is selected from U1, U2, U3, U7;
  • R 8 and R 9 are selected from H or together form ⁇ O;
  • r is independently selected from 0, 1, 2, 3, 4 or 5; in some embodiments, r is independently selected from 0, 1, 2 or 3; in some embodiments, r is independently selected from 0, 1 or 2; in some embodiments, r is independently selected from 1, 2 or 3; in some embodiments, r is independently selected from 2 or 3;
  • r 1 and r 3 are each independently selected from 1, 2 or 3; r 2 is selected from 0 or 1;
  • XU is selected from CH or N;
  • Xu 1 and Xu 2 are each independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -; in some embodiments, Xu 1 and Xu 2 are each independently selected from a bond, -SO 2 -, -SO- or -C(R k3 ) 2 -;
  • two R k1 are directly connected to form a C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 groups selected from R z ;
  • R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R z ; in some embodiments, R k4 is each independently selected from H, OH, NH 2 , CF 3 , CN or C 1-4 alkyl; in some embodiments, R k4 is selected from H;
  • two R k3 are directly connected to form a C 3-8 carbocyclyl or a 4-8 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from R z ;
  • two R k3 are directly connected to form a C 3-6 cycloalkyl or a 4-7 membered heterocycloalkyl, and the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 selected from R z ;
  • U is independently selected from a bond, a C 3-20 carbocyclyl, a C 6-20 aryl, a 3-20 membered heterocyclyl or a 5-20 membered heteroaryl; in some embodiments, U is independently selected from a C 3-7 monocyclyl, a C 4-10 cyclocyclyl, a C 5-12 spirocyclyl, a C 5-10 bridged cyclyl, a 4-7 membered Heteromonocyclic group, 4-10 membered heterocyclyl, 8-15 membered tricyclic heterocyclyl, 12-17 membered tetracyclic heterocyclyl, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 aryl, 5-10 membered heteroaryl;
  • U is selected from a bond, phenylene, benzoazepinene, benzoazepinene, -NHCH(CH 2phenyl )-, pyrimidinyl, 2-benzoxazolone, 2-benzimidazolone;
  • U is selected from a bond, phenylene, benzoazepinene, benzoazepinene, -NHCH(CH 2phenyl )-, pyrimidinyl; in some embodiments, U is selected from a bond, phenylene, benzoazepinene, pyrimidinyl; in some embodiments, U is selected from a bond, phenylene, benzoazepinene, pyrimidinyl; in some embodiments, U is selected from a cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholin
  • Fa is selected from N or CR k1 ;
  • Fb is selected from N or CR k1 ;
  • Fc is selected from O, S, NH, N(CH 3 ) or NR k7a ;
  • Fd is selected from N or CR k1 ;
  • Ff is selected from a bond, O, CH 2 , NH, N(CH 3 );
  • Fg is selected from N or C
  • Fh is selected from N or C
  • Faa is selected from a bond, O, CH 2 ;
  • Fab is selected from O, CH 2 ;
  • Ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 ;
  • Ring F 1 , Ring F 2 , Ring F 3 , Ring F 4 are each independently selected from phenyl or 5-6 membered heteroaryl, and said Ring F 1 , Ring F 2 , Ring F 3 , Ring F 4 are optionally substituted by 1 to 2 R k1 ;
  • R k6 are each independently selected from CO, CH, S( ⁇ O), S( ⁇ O) 2 , CH 2 or N;
  • R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O, N(CH 3 ), N(CH 2 CH 3 ), N(cyclopropyl) or NH;
  • R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 substituents selected from
  • U is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzopyrazolyl
  • M1 is independently selected from a bond, -O-, -S-, -CH2- , -NRq-, -CO- , -NRqCO- , -CONRq- or a 3-12 membered heterocyclyl, the heterocyclyl is optionally substituted by 1 to 4 Rz , and the left side of M1 is connected to U; in some embodiments, M1 is independently selected from a bond, -O-, -S-, -CH2- , -NRq-, -CO- , -NRqCO- , -CONRq- or a 4-7 membered heterocyclyl, the heterocyclyl is optionally substituted by 1 to 4 Rz ; in some embodiments, M1 is selected from a bond, NH, CONH, and the left side of M1 is connected to U; in some embodiments, M1 is selected from a bond, NH; in some embodiments, M1 is selected from a bond, CH2 , NH, N
  • R q is selected from H or C 1-4 alkyl; in some embodiments, R q is selected from H;
  • M4 is selected from -NH- or -O-;
  • R k10 is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R z ;
  • R k12 and R k13 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 R z ;
  • R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 R z ;
  • G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z ;
  • B is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; in some embodiments, B is selected from phenyl or 5-6 membered heteroaryl; in some embodiments, B is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;
  • Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally substituted by 1-3 R z ; in some embodiments, Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 , OH or C 1-4 alkyl; in some embodiments, Ru 3 is each independently selected from halogen, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl or alkoxy is optionally substituted by 1-3 groups selected from F, Cl, CN, NH 2 , OH, methyl or ethyl; in some embodiments, Ru 3 is each independently selected from F, Cl, methyl, ethyl, difluoromethyl,
  • two Ru 1 may be combined with the atoms to which they are attached to form a 3-6 heterocyclic group containing 1-3 heteroatoms selected from N, S and O, wherein the heterocyclic group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • two Ru 2 can form a 3-6 cycloalkyl group together with the atoms to which they are connected, and the cycloalkyl group is optionally further substituted by 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl; in some specific embodiments, alternatively, two Ru 2 can form a cyclopropyl, cyclobutyl or cyclopentyl group together with the atoms to which they are connected, and the cyclopropyl, cyclobutyl or cyclopentyl group is optionally further substituted by 1 to 4 groups selected from F, Cl, methyl, ethyl, methoxy, ethoxy, difluoromethyl or trifluoromethyl;
  • R 10 is selected from H, D, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted by 1-3 groups selected from halogen, CN, NH 2 and OH; in some embodiments, R 10 is selected from H, D, F, Cl, methyl, ethyl, methoxy or ethoxy, wherein the methyl, ethyl, methoxy or ethoxy is optionally substituted by 1-3 groups selected from F, Cl, Br, CN, NH 2 and OH; in some embodiments, R 10 is selected from H, D, F, Cl, methyl, methoxy, wherein the methyl and methoxy are optionally substituted by 1-3 groups selected from F and Cl; in some embodiments, R 10 is selected from H, D or F;
  • the ULM is selected from
  • the ULM is selected from
  • the ULM is selected from
  • the ULM is selected from In some embodiments, the ULM is selected from In some embodiments, the ULM is selected from one of the structural fragments shown in Table K-1;
  • the ULM is selected from one of the structural fragments shown in Table K-2;
  • the PTM is a Pol ⁇ binding moiety
  • the PTM has a structure of formula (I-1),
  • n, p are each independently selected from 0, 1, 2, 3, 4 or 5;
  • X1 is selected from N or CRx1 ;
  • Rx1 is selected from H, D, halogen, OH, CN, NH2 , C1-4 alkyl or C1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted by halogen or D;
  • A is selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-12 membered aryl or 5-12 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, S, and O, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by 1-5 RA ;
  • the alkyl or alkoxy group is optionally substituted with halogen, a group of D;
  • R 1 and R 2 are each independently selected from H, D, halogen, OH, CN, NH 2 , —SF 5 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, —OC 3-6 cycloalkyl, —C 0-4 alkyl-C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, —O-heterocycloalkyl, —C 0-4 alkyl-heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, S and O, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by 1-5 members selected from D
  • R 3 and R 4 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, S and O, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1-5 groups selected from D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy and deuterated C 1-4 alkoxy;
  • R 3 , R 4 together with the atoms to which they are attached form a C 3-6 cycloalkyl group which is optionally substituted by halogen;
  • L is a bond or chemical linking moiety that covalently couples the PTM and ULM;
  • ULM is the E3 ubiquitin ligase binding part.
  • the PTM has a structure of formula (I-1),
  • n, p are each independently selected from 0, 1, 2, 3, 4 or 5;
  • X1 is selected from N or CRx1 ;
  • Rx1 is selected from H, D, halogen, OH, CN, NH2 , C1-4 alkyl or C1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted by halogen or D;
  • A is selected from C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-12 membered aryl or 5-12 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, S, and O, and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted by 1-5 RA ;
  • R 1 and R 2 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -C 0-4 alkyl-C 3-6 cycloalkyl, 4-10 membered heterocycloalkyl, -O-heterocycloalkyl, -C 0-4 alkyl-heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 selected a heteroatom selected from N, S, and O, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with 1
  • R 3 and R 4 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl groups contain 1-3 heteroatoms selected from N, S and O, and the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1-5 groups selected from D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterated C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy and deuterated C 1-4 alkoxy;
  • R 3 , R 4 together with the atoms to which they are attached form a C 3-6 cycloalkyl group which is optionally substituted by halogen;
  • L is a bond or chemical linking moiety that covalently couples the PTM and ULM;
  • ULM is selected from:
  • XU is selected from CH or N;
  • Xu 1 and Xu 2 are each independently selected from a bond, -SO 2 -, -SO- or -C(R k3 ) 2 -;
  • R k3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 groups selected from R z ;
  • R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R z ;
  • two R k3 are directly connected to form a C 3-8 carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z ;
  • U is each independently selected from a bond, a C 3-20 carbocyclyl, a C 6-20 aryl, a 3-20 membered heterocyclyl or a 5-20 membered heteroaryl;
  • M 1 is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z , and the left side of M 1 is connected to U;
  • Rq is selected from H or C1-4 alkyl
  • M4 is selected from -NH- or -O-;
  • R k10 is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R z ;
  • R k12 and R k13 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 R z ;
  • R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 R z ;
  • G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z ;
  • B is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
  • Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1-3 R z ;
  • two Ru 1 may be combined with the atoms to which they are attached to form a 3-6 heterocyclic group containing 1-3 heteroatoms selected from N, S and O, wherein the heterocyclic group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • two Ru 2 may be combined with the atoms to which they are attached to form a 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • r 1 and r 3 are each independently selected from 1, 2 or 3;
  • r2 is selected from 0 or 1.
  • n, m, and p are each independently selected from 0, 1, 2 or 3;
  • X1 is selected from N or CRx1 ;
  • Rx1 is selected from H, D, C1-4 alkyl or halogenated C1-4 alkyl;
  • A is selected from 4-8 membered heterocycloalkyl or 5-10 membered heteroaryl, wherein the heterocycloalkyl and heteroaryl contain 1-3 heteroatoms selected from N, S, and O, and the heterocycloalkyl and heteroaryl are optionally substituted by 1-5 RA ;
  • R 1 and R 2 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, -(CH 2 ) t -C 3-6 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1-5 groups selected from D, halogen, OH, CN, NH 2 , COOH, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3 and R 4 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally substituted with 1 to 5 groups selected from D, halogen, OH, CN, NH 2 , -SF 5 , C 1-4 alkyl, and C 1-4 alkoxy;
  • R 1 and R 2 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , methyl, ethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy;
  • R 3 and R 4 are each independently selected from H, D, halogen, OH, CN, NH 2 , -SF 5 , methyl, ethyl, difluoromethyl, trifluoromethyl;
  • L is selected from a bond, -(L 1 ) a -(Q 1 ) b -(L 2 ) a -(Q 2 ) b -(L 3 ) a -(Q 3 ) b -(L 4 ) a -(Q 4 ) b -, and the left side of L is linked to the PTM;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NR L , C 1-4 alkyl, CO, O, S, C 2-6 alkenyl, C 2-6 alkynyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo-substituted C 1-4 alkoxy;
  • RL is selected from H or C1-4 alkyl
  • a, b are each independently selected from 0, 1, 2 or 3;
  • ULM is selected from:
  • XU is selected from CH or N;
  • Xu 1 and Xu 2 are each independently selected from a bond, -CO-, -SO 2 -, -SO- or -C(R k3 ) 2 -;
  • R k4 is each independently selected from H, OH, NH 2 , CN, CONH 2 , C 1-4 alkyl, C 3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R z ;
  • two R k3 are directly connected to form a C 3-8 carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z ;
  • U is each independently selected from a bond, a C 3-20 carbocyclyl, a C 6-20 aryl, a 3-20 membered heterocyclyl or a 5-20 membered heteroaryl;
  • M 1 is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q - or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z , and the left side of M 1 is connected to U;
  • Rq is selected from H or C1-4 alkyl
  • M4 is selected from -NH- or -O-;
  • R k10 is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R z ;
  • R k12 and R k13 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 R z replaces;
  • R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 4 R z ;
  • G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z ;
  • B is selected from C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;
  • Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1-3 R z ;
  • two Ru 1 may be combined with the atoms to which they are attached to form a 3-6 heterocyclic group containing 1-3 heteroatoms selected from N, S and O, wherein the heterocyclic group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • two Ru 2 may be combined with the atoms to which they are attached to form a 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • r is each independently selected from 0, 1, 2, 3, 4 or 5;
  • r 1 and r 3 are each independently selected from 1, 2 or 3;
  • r 2 is selected from 0 or 1;
  • L is selected from a bond, -(L 1 ) a -(Q 1 ) b -(L 2 ) a -(Q 2 ) b -(L 3 ) a -(Q 3 ) b -(L 4 ) a -(Q 4 ) b -, and the left side of L is linked to the PTM;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NR L , C 1-4 alkyl, CO, O, S, C 2-6 alkenyl, C 2-6 alkynyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo-substituted C 1-4 alkoxy;
  • RL is selected from H or C1-4 alkyl
  • a, b are each independently selected from 0, 1, 2 or 3;
  • ULM is selected from:
  • r is each independently selected from 0, 1, 2, 3, 4 or 5;
  • r 1 and r 3 are each independently selected from 1, 2 or 3; r 2 is selected from 0 or 1;
  • XU is selected from CH or N;
  • U is selected from a bond, phenylene, benzoazepinene, benzoazepinene, -NHCH(CH 2phenyl )-, pyrimidinyl, 2-benzoxazolone, 2-benzimidazolone;
  • M 1 is selected from a bond, NH, CONH, and the left side of M 1 is connected to U;
  • Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 groups selected from halogen, CN, NH 2 , OH or C 1-4 alkyl;
  • two Ru 1 may be combined with the atoms to which they are attached to form a 3-6 heterocyclic group containing 1-3 heteroatoms selected from N, S and O, wherein the heterocyclic group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • two Ru 2 may be combined with the atoms to which they are attached to form a 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • L is selected from a bond, -(L 1 ) a -(Q 1 ) b -(L 2 ) a -(Q 2 ) b -(L 3 ) a -(Q 3 ) b -(L 4 ) a -(Q 4 ) b -, and the left side of L is linked to the PTM;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NR L , C 1-4 alkyl, CO, O, S, C 2-6 alkenyl, C 2-6 alkynyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo-substituted C 1-4 alkoxy;
  • RL is selected from H or C1-4 alkyl
  • a, b are each independently selected from 0, 1, 2 or 3;
  • ULM is selected from:
  • r is each independently selected from 0, 1, 2, 3, 4 or 5;
  • r 1 and r 3 are each independently selected from 1, 2 or 3; r 2 is selected from 0 or 1;
  • XU is selected from CH or N;
  • U is selected from a bond, phenylene, benzoazepinene, benzoazepinene, -NHCH(CH 2phenyl )-, pyrimidinyl;
  • M 1 is selected from a bond, NH, CONH, and the left side of M 1 is connected to U;
  • Ru 3 is each independently selected from halogen, CN, NH 2 , NO 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 groups selected from halogen, CN, NH 2 , OH or C 1-4 alkyl;
  • two Ru 2 may be combined with the atoms to which they are attached to form a 3-6 cycloalkyl group, wherein the cycloalkyl group is optionally further substituted with 1 to 4 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy or halogenated C 1-4 alkyl;
  • L is selected from a bond, -(L 1 ) a -(Q 1 ) b -(L 2 ) a -(Q 2 ) b -(L 3 ) a -(Q 3 ) b -(L 4 ) a -(Q 4 ) b -, and the left side of L is linked to the PTM;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NR L , C 1-4 alkyl, CO, O, S, C 2-6 alkenyl, C 2-6 alkynyl, wherein the alkyl, alkenyl, alkynyl are optionally substituted with 1-3 groups selected from D, halogen, CN, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkoxy, and halo-substituted C 1-4 alkoxy;
  • RL is selected from H or C1-4 alkyl
  • b are each independently selected from 0, 1, 2 or 3;
  • L 1 , L 2 , L 3 , L 4 are each independently selected from NH, C 1-3 alkyl, O, C 2-4 alkynyl, and the alkyl or alkynyl is optionally substituted with 1-3 groups selected from D, halogen, C 1-4 alkyl, or C 1-4 alkoxy; or
  • L 1 , L 2 , L 3 , and L 4 are each independently selected from NH, C 1-3 alkyl, O, CO, and C 2-4 alkynyl, wherein the alkyl and alkynyl are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, and C 1-4 alkoxy;
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently one of the following groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridine , azohexyl, piperidinyl , pyrazolyl, thiazolyl, isopyrazolyl, pyridinyl , phenyl, azetidinylspiroazetidinyl, azetidinylspiroazetyl, azetidinylspiroazacyclohexyl, azetidinylspiroazacyclopentyl, azetidinylspiroazacyclohexyl, azetidinylspiroazacyclopentyl, azetidinylspiroazacyclohexyl, azetidinylspiroazacyclopentyl, a
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently one of the following groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azohexyl , piperidinyl , pyrazolyl, thiazolyl, isopyrazolyl, pyridinyl , phenyl, azetidinylspiroazetidinyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinyl
  • a, b are each independently selected from 0, 1 or 2;
  • ULM is selected from U1, U2, U3, U4, U5, U6, U7, U8, U9, U10, U11;
  • ULM is selected from U12; or
  • ULM is selected from U13 and U14;
  • R 8 and R 9 are selected from H or together form ⁇ O;
  • R 10 is selected from H, D, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 groups selected from halogen, CN, NH 2 and OH;
  • r is each independently selected from 0, 1 or 2;
  • L 1 , L 2 , L 3 , and L 4 are each independently selected from NH, C 1-3 alkyl, O, and C 2-4 alkynyl, wherein the alkyl and alkynyl are optionally substituted with 1 to 3 groups selected from D, halogen, C 1-4 alkyl, and C 1-4 alkoxy;
  • Q 1 , Q 2 , Q 3 , Q 4 are each independently one of the following groups: cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridine , azohexyl, piperidinyl , pyrazolyl, thiazolyl, isopyrazolyl, pyridinyl , phenyl, azetidinylspiroazetidinyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiroazetyl, azetidinylspiro
  • a and b are each independently selected from 0 or 1;
  • ULM is selected from U1, U2, U3, U4, U5, U6;
  • R 8 and R 9 are selected from H or together form ⁇ O;
  • R 10 is selected from H, D, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 3 groups selected from halogen, CN, NH 2 and OH;
  • L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O, CONH, CH 2 CH 2 ,
  • Or L is selected from one of the following structures:
  • L is selected from a bond or L is selected from one of the following structures: acetylene, propyne, O,
  • a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, or pharmaceutically acceptable salt or cocrystal has the structure of formula (II-1) or (II-2),
  • R 3 and R 4 are each independently selected from H, D, F, Cl, OH, CN, NH 2 , -SF 5 , methyl, ethyl, difluoromethyl, trifluoromethyl, and cyclopropyl; or R 3 and R 4 together with the atoms to which they are attached form a cyclopropyl group;
  • a 1 and A 2 are each independently selected from
  • L is selected from a bond or L is selected from one of the following structures:
  • ULM is selected from
  • a compound represented by formula (I), its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal, the compound targeting Pol ⁇ is selected from one of the structures in the following Table 1:
  • the present invention also provides a pharmaceutical composition, which contains the compound described in any of the aforementioned technical solutions, its stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers and/or excipients.
  • composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the aforementioned technical solutions, its stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers and/or excipients.
  • the present invention also provides the use of any of the aforementioned embodiments in the preparation of a drug for treating/preventing a Pol ⁇ -mediated disease.
  • the Pol ⁇ -mediated diseases include, but are not limited to, liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.
  • the present invention also provides a method for treating a disease in a mammal or a human, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of the aforementioned technical solutions, its stereoisomer, deuterated substance, solvate or pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier and/or excipient, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.
  • the present invention also provides a method for treating a disease in a mammal or a human, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition.
  • the mammal in the present invention does not include a human.
  • Effective amount or “therapeutically effective amount” as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300mg, 5-250mg, 5-200mg, 5-150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg , 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-1000
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal and a carrier and/or excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the pharmaceutical composition includes but is not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg 1500 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal or a human comprising administering to a subject a therapeutically effective amount of a compound of the present invention, a stereoisomer, a deuterated substance, a solvate or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and/or excipient, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably liver cancer, breast cancer, ovarian cancer, lung cancer, kidney cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer or head and neck cancer.
  • a method for treating a disease in a mammal or a human comprising administering a pharmaceutical compound of the present invention, a stereoisomer, a deuterated substance, a solvate or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and/or excipient to a subject at a daily dose of 1-1500 mg/day, the daily dose may be a single dose or divided doses.
  • the daily dose includes but is not limited to 10-1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day
  • the daily dose includes but is not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 1200 mg/day, 1400 mg/day, 1500 mg/day.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.
  • the compounds of the present invention or their stereoisomers, deuterated substances, solvates, pharmaceutically acceptable salts or cocrystals are The amounts are in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (deuterium, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • Halogen herein refers to F, Cl, Br, I, or isotopes thereof.
  • Halo or halogen substitution means substitution by one or more halogens selected from F, Cl, Br, I, or isotopes thereof.
  • the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit. When the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens. It usually includes 1-5 halogen substitutions, 1-3 halogen substitutions, 1-2 halogen substitutions, and 1 halogen substitution.
  • Deuterium refers to the isotope of hydrogen (H).
  • Deuterated or “deuterated substance” refers to the situation where the hydrogen atoms on groups such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, thiol, heterocycloalkyl, alkenyl, alkynyl, etc. are replaced by at least one deuterium atom, and the upper limit of the number of deuterations is equal to the sum of the number of hydrogen atoms that can be replaced in the substituted group.
  • the number of deuterations is any integer between 1 and the upper limit, for example, 1-20 deuterium atoms, 1-10 deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.
  • C xy refers to a group containing x to y carbon atoms, for example, a “C 1-6 alkyl group” refers to an alkyl group containing 1 to 6 carbon atoms.
  • Alkyl refers to a monovalent straight or branched saturated aliphatic hydrocarbon group. It is usually an alkyl group of 1 to 20 carbon atoms, or an alkyl group of 1 to 8 carbon atoms, or an alkyl group of 1 to 6 carbon atoms, or an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc., and the alkyl group may be further substituted by a substituent.
  • Alkylene refers to a divalent straight chain or branched chain saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, and the like.
  • Haloalkyl refers to a situation where one or more hydrogen atoms in an alkyl group are replaced by one or more halogen atoms (such as fluorine, chlorine, bromine, iodine or their isotopes).
  • the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced in the alkyl group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit.
  • the alkyl group is substituted by 1-5 halogens, or 1-3 halogens, or 1-2 halogens, or 1 halogen.
  • halogen substituents When the number of halogen substituents is greater than 1, they can be substituted by the same or different halogens. Specific examples include, but are not limited to, -CF3 , -CH2Cl , -CH2CF3 , -CCl2 , CF3 , etc.
  • Alkoxy refers to -O-alkyl.
  • -OC 1-8 alkyl For example, -OC 1-8 alkyl, -OC 1-6 alkyl, -OC 1-4 alkyl or -OC 1-2 alkyl.
  • Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy, etc.; the alkoxy group may be optionally substituted with a substituent.
  • Haloalkoxy refers to -O-haloalkyl.
  • -O-halo C 1-8 alkyl For example, -O-halo C 1-8 alkyl, -O-halo C 1-6 alkyl, -O-halo C 1-4 alkyl or -O-halo C 1-2 alkyl; the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogen atoms that can be replaced by the substituted group. Unless otherwise specified, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen substituents, 1-3 halogen substituents, 1-4 halogen substituents, 1-2 ...
  • halogen substituents when the number of halogen substituents is greater than 1, they may be substituted by the same or different halogens; non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, and the like.
  • alkenyl group may be optionally further substituted by a substituent.
  • Alkynyl refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C ⁇ C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms.
  • Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; the alkynyl group may be optionally substituted with a substituent.
  • Alkyne refers to a straight or branched divalent unsaturated hydrocarbon group containing a carbon-carbon triple bond (C ⁇ C), typically containing 2-6 carbon atoms, further containing 2-4 carbon atoms, non-limiting examples include ethynylene, propynylene, butynylene, and the alkynylene group may be optionally substituted with a substituent.
  • C ⁇ C carbon-carbon triple bond
  • Cycloalkyl refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. Bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. Bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole is not aromatic. The connection site can be on the aromatic ring or on the non-aromatic ring.
  • the cycloalkyl contains 3 to 20 carbon atoms, further contains 3-8 carbon atoms, and further contains 3-6 carbon atoms; when it is a monocyclic cycloalkyl, it contains 3-15 carbon atoms, or 3-10 carbon atoms, or 3-8 carbon atoms, or 3-6 carbon atoms; when it is a bicyclic or polycyclic cycloalkyl, it contains 5-12 carbon atoms, or 5-11 carbon atoms, or 6-10 carbon atoms; non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, butenyl, cyclopentenyl, cyclohexenyl, The cycloalkyl group may be optionally substituted with a substituent.
  • Cycloalkylene refers to a divalent radical of a cycloalkyl group.
  • Aryl refers to a carbocyclic ring having aromaticity and not containing heteroatoms, including monocyclic aromatic groups and condensed aromatic groups. It usually contains 6 to 13 carbon atoms, further contains 6 to 9 carbon atoms, further is phenyl, non-limiting examples include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the aryl group may be optionally substituted with a substituent.
  • Carbocycle or “carbocyclyl” refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl. Carbocycles can be monocyclic, bicyclic or polycyclic, including bridged, fused and spirocyclic rings and combinations thereof. Carbocycles typically have 3 to 12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms.
  • monocyclic carbocycles are Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, etc.
  • the bicyclic bridge ring includes etc.
  • double ring and ring include etc.
  • bicyclic spiro ring includes The carbocyclic ring may be optionally substituted with a substituent.
  • Heterocycloalkyl refers to a saturated or partially unsaturated non-aromatic carbon ring containing 1, 2, 3 or 4 heteroatoms selected from N, S and O. Heterocycloalkyl can be monocyclic, bicyclic or polycyclic.
  • the bicyclic or polycyclic ring can be a bridged ring, a cyclic ring, a spirocyclic ring or a combination thereof.
  • the bicyclic or polycyclic ring can include one or more aromatic rings or heteroaromatic rings, but the ring system as a whole is not aromatic, and the connection site can be on the aromatic ring or on the non-aromatic ring.
  • the heterocycloalkyl group is a 3-20-membered ring.
  • it is usually a 3-15-membered ring, or a 3-10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring;
  • it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5-12-membered ring, or a 5-11-membered ring, or a 6-9-membered ring.
  • the heteroatoms N and S therein include their oxidation states.
  • heterocycloalkyl examples include azetidinyl, morpholinyl, piperazinyl, tetrahydropyrazine, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azocycloolyl, azocyclohexenyl, oxolyl, oxenyl, and the like, and the heterocycloalkyl may be optionally substituted with a substituent.
  • Heteroaromatic ring refers to a ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states and having aromaticity, which may be a monocyclic, bicyclic or polycyclic ring, and the bicyclic or polycyclic ring may be a bridged ring, a fused ring, a spirocyclic ring and a combination thereof; when it is a bicyclic or polycyclic ring, it may be a condensation of a heteroaryl and an aryl, or a condensation of a heteroaryl and a heteroaryl, wherein either the heteroaryl or the aryl may be a connection site.
  • Non-limiting examples include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, purinyl,
  • the heteroaryl group may be optionally substituted by a substituent.
  • Heterocycle or “heterocyclyl” refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, and its meaning includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles or their combinations. It is usually a 3-12 membered heterocycle or a 5-12 membered heterocycle, or a 5-7 membered heterocycle.
  • the heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl , dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazoly
  • Heterocyclylene refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.
  • Spiro refers to a polycyclic group that shares a carbon atom (called spiro atom) between rings, which may contain 0 or more double bonds or triple bonds, and may contain 0 to 5 heteroatoms selected from N, O, S, P, Si and their oxidation states.
  • spiro ring is a 6-14-membered ring, or a 6-12-membered ring, or a 6-10-membered ring.
  • the spiro ring is a trispirotri (indicating a three-membered ring spirotricyclic ring), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa.
  • spiro rings include The spiro ring may be optionally substituted with a substituent.
  • Parallel ring refers to a polycyclic group in which the rings share two adjacent ring atoms and a chemical bond, and may contain one or more double bonds or triple bonds, and the rings may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states.
  • the ring is a 5-20-membered ring, or a 5-14-membered ring, or a 5-12-membered ring, or a 5-10-membered ring.
  • the ring is a three-to-four ring (indicates a ring formed by a three-membered ring and a four-membered ring.
  • IUPC naming rules it may be a three-membered ring as the basic ring or a four-membered ring as the basic ring. The same applies below), a three-to-five ring, a three-to-six ring, a four-to-four ring, a four-to-five ring, a four-to-six ring, a five-to-five ring, a five-to-six ring, and a six-to-six ring.
  • Non-limiting examples of parallel rings include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, ;
  • the cyclic ring may be optionally substituted by a substituent.
  • Bridged ring means two non-adjacent ring atoms shared between two rings, and may contain one or more double bonds or triple bonds.
  • the bridged ring may contain 0 to 5 heteroatoms selected from N, S, O, P, Si and their oxidation states. Usually the ring atoms of the bridged ring are 5 to 20, or 5 to 14, or 5 to 12, or 5 to 10.
  • Non-limiting examples of bridged rings include adamantane,
  • substitution refers to any substitution at a position permitted by chemical theory, and the number of substituents complies with the chemical bonding rules.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • a “pharmaceutical composition” refers to a mixture of one or more compounds described herein, or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals thereof, with other ingredients, wherein the other ingredients include physiologically/pharmaceutically acceptable carriers and/or excipients.
  • Carrier refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ.
  • Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.
  • Excipient refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and/or vehicle that is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, Suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners.
  • Examples of pharmaceutical excipients include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and cross-linked carboxymethylcellulose (e.g., cross-linked sodium carboxymethylcellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn starch, etc.
  • sugars such as lactose, glucose and sucrose
  • starches such as corn starch and potato starch
  • cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl
  • glycols such as propylene glycol
  • polyols such as glycerol, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as agar
  • buffers such as magnesium hydroxide and aluminum hydroxide
  • Stereoisomers include “stereoisomers” and “tautomers”.
  • Stepoisomers refer to isomers produced by the same order of connection of atoms or atomic groups in molecules, but different spatial arrangements. Stereoisomers include cis-trans isomers, optical isomers, and conformational isomers.
  • Teautomers refer to the conversion of one functional group to another through a reversible chemical reaction called tautomerization, usually caused by the concomitant migration of hydrogen atoms and ⁇ bonds (double bonds or triple bonds).
  • the following pairs of compounds aldehyde/keto-enol, imine-enamine, and when the present invention describes the left-hand compound in which the pyrimidine ring is substituted with OH, the tautomeric compound on the right is also included.
  • Solvate refers to a substance formed by a stoichiometric or non-stoichiometric amount of a solvent that is bound to the compound or salt of the present invention by non-covalent forces between molecules.
  • the solvent is water, it is a hydrate.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • PE: EA (v/v) 2:1
  • Step 3 Sodium hydride (0.21 g, 5.34 mmol, 60% wt) was dissolved in THF (30 mL), cooled to 0°C, and compound 1C (1.35 g, 4.38 mmol) was added in batches. After 20 minutes at room temperature, 5-bromo-1,3,4-thiadiazole-2-amine (1.03 g, 5.69 mmol) was added in batches, and then the temperature was raised to room temperature for 5 hours. Saturated sodium bicarbonate aqueous solution (50 mL) was added to quench the reaction, and ethyl acetate (80 mL ⁇ 3) was used for extraction.
  • Step 4 Dissolve 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (1E) (0.24 g, 0.86 mmol) (prepared by referring to the method described in WO2022118210) and compound 1D (0.35 g, 0.86 mmol) in DMF (10 mL), add 1-methyl-1H-imidazole (0.21 g, 2.58 mmol), stir evenly, add TCFH (0.29 g, 1.03 mmol) in batches, and react at room temperature for 30 minutes after the addition is complete. After the reaction is completed, add saturated brine (50 mL) and extract with ethyl acetate (50 mL ⁇ 3).
  • Step 5 Dissolve compound 1F (0.38 g, 0.57 mmol) in DCM (10 mL), stir evenly and add trifluoroacetic acid (2 mL) dropwise. After the addition is complete, react at room temperature for 1 hour. After the reaction is completed, concentrate under reduced pressure. Add methanol (2 mL) and toluene (10 mL) to the residue, mix evenly, and concentrate under reduced pressure. Repeat this operation three times and add DCM (20 mL) and methanol (2 mL) to the substrate. Stir evenly and add potassium carbonate (0.56 g, 4.0 mmol). Continue stirring for ten minutes and filter. The filtrate is concentrated under reduced pressure to obtain the crude product of the target compound 1G, which is directly reacted in the next step.
  • Step 6 Compound 1G (0.32 g, 0.57 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1H) (0.31 g, 1.12 mmol) were dissolved in DMSO (10 mL), and DIPEA (0.44 g, 3.4 mmol) was added. After stirring, the mixture was heated to 100°C and reacted for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • PE: EA (v/v) 2:1
  • PE: EA (v/v) 1:1
  • Step 3 Sodium hydride (0.39 g, 9.76 mmol, 60% wt) was dissolved in tetrahydrofuran (40 mL), cooled to 0°C, and compound 2B (2.58 g, 8.00 mmol,) was added in batches. After reacting at room temperature for 20 minutes, the mixture was cooled to 0°C, and 5-bromo-1,3,4-thiadiazole-2-amine (2.16 g, 12.00 mmol) was added in batches, and then the mixture was heated to room temperature for 5 hours.
  • Step 4 Dissolve 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (1E) (0.26 g, 0.95 mmol) and 2C (0.40 g, 0.95 mmol) in DMF (10 mL). Add 1-methyl-1H-imidazole (0.23 g, 2.85 mmol), stir evenly, add TCFH (0.32 g, 1.14 mmol) in batches, and react at room temperature for 1 hour.
  • Step 5 Dissolve compound 2D (0.46 g, 0.67 mmol) in DCM (10 mL), stir evenly and add trifluoroacetic acid (2 mL) dropwise. After the addition is complete, react at room temperature for 1 hour. After the reaction is completed, concentrate under reduced pressure, add methanol (3 mL) and toluene (10 mL) to the residue, mix evenly, and concentrate under reduced pressure. Repeat this operation three times and add DCM (20 mL) and methanol (2 mL) to the substrate.
  • Step 6 Compound 2E (0.39 g, 0.67 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1H) (0.37 g, 1.34 mmol) were dissolved in DMSO (10 mL), and DIPEA (0.52 g, 4.0 mmol) was added. After stirring, the mixture was reacted at 100°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • PE: EA (v/v) 2:1
  • PE:EA (v/v) 1:1
  • Step 4 Compound 3D (2.65 g, 8.38 mmol) was dissolved in THF (30 mL), cooled to 0°C, N-Boc-4-(hydroxymethyl)piperidine (2.16 g, 10.06 mmol) was added, and potassium tert-butoxide (1.13 g, 10.06 mmol) was added in batches, and then the temperature was raised to room temperature for reaction for 30 minutes. Saturated sodium bicarbonate aqueous solution (50 mL) was added to quench the reaction, and ethyl acetate (80 mL ⁇ 2) was used for extraction.
  • Step 5 Dissolve compound 3E (2.97 g, 6.59 mmol) in THF (30 mL), add tetrabutylammonium fluoride (2.07 g, 7.92 mmol), and react at room temperature for 1 h. After reduced pressure concentration, silica gel column chromatography (EA) was used to obtain the target compound 3F (1.7 g, yield 76.68%).
  • Step 6 Sodium hydride (0.30 g, 7.5 mmol, 60% wt) was dissolved in THF (30 mL), and compound 3F (1.7 g, 5.05 mmol) was added in batches at 0°C. After the addition was complete, the mixture was stirred at room temperature for 20 minutes. Carbon disulfide (0.57 g, 7.51 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 20 minutes. Methyl iodide (1.07 g, 7.51 mmol) was added dropwise. After the addition was complete, the mixture was reacted for 30 minutes.
  • Step 8 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (1E) (0.26 g, 0.95 mmol) and compound 3H (0.41 g, 0.95 mmol) were dissolved in DMF (10 mL), 1-methyl-1H-imidazole (0.23 g, 2.85 mmol) was added, and TCFH (0.32 g, 1.14 mmol) was added in batches after stirring. The mixture was reacted at room temperature for 1 hour. After the reaction, saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 9 Dissolve compound 3I (0.38 g, 0.55 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL) dropwise after stirring, and react at room temperature for 1 hour after the addition is complete. After the reaction is completed, concentrate under reduced pressure, add methanol (3 mL) and toluene (10 mL) to the residue, mix well, and concentrate under reduced pressure. Repeat this operation three times and add DCM (20 mL) and methanol (2 mL) to the substrate. Add potassium carbonate (0.56 g, 4.0 mmol) after stirring well, continue stirring for ten minutes and filter, and the filtrate is concentrated under reduced pressure to obtain the crude product of the target compound 3J, which is directly reacted in the next step.
  • Step 10 Compound 3J (0.33 g, 0.55 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1H) (0.30 g, 1.1 mmol) were dissolved in DMSO (10 mL), and DIPEA (0.21 g, 1.65 mmol) was added and stirred evenly, and then reacted at 100°C for 8 hours. After the reaction was completed, it was cooled to room temperature, saturated brine (30 mL) was added, and extracted with ethyl acetate (50 mL ⁇ 3).
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • the trifluoroacetate of 8A (synthesized by the method described in reference patent WO2022118210) (588 mg, 0.64 mmol) was dissolved in DMSO (10 mL), and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (354 mg, 1.28 mmol) and diisopropylethylamine (414 mg, 3.2 mmol) were added in sequence, and the temperature was raised to 100°C for 8 hours. TLC/LCMS showed that the reaction was complete, cooled to room temperature, saturated brine (20 mL) was added, and EA (20 ⁇ 2 mL) was used for extraction.
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Step 1 Dissolve trans-3-(4-methoxybenzoyl)acrylic acid (83 mg, 0.4 mmol) in DMF (10 mL), add diisopropylethylamine (62 mg, 0.48 mmol), HATU (181 mg, 0.48 mmol) in turn, and stir at room temperature for 20 minutes.
  • DMF diisopropylethylamine
  • HATU 181 mg, 0.48 mmol
  • Embodiment 11 is a diagrammatic representation of Embodiment 11:
  • Trans-3-(4-trifluoromethylbenzoyl)acrylic acid (98 mg, 0.4 mmol) was dissolved in DMF (10 mL), and diisopropylethylamine (62 mg, 0.48 mmol) and HATU (183 mg, 0.48 mmol) were added in sequence, and stirred at room temperature for 20 minutes.
  • the trifluoroacetate of 7A (264 mg, 0.3 mmol) was dissolved in DMF (5 mL), and diisopropylethylamine (194 mg, 1.5 mmol) was added. After stirring for 20 minutes, it was added to the acid reaction solution and reacted at room temperature for 1 hour.
  • Embodiment 12 is a diagrammatic representation of Embodiment 12
  • Trans-3-(4-methoxybenzoyl)acrylic acid (124 mg, 0.6 mmol) was dissolved in DMF (10 mL), and diisopropylethylamine (93 mg, 0.72 mmol) and HATU (274 mg, 0.72 mmol) were added in sequence, and stirred at room temperature for 20 minutes.
  • 8A trifluoroacetate (241 mg, 0.45 mmol) was dissolved in DMF (5 mL), and diisopropylethylamine (291 mg, 2.25 mmol) was added. After stirring for 20 minutes, it was added to the acid reaction solution and reacted at room temperature for 1 hour.
  • Embodiment 13 is a diagrammatic representation of Embodiment 13:
  • Trans-3-(4-trifluoromethylbenzoyl)acrylic acid (147 mg, 0.6 mmol) was dissolved in DMF (10 mL), and diisopropylethylamine (93 mg, 0.72 mmol) and HATU (274 mg, 0.72 mmol) were added in sequence, and the mixture was reacted at room temperature for 20 minutes.
  • the trifluoroacetate of 8A (241 mg, 0.45 mmol) was dissolved in DMF (5 mL), and diisopropylethylamine (291 mg, 2.25 mmol) was added. After stirring for 20 minutes, the mixture was added to the acid reaction solution and reacted at room temperature for 1 hour.
  • Embodiment 14 is a diagrammatic representation of Embodiment 14:
  • Trans-3-(4-methoxybenzoyl)acrylic acid 130 mg, 0.63 mmol was dissolved in DMF (10 mL), and diisopropylethylamine (97 mg, 0.75 mmol) and HATU (286 mg, 0.75 mmol) were added in sequence, and stirred at room temperature for 20 minutes.
  • 9A trifluoroacetate 218 mg, 0.47 mmol was dissolved in DMF (5 mL), and diisopropylethylamine (303 mg, 2.35 mmol) was added. After stirring for 20 minutes, it was added to the acid reaction solution and reacted at room temperature for 1 hour.
  • Embodiment 15 is a diagrammatic representation of Embodiment 15:
  • Step 1 Dissolve trans-3-(4-trifluoromethylbenzoyl)acrylic acid (153 mg, 0.63 mmol) in DMF (10 mL), add diisopropylethylamine (97 mg, 0.75 mmol), HATU (286 mg, 0.75 mmol) in turn, and stir at room temperature for 20 minutes.
  • DMF diisopropylethylamine
  • HATU HATU
  • Step 1 Dissolve trans-3-(4-trifluoromethylbenzoyl)acrylic acid (153 mg, 0.63 mmol) in DMF (10 mL), add diisopropylethylamine (97 mg, 0.75 mmol), HATU (286 mg, 0.75 mmol) in turn, and stir at room temperature for 20 minutes.
  • dissolve the trifluoroacetate of 9A (218 mg, 0.47 mmol) in DMF (5 mL)
  • diisopropylethylamine 303 mg, 2.35 mmol
  • Step 1 Dissolve compound 1G (250 mg, 0.44 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (163 mg, 0.88 mmol) in methanol (10 mL), add two drops of acetic acid, stir at room temperature for 6 h, then add sodium cyanoborohydride (55 mg, 0.88 mmol) in an ice bath, naturally warm to room temperature and stir for 1 h.
  • Step 2 Dissolve compound 18A (198 mg, 0.27 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 2 hours. Concentrate the reaction solution, add dichloromethane (4 mL), and drop triethylamine to adjust the pH to 6-7. Concentrate to obtain a brown crude target compound 18B, which does not need further purification and is directly used in the next step.
  • Step 3 Dissolve the crude compound 18B in dimethyl sulfoxide (5 mL), add compound 1H (97 mg, 0.35 mmol) and triethylamine (81 mg, 0.81 mmol) in sequence, and stir at 100°C for 4 hours.
  • Step 1 Dissolve compound 1G (250 mg, 0.44 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (188 mg, 0.88 mmol) in methanol (10 mL), add two drops of acetic acid, stir at room temperature for 6 h, then add sodium cyanoborohydride (55 mg, 0.88 mmol) in an ice bath, naturally warm to room temperature, and stir for 1 h. After TLC detection, the reaction solution was concentrated, water (20 mL) was added, and dichloromethane (20 mL ⁇ 2) was extracted.
  • Step 2 Dissolve compound 19A (181 mg, 0.25 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 2 hours. Concentrate the reaction solution, then add dichloromethane (4 mL), and adjust the pH to 6-7 with triethylamine, and concentrate to obtain a brown crude target compound 19B. No further purification is required and it is directly used in the next step.
  • Step 3 Dissolve the crude compound 19B in anhydrous dimethyl sulfoxide (5 mL), add compound 1H (86 mg, 0.31 mmol), triethylamine (75 mg, 0.74 mmol) in sequence, and stir at 100°C for 4 hours.
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Step 1 Dissolve 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid 20A (synthesized by the method described in reference patent WO2022118210) (0.12 g, 0.46 mmol) and tert-butyl 4-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)piperidine-1-carboxylate (0.17 g, 0.55 mmol) in DMF (10 mL) in turn, add N-methylimidazole (0.11 g, 1.38 mmol), stir evenly, add TCFH (0.19 g, 0.69 mmol) in batches, and react at room temperature for 1 hour.
  • Step 2 Compound 20B (0.12 g, 0.22 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise after stirring. After the addition was complete, the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and methanol (3 mL) and toluene (10 mL) were added to the residue. After mixing, the mixture was concentrated under reduced pressure. The operation was repeated three times to obtain the trifluoroacetate salt of the target compound 20C (0.12 g, yield 100%).
  • Step 3 Dissolve compound 20C (0.15 g, 0.26 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.14 g, 0.52 mmol) in DMSO (10 mL), add DIPEA (0.10 g, 0.78 mmol), stir evenly and react at 100 °C for 8 hours.
  • Embodiment 21 is a diagrammatic representation of Embodiment 21.
  • Step 1 Dissolve 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid 20A (0.12 g, 0.46 mmol) and compound 1D (0.22 g, 0.54 mmol) in DMF (10 mL), add N-methylimidazole (0.11 g, 1.38 mmol), stir evenly, add TCFH (0.19 g, 0.69 mmol) in batches, and react at room temperature for 1 hour.
  • Step 2 Compound 21A (0.15 g, 0.23 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added dropwise after stirring. After the addition was complete, the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and methanol (3 mL) and toluene (10 mL) were added to the residue. After mixing, the mixture was concentrated under reduced pressure. The operation was repeated three times to obtain the trifluoroacetate salt of the target compound 21B (0.15 g, yield 100%).
  • Step 3 Compound 21B (0.15 g, 0.23 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.15 g, 0.54 mmol) were dissolved in DMSO (10 mL), and DIPEA (0.10 g, 0.81 mmol) was added. After stirring, the mixture was reacted at 100°C for 8 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Embodiment 22 is a diagrammatic representation of Embodiment 22.
  • Embodiment 23 is a diagrammatic representation of Embodiment 23.
  • Embodiment 24 is a diagrammatic representation of Embodiment 24.
  • Embodiment 25 is a diagrammatic representation of Embodiment 25.
  • Embodiment 26 is a diagrammatic representation of Embodiment 26.
  • Step 1 Using 7A (735 mg, 1.55 mmol) and tert-butyl 3-oxoazetidin-1-carboxylate (2.39 g, 13.95 mmol) as raw materials, refer to the operation of Step 1 of Example 18 to obtain Compound 26A (520 mg, yield 63%).
  • Step 2 Using compound 26A (520 mg, 0.83 mmol) as raw material, refer to the second step of Example 18 to obtain compound 26B (387 mg, yield 88%).
  • Step 3 Using compound 26B (129 mg, 0.24 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (133 mg, 0.48 mmol) as raw materials, refer to the third step of Example 18 to obtain compound 26 (21 mg, yield 11%).
  • Embodiment 27 is a diagrammatic representation of Embodiment 27.
  • Step 1 Using 7A (465 mg, 0.98 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (726 mg, 3.92 mmol) as raw materials, refer to the operation of Step 1 of Example 18 to obtain Compound 27A (316 mg, yield 50%).
  • Step 2 Using compound 27A (316 mg, 0.49 mmol) as raw material, refer to the operation of step 2 of Example 18 to obtain compound 27B (58 mg, yield 22%).
  • Step 3 Using compound 27B (58 mg, 0.11 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (61 mg, 0.22 mmol) as raw materials, refer to the operation of step 3 of Example 18 to obtain compound 27 (5 mg, yield 6%).
  • Embodiment 28 is a diagrammatic representation of Embodiment 28:
  • Step 1 7A (442 mg, 0.93 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (793 mg, 3.72 mmol) were used as raw materials.
  • the material was prepared by referring to the operation of the first step of Example 18 to obtain compound 28A (316 mg, yield 50%) (342 mg, yield 55%).
  • Step 2 Using compound 28A (342 mg, 0.51 mmol) as raw material, refer to the operation of step 2 of Example 18 to obtain compound 28B (262 mg, yield 90%).
  • Step 3 Using compound 28B (262 mg, 0.46 mmol) and 2-(2,6-dioxo-piperidin-3-yl)-5-fluoro-isoindole-1,3-dione (254 mg, 0.92 mmol) as raw materials, refer to the operation of step 3 of Example 18 to obtain compound 28 (22 mg, yield 6%).
  • Embodiment 29 is a diagrammatic representation of Embodiment 29.
  • Step 1 Using compound 29A (2.51 g, 8.59 mmol) (synthesized by referring to CN112979655A) as raw material, refer to the sixth step operation method of Example 3 to obtain the target compound 29B (2.6 g, yield 79%).
  • Step 2 Using compound 29B (2.6 g, 6.80 mmol) as raw material, refer to the seventh step of Example 3 to obtain the target compound 29C (2.4 g, yield 90%).
  • Step 3 Compound 20A (0.61 g, 2.35 mmol) and compound 29C (0.92 g, 2.35 mmol) were used as raw materials and the operation method of step 8 of Example 3 was referred to to obtain compound 29D (1.2 g, yield 80%).
  • Step 4 Using compound 29D (1.20 g, 1.89 mmol) as raw material, refer to the ninth step of Example 3 to obtain compound 29E (0.76 g, yield 79%).
  • Step 5 Using compound 29E (0.10 g, 0.19 mmol) as raw material, refer to the procedure of Example 4 to obtain compound 29 (42 mg, yield 31%).
  • Embodiment 30 is a diagrammatic representation of Embodiment 30.
  • Embodiment 31 is a diagrammatic representation of Embodiment 31.
  • Compound 31 was obtained by using compound 29E (0.10 g, 0.19 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1H) (0.16 g, 0.57 mmol) as raw materials and referring to the operation method of step 10 of Example 3.
  • Embodiment 32 is a diagrammatic representation of Embodiment 32.
  • Step 2 Compound 32A (98 mg, 0.15 mmol) was dissolved in methanol (5 mL), and zinc powder (98 mg, 1.5 mmol) and ammonium chloride (24 mg, 0.45 mmol) were added, and the mixture was reacted at room temperature for 3 hours. After the reaction, saturated brine (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 32B (81 mg, yield: 86%).
  • Embodiment 33 is a diagrammatic representation of Embodiment 33.
  • Step 1 Sodium hydride (0.48 g, 12 mmol, 60% wt) was dissolved in DMF (20 mL), and compound N-Boc-4-hydroxypiperidine (2.42 g, 12 mmol) was added in batches at 0°C. After the addition was complete, the mixture was stirred at room temperature for 20 minutes, and then a solution of compound 3D (3.2 g, 10.1 mmol) in DMF (10 mL) was added dropwise. After the addition was complete, the reaction was continued for 2 hours. Saturated aqueous sodium bicarbonate solution (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL ⁇ 2).
  • Step 2 Using compound 33A (1.72 g, 3.94 mmol) as raw material, refer to the fifth step of Example 3 to obtain the target compound 33B (1.21 g, yield 95%).
  • Step 3 Using compound 33B (1.21 g, 3.75 mmol) as raw material, refer to the operation method of step 6 of Example 3 to obtain the target compound 33C (1.34 g, yield 86.6%).
  • Step 4 Using compound 33C (1.34 g, 3.25 mmol) as raw material, refer to the seventh step of Example 3 to obtain the target compound 33D (0.85 g, yield 62%).
  • Step 5 Using 4-(2-fluoro-6-methoxyphenyl)-6-methylnicotinic acid (20A) (0.26 g, 1.0 mmol) and compound 33D (0.42 g, 1.0 mmol) as raw materials, refer to the operation method of step 8 of Example 3 to obtain compound 33E (0.49 g, yield 74%).
  • Step 6 Using compound 33E (0.49 g, 0.74 mmol) as raw material, refer to the operation method of step 9 of Example 3 to obtain compound 33F (0.42 g, yield 100%).
  • Step 7 Using compound 33F (0.14 g, 0.25 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1H) (0.21 g, 0.75 mmol) as raw materials, refer to the operation method of step 10 of Example 3 to obtain compound 33 (65 mg, yield: 32%).
  • Embodiment 34 is a diagrammatic representation of Embodiment 34.
  • Step 1 Using compound 21B (200 mg, 0.36 mmol) and p-fluoronitrobenzene (62 mg, 0.44 mmol) as raw materials, refer to the first step of Example 32 to obtain the target compound 35A (170 mg, 71%).
  • Step 2 Using compound 35A (170 mg, 0.25 mmol) as raw material, refer to the second step operation method of Example 32 to obtain the target compound 35B (128 mg, 80%).
  • Step 3 Using compound 35B (128 mg, 0.20 mmol) and 3-bromopiperidine-2,6-dione (58 mg, 0.30 mmol) as raw materials, refer to the third step operation method of Example 32 to obtain the target compound 35 (30 mg, 20%).
  • Embodiment 36 is a diagrammatic representation of Embodiment 36.
  • Step 1 Using compound 20C (0.20 g, 0.43 mmol) and 1-Boc-3-azetidinone (0.09 g, 0.52 mmol) as raw materials, refer to the first step of Example 18 to obtain compound 36A (0.23 g, yield 86%).
  • Step 2 Using compound 36A (0.23 g, 0.37 mmol) as raw material, refer to the second step operation method of Example 20 to obtain the trifluoroacetate salt of target compound 36B (0.23 g, yield 100%).
  • Step 3 Using compound 36B (0.12 g, 0.19 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.14 g, 0.52 mmol) as raw materials, refer to the third step operation method of Example 18 to obtain compound 36 (10 mg, yield 6.67%).
  • Embodiment 37 is a diagrammatic representation of Embodiment 37.
  • Step 1 Dissolve 5-hydroxypyridine-2-carboxylic acid methyl ester (1A) (2.0 g, 13.0 mmol) and 3-iodoazetidine-1-carboxylic acid tert-butyl ester (7.4 g, 26.0 mmol) in DMF (100 mL), add cesium carbonate (8.4 g, 26.0 mmol) and cuprous iodide (2.5 g, 13.0 mmol) in turn, and stir overnight at 100 ° C under nitrogen atmosphere.
  • cesium carbonate 8.4 g, 26.0 mmol
  • cuprous iodide 2.5 g, 13.0 mmol
  • Step 2 Compound 37A (3.0 g, 9.73 mmol) was used as a raw material and the second step operation method of Example 1 was followed to obtain compound 37B (2.3 g, yield 84%).
  • Step 3 Compound 37B (2.3 g, 8.21 mmol) was used as a raw material and the operation method of step 6 of Example 3 was referred to obtain compound 37C (2.5 g, yield 82%).
  • Step 4 Compound 37C (2.5 g, 6.75 mmol) was used as a raw material and the operation method of step 7 of Example 3 was followed to obtain compound 37D (2.5 g, yield 96%).
  • Step 5 Compound 37E (0.6 g, yield 71%) was obtained by using compound 37D (0.5 g, 1.32 mmol) as raw material and referring to the eighth step of Example 3.
  • Step 6 Compound 37E (0.6 g, 0.94 mmol) was used as a raw material and the operation method of step 9 of Example 3 was followed to obtain compound 37F (0.5 g, yield 98%).
  • Step 7 Compound 37F (0.25 g, 0.46 mmol) was used as a raw material and the target compound 37 (50 mg, yield 13%) was obtained by referring to the tenth step of Example 3.
  • Embodiment 38 is a diagrammatic representation of Embodiment 38.
  • Step 1 Using compound 29C (0.31 g, 0.79 mmol) as raw material, refer to the fourth step of Example 1 to obtain the target compound 38A (0.42 g, yield 81.5%).
  • Step 2 Using compound 38A (0.42 g, 0.64 mmol) as raw material, refer to the fifth step of Example 1 to obtain the target compound 38B (0.32 g, yield 91%).
  • Step 3 Using compound 38B (0.32 g, 0.58 mmol) as raw material, refer to the first step of Example 32 to obtain the target compound 38C (0.26 g, yield 67%).
  • Step 4 Compound 38C (0.26 g, 0.39 mmol) was used as a raw material and the target was obtained by referring to the second step of Example 32.
  • Compound 38D (0.15 g, yield 60%).
  • Step 5 Using compound 38D (0.15 g, 0.23 mmol) and compound 32C as raw materials, refer to the third step operation method of Example 32 to obtain the target compound 38 (18 mg, yield 10%).
  • Step 1 Dissolve compound 29C (0.31 g, 0.79 mmol) and compound 1E (0.24 g, 0.87 mmol) in DMF (20 mL), add 1-methyl-1H-imidazole (0.21 g, 2.58 mmol), stir evenly, add TCFH (0.29 g, 1.03 mmol) in batches, and react at room temperature for 20 minutes after the addition is complete. After the reaction is completed, add saturated brine (50 mL) and extract with ethyl acetate (50 mL ⁇ 3).
  • Step 2 Dissolve compound 38A (0.42 g, 0.64 mmol) in DCM (10 mL), add trifluoroacetic acid (2 mL) dropwise after stirring, and react at room temperature for 1 hour after the addition is complete. After the reaction is completed, concentrate under reduced pressure, add methanol (2 mL) and toluene (10 mL) to the residue, mix well, and concentrate under reduced pressure. Repeat this operation three times, then add DCM (20 mL) and methanol (2 mL) to the substrate. Add potassium carbonate (0.56 g, 4.0 mmol) after stirring well, continue stirring for ten minutes, and filter. The filtrate is concentrated under reduced pressure to obtain the target compound 38B (0.32 g, yield 91%).
  • Step 3 Dissolve compound 38B (0.32 g, 0.58 mmol) and p-fluoronitrobenzene (0.12 g, 0.85 mmol) in DMSO (10 mL), add triethylamine (100 mg, 1.0 mmol), stir evenly and react at 50 ° C for 16 hours. After the reaction, add saturated brine (30 mL) and extract with ethyl acetate (50 mL ⁇ 3).
  • Step 4 Dissolve compound 38C (0.26 g, 0.39 mmol) in methanol (30 mL), add zinc powder (0.26 g, 4.0 mmol) and ammonium chloride (0.21 g, 4.0 mmol), and react at room temperature for 3 hours. After the reaction, add saturated brine (20 mL), extract with ethyl acetate (30 mL ⁇ 3), dry the combined organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain the target compound 38D (0.15 g, yield 60%).
  • Embodiment 39 is a diagrammatic representation of Embodiment 39.
  • Step 1 Using compound 38B (0.12 g, 0.22 mmol) as raw material, refer to the sixth step of Example 1 to obtain the target compound 39 (82 mg, yield 46%).
  • Embodiment 40 is a diagrammatic representation of Embodiment 40.
  • Step 1 Using compound 1G (0.15 g, 0.26 mmol) and compound 40A as raw materials, refer to the sixth step of Example 1 to obtain the target compound 40 (72 mg, yield 33%).
  • Embodiment 41 is a diagrammatic representation of Embodiment 41.
  • Step 1 Using compound 1G (0.15 g, 0.26 mmol) and compound 41A as raw materials, refer to the sixth step of Example 1 to obtain the target compound 41 (85 mg, yield 38%).
  • Embodiment 42 is a diagrammatic representation of Embodiment 42.
  • Step 1 Using compound 1G (0.43 g, 0.76 mmol) as raw material, refer to the first step operation method of Example 32 to obtain the target compound 42A (0.35 g, yield 67%).
  • Step 2 Using compound 42A (0.35 g, 0.51 mmol) as raw material, refer to the second step operation method of Example 32 to obtain the target compound 42B (0.18 g, yield 54%).
  • Step 3 Using compound 42B (0.18 g, 0.27 mmol) and compound 32C as raw materials, refer to the third step operation method of Example 32 to obtain the target compound 42 (13 mg, yield 6.2%).
  • Embodiment 43 is a diagrammatic representation of Embodiment 43.
  • Step 1 Using compound 20C (276 mg, 0.6 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (447 mg, 2.4 mmol) as raw materials, refer to the first step operation method of Example 18 to obtain the target compound 43A (268 mg, yield 71%).
  • Step 2 Using compound 43A (268 mg, 0.43 mmol) as raw material, refer to the second step operation method of Example 20 to obtain the trifluoroacetate salt of target compound 43B (212 mg, yield 80%).
  • Step 3 Using compound 43B (212 mg, 0.34 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (188 mg, 0.68 mmol) as raw materials, refer to the third step of Example 18 to obtain the target compound 43 (44 mg, yield 16%).
  • Embodiment 44 is a diagrammatic representation of Embodiment 44.
  • Step 1 Using compound 20A (261 mg, 1 mmol) and compound 44A (266 mg, 1 mmol) (synthesized by referring to WO2022118210) as raw materials, refer to the eighth step of Example 3 to obtain compound 44B (330 mg, yield 65%).
  • Step 2 Compound 44B (330 mg, 0.65 mmol) was dissolved in methanol (10 mL) and water (10 mL), and lithium hydroxide monohydrate (137 mg, 3.25 mmol) was added, and the mixture was reacted at room temperature for 5 hours. TLC/LCMS showed that the reaction was complete, and the methanol was removed by concentration. The remaining aqueous solution was adjusted to acidity with 1M dilute hydrochloric acid, and a white solid was precipitated. After filtration, compound 44C (220 mg, yield 68%) was obtained.
  • Step 3 Using compound 44C (100 mg, 0.2 mmol) and 3-amino-2,6-piperidinedione hydrochloride (33 mg, 0.2 mmol) as raw materials, refer to the eighth step of Example 3 to obtain compound 44 (47 mg, yield 39%).
  • Embodiment 45 is a diagrammatic representation of Embodiment 45.
  • Embodiment 46 is a diagrammatic representation of Embodiment 46.
  • Step 1 Using compound 20C (458 mg, 1 mmol) and p-fluoronitrobenzene (212 mg, 1.5 mmol) as raw materials, refer to the first step operation method of Example 32 to obtain compound 46A (490 mg, yield 85%).
  • Step 2 Using compound 46A (490 mg, 0.85 mmol) as raw material, refer to the second step operation method of Example 32 to obtain compound 46B (140 mg, yield 30%).
  • Step 3 Using compound 46B (140 mg, 0.25 mmol) and 3-bromopiperidine-2,6-dione (32C) (144 mg, 0.75 mmol) as raw materials, refer to the third step operation method of Example 32 to obtain compound 46 (28 mg, yield 17%).
  • Embodiment 47 is a diagrammatic representation of Embodiment 47.
  • Step 1 Dissolve compound 44A (2.0 g, 7.52 mmol) in tetrahydrofuran (4 mL), add lithium borohydride (828.6 mg, 37.60 mmol) in batches under an ice bath, and naturally warm to room temperature after addition.
  • Step 2 Using compound 47A (984.44 mg, 4.14 mmol) as raw material, refer to the operation method of the first step of Example 20 to obtain the target compound 47B (1.21 g, 61%).
  • Step 3 Compound 47B (400 mg, 0.83 mmol) was dissolved in chloroform (4 mL), and active manganese dioxide (1.44 g, 16.60 mmol) was added, and the temperature was raised to 60° C. After TLC detection, the reaction was completed, and the mixture was cooled to room temperature, and then filtered through diatomaceous earth. The filtrate was concentrated to obtain the crude target compound 47C, which was directly used for the next step without purification.
  • Step 4 Using the crude compound 47C obtained in the previous step and 3-(4-((piperidin-4-yl)phenyl)amino)piperidine-2,6-dione (synthesized by the method described in reference patent WO202232026) (238.21 mg, 0.83 mmol) as raw materials, refer to the operation of the first step of Example 19 to obtain compound 47 (218.17 mg, yield 35%).
  • Embodiment 48 is a diagrammatic representation of Embodiment 48.
  • Step 1 Dissolve compound 47B (800 mg, 1.66 mmol) in tetrahydrofuran (4 mL), add triethylamine (503.95 mg, 4.99 mmol), then add methanesulfonyl chloride (286.35 mg, 2.49 mmol) dropwise under ice bath, and after completion of the addition, warm the temperature to room temperature for reaction.
  • Step 2 Compound 48A (578.67 mg, 1.04 mmol) was dissolved in dimethyl sulfoxide (4 mL), triethylamine (313.66 mg, 3.11 mmol) and 4-hydroxythalidomide (370.45 mg, 1.35 mmol) were added in sequence, and then the temperature was raised to 60°C. After TLC detection, the reaction was completed, water (20 mL) was added, and ethyl acetate (20 mL ⁇ 2) was used for extraction.
  • the combined organic phase was washed with water (20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentrating the organic phase was purified using a medium-pressure preparation instrument Biotage Isolera One (20 g silica gel column, eluent: 0-10% MeOH/DCM) to obtain the target compound 48 (38 mg, 9%).
  • Embodiment 49 is a diagrammatic representation of Embodiment 49.
  • the combined organic phases were washed with water (20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the organic phase was purified using a medium pressure preparation instrument Biotage Isolera One (20 g silica gel column, eluent: 0-10% MeOH/DCM) to obtain the target compound 49 (160 mg, 55%).
  • Embodiment 50 is a diagrammatic representation of Embodiment 50.
  • the combined organic phase was washed with water (20 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentrating the organic phase was eluted using a medium-pressure preparation instrument Biotage Isolera One (20 g silica gel column, The target compound 50 (167 mg, 56%) was obtained by purification using 1% MeOH/DCM (solvent: 0-10% MeOH/DCM).
  • Embodiment 51 is a diagrammatic representation of Embodiment 51.
  • Step 1 Using compound 51A (15 g, 79.78 mmol) as raw material, refer to step 6 of Example 3 to obtain a crude product 51B (20 g, 90.13%), which was directly used in the next step without further purification.
  • Step 2 Using compound 51B (20 g, 71.89 mmol) as raw material, refer to step 7 of Example 3 to obtain compound 51C (5.3 g, 25.67%).
  • Step 3 Compound 51C (0.8 g, 2.79 mmol), 51D (1.01 g, 5.58 mmol), cuprous iodide (52.95 mg, 0.28 mmol), bistriphenylphosphine palladium dichloride (195.16 mg, 0.28 mmol) were dissolved in N,N-dimethylacetamide (3 mL) and triethylamine (3 mL) in sequence, and stirred at 80°C under nitrogen atmosphere for overnight reaction. After the reaction, saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 4 Using 51E (0.24 g, 0.62 mmol) and 1E (0.38 g, 1.24 mmol) as raw materials, refer to the operation method of Step 8 of Example 3 to obtain the target compound 51F (230 mg, 57.24%).
  • Step 5 Using compound 51F (100 mg, 0.15 mmol) as raw material, refer to the operation method of step 9 of Example 3 to obtain the target compound 51G (60 mg, 70.96%).
  • Step 6 Using compound 51G (60 mg, 0.11 mmol) and 1H (61 mg, 0.22 mmol) as raw materials, refer to the operation method of step 10 of Example 3 to obtain compound 51 (18 mg, 20.38%).
  • Embodiment 52 is a diagrammatic representation of Embodiment 52.
  • Step 1 Using compound 51C (0.5 g, 1.74 mmol) and 52A (1.09 g, 5.22 mmol) as raw materials, refer to the third step of Example 51 to obtain compound 52B (380 mg, 52.56%).
  • Step 2 Using 52B (0.28 g, 0.67 mmol) and 1E (0.37 g, 1.33 mmol) as raw materials, refer to the eighth step of Example 3 to obtain the target compound 52C (320 mg, 70.63%).
  • Step 3 Using compound 52C (220 mg, 0.32 mmol) as raw material, refer to the operation method of step 9 of Example 3 to obtain the target compound 52D (90 mg, 47.34%).
  • Step 4 Using compound 52D (90 mg, 0.16 mmol) and 1H (88 mg, 0.32 mmol) as raw materials, refer to the operation method of step 10 of Example 3 to obtain compound 52 (24.55 mg, 18.4%).
  • Embodiment 53 is a diagrammatic representation of Embodiment 53.
  • Step 1 53A (500.0 mg, 1.86 mmol), biboronic acid pinacol ester (560.0 mg, 2.22 mmol), [1,1'- [Bis(diphenylphosphino)ferrocene]Palladium dichloride (140.0 mg, 0.19 mmol) and potassium acetate (550.0 mg, 5.60 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 90°C for 4 hours under nitrogen atmosphere. LC-MS showed that the reaction was complete, and the reaction solution was cooled to room temperature and poured into water (30 mL). Solid precipitated and filtered. The filter cake was dried to obtain product 53B, which was used directly in the next step without further purification (400.0 mg, 68.23%).
  • Step 2 Using 20A (2.0 g, 7.66 mmol) and 51C (2.42 g, 8.43 mmol) as raw materials, refer to the eighth step of Example 3 to obtain compound 53C (2.6 g, 64.0%).
  • Embodiment 54 is a diagrammatic representation of Embodiment 54:
  • Step 1 Dissolve 54A (synthesized by the method described in reference patent WO2022012622A1) (50.0 mg, 0.16 mmol), biboric acid pinacol ester (50.0 mg, 0.19 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (12.0 mg, 0.016 mmol) and potassium acetate (47.0 mg, 0.48 mmol) in 1,4-dioxane (5 mL) in sequence, and react at 90 ° C for 4 hours under nitrogen atmosphere.
  • LC-MS showed that the reaction was complete, cooled to room temperature, and concentrated to obtain a crude product 54B (43.0 mg, 99.9%), which was directly used in the next step reaction.
  • Step 2 Using 54B (43.0 mg, 0.16 mmol) and 53C (100.0 mg, 0.19 mmol) as raw materials, refer to the third step of Example 53 to obtain the target compound 54 (8.0 mg, 7.41%).
  • Embodiment 55 is a diagrammatic representation of Embodiment 55:
  • Step 1 Dissolve compound 55A (10 g, 55.87 mmol) in toluene (100 mL), add N,N-dimethylformamide dimethyl acetal (33.24 g, 279 mmol), heat to 100 ° C and stir for 4 hours. After TLC detection, the reaction is complete, cool to room temperature, and concentrate under reduced pressure to obtain a crude product, which is purified using a medium-pressure preparation instrument Biotage Isolera One (220 g silica gel column, eluent: 0-20% PE/EA) to obtain the target compound 55B (8.5 g, 65%).
  • Biotage Isolera One (220 g silica gel column, eluent: 0-20% PE/EA
  • Step 2 Under an ice bath, the compound tert-butyl 4-[6-hydroxymethyl-3-pyridinyl]-1-piperidinecarboxylate (4 g, 13.65 mmol) (synthesized according to the method described in reference patent WO2022111636) was dissolved in tetrahydrofuran (40 mL), and sodium hydride (1.64 g, 40.96 mmol, 60% wt) was slowly added under a nitrogen atmosphere and stirred for 0.5 hours. Then, a tetrahydrofuran solution (20 mL) of compound 55B (4.79 g, 20.48 mmol) was slowly added dropwise, stirred for one hour in an ice bath, and warmed to room temperature.
  • the reaction was completed by TLC detection.
  • the reaction solution was slowly poured into ice water, and water (60 mL) was added. Extraction was performed with ethyl acetate (200 mL ⁇ 2).
  • the organic phase was washed with water (200 mL), washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration of the organic phase was purified using a medium-pressure preparation instrument Biotage Isolera One (120 g silica gel column, eluent: 30-80% DCM/EA) to obtain the target compound 55C (1.6 g, 29.85%).
  • Step 3 Compound 55C (1.0 g, 2.54 mmol) and compound 20A (0.73 g, 2.80 mmol) were dissolved in acetonitrile (30 mL), and di-tert-butyl dicarbonate (1.78 g, 6.35 mmol), 4-dimethylaminopyridine (15.49 mg, 0.127 mmol) and 2,6-dimethylpyridine (26.75 mg, 0.25 mmol) were added in sequence, and stirred in microwave at 100°C for 6 hours.
  • the reaction was completed by TLC detection, and the reaction solution was concentrated to obtain a brown crude product, which was purified using a medium-pressure preparation instrument Biotage Isolera One (40 g silica gel column, eluent: 50-100% DCM/EA) to obtain the target compound 55D (1.0 g, 61.9%).
  • a medium-pressure preparation instrument Biotage Isolera One 40 g silica gel column, eluent: 50-100% DCM/EA
  • Step 4 Using compound 55D (1.0 g, 1.57 mmol) as raw material, refer to the ninth step of Example 3 to obtain the target compound 55E (0.80 g, yield 95.24%).
  • Step 5 Using compound 55E (0.10 g, 0.19 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (62 mg, 0.23 mmol) as raw materials, refer to the operating method of step 10 of Example 3 to obtain compound 55 (30 mg, yield 20.4%).
  • Embodiment 56 is a diagrammatic representation of Embodiment 56.
  • Step 1 Using compound 55E (0.50 g, 0.93 mmol) and 3,4-difluoronitrobenzene (0.18 g, 1.12 mmol) as raw materials, refer to the operation method of the first step of Example 32 to obtain compound 56A (0.47 g, yield 75%).
  • Step 2 Using compound 56A (0.47 g, 0.70 mmol) as raw material, refer to the operation method of step 2 of Example 32 to obtain compound 56B (0.25 g, yield 55%).
  • Step 3 Using compound 56B (0.25 g, 0.38 mmol) and 3-bromopiperidine-2,6-dione (0.15 g, 0.76 mmol) as raw materials, refer to the operation method of step 3 of Example 32 to obtain compound 56 (70 mg, yield 24.5%).
  • Embodiment 57
  • Embodiment 58
  • Example 3 Using compound 57A (0.10 g, 0.24 mmol) and compound 38B (0.13 g, 0.24 mmol) as raw materials, the eighth step of Example 3 was followed to obtain compound 58 (55 mg, yield 24%).
  • Embodiment 59 is a diagrammatic representation of Embodiment 59.
  • Step 1 Dissolve compound 38B (1.0 g, 1.80 mmol) and 2,4-difluoronitrobenzene (0.38 g, 2.4 mmol) in DMSO (20 mL), add triethylamine (0.30 g, 3.0 mmol), stir evenly and react at 60 ° C for 6 hours. After the reaction, add saturated brine (40 mL) and extract with ethyl acetate (80 mL ⁇ 2).
  • Step 2 Compound 59A (1.1 g, 1.59 mmol) was dissolved in methanol (20 mL) and tetrahydrofuran (6 mL), and zinc powder (1.05 g, 16 mmol) and ammonium chloride (0.86 g, 16 mmol) were added, and the mixture was reacted at room temperature for 3 hours. After the reaction, saturated brine (40 mL) was added, and the mixture was extracted with ethyl acetate (80 mL ⁇ 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 59B (0.63 g, yield: 60%).
  • Embodiment 60 is a diagrammatic representation of Embodiment 60.
  • Step 1 Using compound 38B (0.33 g, 0.60 mmol) as raw material, refer to the first step operation method of Example 19 to obtain the target compound 60A (0.26 g, yield 58%).
  • Step 2 Using compound 60A (0.26 g, 0.35 mmol) as raw material, refer to the ninth step of Example 3 to obtain the target compound 60B (0.21 g, yield 93%).
  • Step 3 Using compound 60B (0.21 g, 0.28 mmol) as raw material, refer to the third step operation method of Example 19 to obtain the target compound 60 (0.14 g, yield 48%).
  • Step 1 Using compound 38B (0.30 g, 0.54 mmol) as raw material, refer to the first step operation method of Example 18 to obtain the target compound 61A (0.16 g, yield 41%).
  • Step 2 Using compound 61A (0.26 g, 0.39 mmol) as raw material, refer to the ninth step of Example 3 to obtain the target compound 61B (0.12 g, yield 87%).
  • Step 3 Using compound 61B (0.12 g, 0.19 mmol) as raw material, refer to the third step operation method of Example 18 to obtain the target compound 61 (18 mg, yield 17%).
  • Embodiment 62
  • Step 1 Dissolve compound 29E (0.25 g, 0.47 mmol) and 62A (0.29 g, 1.0 mmol) in DMF (20 mL), add triethylamine (0.15 g, 1.5 mmol) and potassium iodide (0.17 g, 1.0 mmol), stir evenly and react at 60 ° C for 5 hours. After the reaction, add saturated brine (40 mL) and extract with ethyl acetate (80 mL ⁇ 2).
  • Step 2 Compound 62B (0.14 g, 0.19 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1.2 mL) was added dropwise after stirring. After the addition was complete, the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product of the target compound 62C, which was directly subjected to the next step of reaction.
  • Embodiment 63
  • Step 1 Using compound 63A (0.22 g, 0.75 mmol) (prepared by referring to WO2023050007A1) as a raw material, refer to the fourth step operation method of Example 1 to obtain compound 63B (0.33 g, yield 64%).
  • Step 2 Compound 63B (0.33 g, 0.48 mmol) was used as a raw material and the operation method of step 5 of Example 1 was followed to obtain compound 63C (0.20 g, yield 72%).
  • Step 3 Compound 63 (80 mg, yield 28%) was obtained by using compound 63C (0.20 g, 0.34 mmol) as raw material and referring to the sixth step of Example 1.
  • Embodiment 64 is a diagrammatic representation of Embodiment 64.
  • Step 1 Dissolve compound 1G (0.55 g, 0.97 mmol) and 64A (0.25 g, 0.97 mmol) (synthesized by referring to US2012252778) in DMF (10 mL), add 1-methyl-1H-imidazole (0.24 g, 2.91 mmol), stir evenly, and then add in batches TCFH (0.30 g, 1.07 mmol). After the addition was complete, the mixture was reacted at room temperature for 30 minutes. After the reaction was completed, saturated brine (50 mL) was added and extracted with ethyl acetate (50 mL ⁇ 3).
  • Step 2 Compound 64B (380 mg, 0.47 mmol) was used as a raw material and the operation method of step 5 of Example 1 was followed to obtain compound 64C (270 mg, yield 81%).
  • Step 3 Using compound 64C (100 mg, 0.14 mmol) as raw material, refer to the sixth step of Example 1 to obtain compound 64 (20 mg, yield 15%).
  • Embodiment 65 is a diagrammatic representation of Embodiment 65.
  • Step 2 Compound 65B (160 mg, 0.46 mmol) and compound 1D (187 mg, 0.46 mmol) were used as raw materials and the operation method of step 8 of Example 3 was referred to to obtain compound 65C (220 mg, yield 72%).
  • Step 3 Using compound 65C (220 mg, 0.33 mmol) as raw material, refer to the second step of Example 20 to obtain the target compound 65D (149 mg, yield 80%).
  • Step 4 Using compound 65D (149 mg, 0.26 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (144 mg, 0.53 mmol) as raw materials, refer to the third step operation method of Example 18 to obtain the target compound 65 (50 mg, yield 23%).
  • Embodiment 66
  • Step 1 Using compound 1G (568 mg, 1 mmol) and 3,4-difluoronitrobenzene (238 mg, 1.5 mmol) as raw materials, refer to the first step operation method of Example 59 to obtain compound 66A (380 mg, yield 54%).
  • Step 2 Using compound 66A (380 mg, 0.54 mmol) as raw material, refer to the second step operation method of Example 59 to obtain compound 66B (260 mg, yield 70%).
  • Step 3 Using compound 66B (260 mg, 0.38 mmol) and 3-bromopiperidine-2,6-dione (32C) (438 mg, 2.28 mmol) as raw materials, refer to the third step operation method of Example 59 to obtain compound 66 (5 mg, yield 2%).
  • Embodiment 67 is a diagrammatic representation of Embodiment 67.
  • Step 1 Using compound 64A (385 mg, 1.49 mmol) (synthesized by referring to US2012252778) and compound 38B (821 mg, 1.49 mmol) as raw materials, refer to the eighth step of Example 3 to obtain compound 67A (590 mg, yield 50%).
  • Step 2 Using compound 67A (590 mg, 0.74 mmol) as raw material, refer to the second step operation method of Example 20 to obtain the target compound 67B (413 mg, yield 80%).
  • Step 3 Using compound 67B (139 mg, 0.20 mmol) and 2-(2,6-dioxopiperidine-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (111 mg, 0.40 mmol) as raw materials, refer to the third step operation method of Example 18 to obtain the target compound 67 (40 mg, yield 21%).
  • Embodiment 68
  • Embodiment 69
  • Step 1 Compound 69A (16.7 g, 40 mmol) and p-iodoaniline (10.5 g, 48 mmol) were dissolved in dioxane (500 mL) and water (100 mL), potassium carbonate (11 g, 80 mmol) and Pd(dppf)Cl 2 (2.93 g, 4 mmol) were added in sequence, and the temperature was raised to 80°C for 6 hours under a nitrogen atmosphere.
  • Step 4 Using compound 69D (101 mg, 0.36 mmol) and compound 29E (193 mg, 0.36 mmol) as raw materials, refer to the second step operation method of Example 65 to obtain the target compound 69 (96 mg, yield 34%).
  • Embodiment 70 is a diagrammatic representation of Embodiment 70.
  • Embodiment 71
  • Step 1 Using compound 29E (0.77 g, 1.44 mmol) and 3,4-difluoronitrobenzene (0.34 g, 2.16 mmol) as raw materials, refer to the operation method of the first step of Example 32 to obtain compound 71A (0.70 g, yield 72.47%).
  • Step 2 Using compound 71A (0.7 g, 1.04 mmol) as raw material, refer to the operation method of step 2 of Example 32 to obtain compound 71B (0.56 g, yield 83.8%).
  • Step 3 Using compound 71B (0.56 g, 0.87 mmol) and 3-bromopiperidine-2,6-dione (0.42 g, 2.19 mmol) as raw materials, refer to the operation method of step 3 of Example 32 to obtain compound 71 (24 mg, yield 3.65%).
  • Embodiment 72 is a diagrammatic representation of Embodiment 72.
  • Embodiment 73
  • Step 1 Dissolve compound 29E (0.30 g, 0.56 mmol) and 64A (0.15 g, 0.56 mmol) (synthesized by reference to patent US2012252778) in DMF (10 mL), add 1-methyl-1H-imidazole (0.10 g, 1.23 mmol), stir evenly and add TCFH (0.19 g, 0.67 mmol) in batches, react at room temperature for 30 minutes after adding completely. After the reaction is completed, add saturated brine (50 mL) and extract with ethyl acetate (50 mL ⁇ 3).
  • Step 2 Compound 73A (240 mg, 0.31 mmol) was used as a raw material and the operation method of step 5 of Example 1 was followed to obtain compound 73B (190 mg, yield 90%).
  • Step 3 Compound 73 (65 mg, yield 25%) was obtained by referring to the sixth step of Example 1 with compound 73B (190 mg, 0.28 mmol) as the raw material.
  • Embodiment 74
  • Step 1 Compound 74A (2.0 g, 10.66 mmol) and compound 74B (3.15 g, 10.66 mmol) were dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (3 mL), and Pd(dppf)Cl 2 (748 mg, 1.07 mmol) and potassium carbonate (4.4 g, 31.98 mmol) were added in sequence, and stirred overnight at 75°C under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, filtered through diatomaceous earth, and water (50 mL) was added to the filtrate, and extracted with ethyl acetate (40 mL ⁇ 3).
  • Step 2 Compound 74C (2.07 g, 7.49 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (500 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. After the filtrate was combined, it was concentrated under reduced pressure to obtain a crude compound 74D (1.83 g, yield 88%), which was used directly in the next step without further purification.
  • Step 3 Using compound 74D (1.83 g, 6.57 mmol) as raw material, refer to the sixth step of Example 3 to obtain compound 74E (1.66 g, yield 69%).
  • Step 4 Using compound 74E (1.66 g, 4.50 mmol) as raw material, refer to the seventh step of Example 3 to obtain compound 74F (0.87 g, yield 51%).
  • Step 5 Using compound 74F (0.87 g, 2.30 mmol) as raw material, refer to the operation method of step 4 of Example 1 to obtain compound 74G (0.91 g, yield 62%).
  • Step 6 Using compound 74G (0.91 g, 1.43 mmol) as raw material, refer to the operation method of step 5 of Example 1 to obtain compound 74H (0.58 g, yield 76%).
  • Step 7 Using compound 74H (0.58 g, 1.08 mmol) as raw material, refer to the first step of Example 32 to obtain compound 74I (0.48 g, yield 68%).
  • Step 8 Using compound 74I (0.48 g, 0.73 mmol) as raw material, refer to the second step operation method of Example 32 to obtain compound 74J (0.26 g, yield 56%).
  • Step 9 Using compound 74J (0.26 g, 0.41 mmol) and compound 32C as raw materials, refer to the third step operation method of Example 32 to produce compound 74 (38 mg, yield 12%).
  • Embodiment 75 is a diagrammatic representation of Embodiment 75.
  • Step 1 Compound 75A (0.1 g, 0.49 mmol) (prepared by the method described in reference patent WO2022272074) was dissolved in dry dichloromethane, replaced with nitrogen, cooled to 0°C in an ice-water bath, and triethylamine (0.15 g, 1.47 mmol) and chloroacetyl chloride (55 mg, 0.49 mmol) were added, and then warmed to room temperature for 1 hour.
  • Embodiment 76
  • Step 1 Compound 64C (0.5 g, 0.71 mmol) and 76A (0.17 g, 1.1 mmol) were used as raw materials and the reaction mixture was prepared according to Example 32. The first step of the operation method gave compound 76B (0.4 g, yield 66%).
  • Step 2 Using compound 76B (0.4 g, 0.47 mmol) as raw material, refer to the second step operation method of Example 32 to obtain compound 76C (0.2 g, yield 52%).
  • Step 3 Using compound 76C (50 mg, 0.06 mmol) as raw material, refer to the third step operation method of Example 32 to obtain compound 76 (20 mg, yield 36%).
  • Embodiment 77
  • Embodiment 78
  • the culture medium for DLD-1BRCA2-/- cells was 1640 medium (containing 10% FBS and 1X Penicillin/Streptomycin). The cells were cultured in a 37°C, 5% CO 2 incubator. The cells were seeded into a 96-well plate (Corning, CAT#3603) at a density of 500 cells/100 ⁇ L and cultured overnight at 37°C, 5% CO 2. On the second day, 1 ⁇ L of 100x culture medium containing different concentrations of the test compound was added to each well, with 3 replicates for each concentration. A DMSO solvent control group and a negative control group were also set up, both with 3 replicates.
  • the culture was continued at 37°C, 5% CO 2 for 10 days, and the culture medium containing the compound was replaced on the 4th and 7th days, respectively.
  • 60 ⁇ L of detection reagent Cell Viability Assay, Promega, G7573
  • the cells were placed on an oscillator and incubated in the dark for 15 minutes, and then the fluorescence signal was measured on a PHERAstar FSX multifunctional microplate reader (BMG LABTECH).
  • GraphPad Prism software was used to calculate the IC 50 value.
  • the compounds of the present invention have an IC 50 value of less than 1000 nM for the inhibitory activity on the proliferation of DLD-1BRCA2-/- cells, some preferred compounds have an IC 50 ⁇ 500 nM, some more preferred compounds have an IC 50 ⁇ 200 nM, some more preferred compounds have an IC 50 ⁇ 100 nM, some more preferred compounds have an IC 50 ⁇ 50 nM, and some more preferred compounds have an IC 50 ⁇ 10 nM.
  • the IC 50 values of some specific compounds are shown in Table 1, wherein A represents IC 50 ⁇ 100 nM, B represents 100 nM ⁇ IC 50 ⁇ 500 nM, and C represents 500 nM ⁇ IC 50 .
  • the compounds of the present invention have a good inhibitory effect on the proliferation of DLD-1BRCA2-/- cells.
  • the IC 50 of the cell proliferation inhibition activity of compound 38 is 2.21nM
  • the IC 50 of the control compound DZ-01 is 13.78nM.
  • DZ-01 is Cpd184 in patent WO2020243459, and is synthesized according to the method described in the reference patent.
  • Use Echo to transfer 0.1 ⁇ L of the compound to the 384 reaction microplate (Optiplate 384), ensuring that the final DMSO content is 1% (in duplicate).
  • Add 5 ⁇ L of POLQ-N enzyme solution to each well of the microplate and incubate at 25°C for 10 minutes.
  • the wells containing 1% DMSO and enzyme are used as high control, and the wells containing the same amount of DMSO and buffer are used as low control.
  • Add 5 ⁇ L of ssDNA and ATP solution mixture to each well and incubate at 25°C for 60 minutes (final concentration: 1nM POLQ-N, 50nM ssDNA, 50 ⁇ M ATP).
  • the compounds of the present invention have an IC 50 value of less than 1000 nM for Pol ⁇ , some preferred compounds have an IC 50 ⁇ 500 nM, some more preferred compounds have an IC 50 ⁇ 200 nM, some more preferred compounds have an IC 50 ⁇ 100 nM, some more preferred compounds have an IC 50 ⁇ 50 nM, and some more preferred compounds have an IC 50 ⁇ 10 nM.
  • the IC 50 values of some specific compounds are shown in Table 1, wherein A represents IC 50 ⁇ 10 nM, B represents 10 nM ⁇ IC 50 ⁇ 100 nM, and C represents IC 50 >100 nM.
  • the compounds of the present invention have a good inhibitory effect on Pol ⁇ enzyme activity.
  • the IC 50 of compound 38 on Pol ⁇ enzyme inhibition activity is 0.62 nM
  • the IC 50 of the control compound DZ-01 is 5.30 nM.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • intragastric administration solvent 5% DMSO + 5% HS-15 + 30% PEG400 + 60% (20% SBE- ⁇ -CD)
  • the compounds of the present invention have good pharmacokinetic characteristics in rats, for example, the bioavailability of Example Compound 38 is >98%.
  • mice Male C57 mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Test compound intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 5% DMSO + 5% HS-15 + 30% PEG400 + 60% (20% SBE- ⁇ -CD), DW-01: intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in mice.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC 50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • Example Compound 38 have no significant inhibitory effect on the five isozymes of human liver microsomal cytochrome P450 (CYP).

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Abstract

L'invention concerne un composé tel que représenté par la formule (I), un stéréoisomère, une substance deutérée, un solvate, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci, ou une composition pharmaceutique le contenant, et son utilisation en tant que composé ciblant Polθ dans la préparation d'un médicament pour le traitement de maladies associées. Chaque groupe présent dans la formule (I) est tel que défini dans la description.
PCT/CN2024/071923 2023-01-14 2024-01-12 COMPOSÉ CIBLANT POLθ ET SON UTILISATION Ceased WO2024149349A1 (fr)

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CN118515661A (zh) * 2024-07-22 2024-08-20 中国药科大学 一种靶向降解Polθ的化合物及其制备方法和用途
WO2025021198A1 (fr) * 2023-07-27 2025-01-30 Danatlas Pharmaceuticals Co., Ltd. Agents de dégradation de polq, compositions et utilisations associées
WO2025036490A1 (fr) * 2023-08-17 2025-02-20 海思科医药集团股份有限公司 INHIBITEUR D'ADN POLYMÉRASE θ ET SON UTILISATION

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CN114127062A (zh) * 2019-05-31 2022-03-01 伊迪亚生物科学有限公司 作为DNA聚合酶Theta抑制剂的噻二唑基衍生物
WO2022118210A1 (fr) * 2020-12-02 2022-06-09 Ideaya Biosciences, Inc. Dérivés substitués de thiadiazolyle comme inhibiteurs de l'adn polymérase thêta
WO2022259204A1 (fr) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. Composés thiadiazolyle liés à o utilisés en tant qu'inhibiteurs de l'adn polymérase thêta

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WO2025021198A1 (fr) * 2023-07-27 2025-01-30 Danatlas Pharmaceuticals Co., Ltd. Agents de dégradation de polq, compositions et utilisations associées
WO2025036490A1 (fr) * 2023-08-17 2025-02-20 海思科医药集团股份有限公司 INHIBITEUR D'ADN POLYMÉRASE θ ET SON UTILISATION
CN118515661A (zh) * 2024-07-22 2024-08-20 中国药科大学 一种靶向降解Polθ的化合物及其制备方法和用途
CN118515661B (zh) * 2024-07-22 2024-11-15 中国药科大学 一种靶向降解Polθ的化合物及其制备方法和用途

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